ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY SUBCOMMITTEE
OF THE ANTI-INFECTIVE DRUGS ADVISORY
COMMITTEE
OPEN SESSION
Wednesday, June 11, 2003
8:35 a.m.
Holiday Inn Gaithersburg
The Ballrooms
2 Montgomery Village Avenue
Gaithersburg, Maryland
PARTICIPANTS
Joan P. Chesney, M.D., Chair
Thomas H. Perez, R.Ph., M.P.H. Executive Secretary
MEMBERS
Steve Ebert, Pharm.D (Consumer Representative)
Mary Glodé, M.D.
SGE CONSULTANTS
Michael Aschner, M.D.
David Danford, M.D.
Norman C. Fost, M.D., M.P.H.
John Freeman, M.D.
Susan Fuchs, M.D.
Richard Gorman, M.D., FAAP
Mark Hudak, M.D.
Stanley Ip, M.D.
Joseph Lau, M.D.
Naomi Luban, M.D.
Robert Nelson, M.D., Ph.D.
Judith O'Fallon, Ph.D.
William Oh, M.D.
Don Mattison, M.D.
Thomas Newman, M.D., M.P.H.
Rebecca Flynn O'Brien, M.D.
Kevin Smith, Ph.D.
David Stevenson, M.D.
Benjamin Wilfond, M.D.
GUEST SPEAKERS
Susan Sheridan
Connie Schomann, R.N.
Marshallyn Yeargin-Allsop, M.D.
FDA
Robert Justice, M.D.
Susan Cummins, M.D.
Dianne Murphy, M.D.
C O N T E N T S
Call to Order/Introductions
Joan P. Chesney,
M.D. 4
Meeting Statement
Thomas H. Perez,
R.Ph., M.P.H. 9
Opening Comments
Dianne Murphy, M.D. 11
Historical Background and Selected Recent
Research Findings
Tom Newman, M.D.,
M. 16
Agency for Healthcare Research and Quality Report
Joseph Lau, M.D. 54
Stanley Ip, M.D. 67
Rebecca O'Brien,
M.D. 77
Discussion of Presentations 95
Phototherapy
William Oh, M.D. 122
Outpatient Phototherapy
Connie Schomann 153
A Parent's Perspective
Sue Sheridan 171
Kernicterus Surveillance
Marshallyn
Yeargin-Allsop, M.D. 195
Metalloporphyrin Heme Oxygenase Inhibitors
David Stevenson,
M.D. 195
Open Public Hearing
Attallah Kappas,
M.D. 243
Vinod K. Bhutani,
M.D. 253
Martin J. Hatlie,
JD 258
Duane Alexander,
M.D. 273
Andrew Moosa, M.D. 277
Jerold F. Lucey,
M.D. 282
Timos Valaes, M.D. 287
Murray Goldstein,
D.O. 294
Ethical Issues
Robert Nelson,
M.D., Ph.D. 298
Discussion of Questions 2, 3 and 4 316
Committee Final Comments 378
P R O C E E D
I N G S
Call to Order/Introductions
DR.
CHESNEY: Good morning. We are ready to begin what is going to be a
very full day. I would like to welcome
you all to this Pediatric Advisory Subcommittee Meeting.
I
would like to start with the usual roll call, if we could maybe start down at
this end with Dr. Murphy.
DR.
MURPHY: Dr. Dianne Murphy. I am the Office Director for the Office of
Counterterrorism and Pediatric Drug Development and also the Office Director
for the Office of Pediatric Therapeutics.
Thank you.
DR.
CUMMINS: I am Dr. Susan Cummins. I am a team leader in the Division of
Pediatric Drug Development with the FDA.
DR.
JUSTICE: Robert Justice, Director of the
Division of Gastrointestinal and Coagulation Drug Products at FDA.
DR.
NELSON: Robert Nelson, pediatric
critical care medicine at Children's Hospital, Philadelphia, and a member of
the committee.
DR.
GLODE: Mimi Glodé. I am head of the section of Pediatric
Infectious Disease at the Department of Pediatrics, the University of Colorado,
School of Medicine, Denver, Colorado, member of the committee.
DR.
DANFORD: David Danford. I am Professor of Pediatrics in the section
of Cardiology, University of Nebraska Medical Center, Creighton
University. I am a member of the
committee.
DR.
FUCHS: Susan Fuchs, Associate Professor
of Pediatrics, Northwestern University Medical School, and pediatric emergency
physician, Children's Memorial Hospital, Chicago.
DR.
O'FALLON: Judith O'Fallon, statistician
at the Mayo Clinic Cancer Center, Rochester, Minnesota.
DR.
HUDAK: Mark Hudak, Professor of
Pediatrics and a neonatologist at University of Florida, Jacksonville.
DR.
FOST: Norman Fost, University of
Wisconsin, Professor of Pediatrics, Director of the Bioethics program and Chair
of the IRB.
DR.
CHESNEY: Joan Chesney. I am Professor of Pediatrics in the Division
of Infectious Diseases at the University of Tennessee Health Science Center.
MR.
PEREZ: Tom Perez, Executive Secretary to
this meeting.
DR.
EBERT: Steve Ebert, Professor of
Pharmacy at University of Wisconsin, Madison, an Infectious Diseases at Meriter
Hospital in Madison.
DR.
GORMAN: Rich Gorman, pediatrician in
private practice in Ellicott City, Maryland, and a member of the committee.
DR.
MATTISON: Don Mattison, staff at NICHD.
DR.
IP: Stanley Ip, Assistant Professor of
Pediatrics at Tufts University Medical School.
DR.
FREEMAN: John Freeman, Professor of
Pediatrics and Neurology at Johns Hopkins.
DR.
ASCHNER: Michael Aschner, Professor of
Physiology and Pharmacology at Wake Forest University School of Medicine.
DR.
O'BRIEN: Rebecca O'Brien, Assistant
Professor at Tufts University School of Medicine in the Division of General
Pediatrics at the Floating Hospital in New England Medical Center.
DR.
WILFOND: I am Ben Wilfond, a pediatric
pulmonologist at the National Human Genome Research Institute and also with the
Department of Clinical Bioethics at the NIH.
DR.
SMITH: Kevin Smith, Vice Chancellor of
Research and Dean at the Graduate School and Professor of Chemistry at
Louisiana State University.
DR.
OH: I am Bill Oh. I am a neonatologist who is Professor and
Chair of Pediatrics at Brown Medical School.
DR.
NEWMAN: I am Thomas Newman, Professor of
Epidemiology and Biostatistics and Pediatrics at UCSF and a general
pediatrician.
DR.
LAU: I am Joseph Lau, Professor of
Medicine at New England Medical Center, and the Director of Agency for
Healthcare Research and Quality Evidence-Based Practice Center.
DR.
STEVENSON: David Stevenson. I am a neonatologist and Professor of
Pediatrics at Stanford University, also serving as Senior Associate Dean for
Academic Affairs at that institution.
DR.
CHESNEY: Thank you.
Today's
session is devoted to the current epidemiology and therapeutic interventions
relevant to hyperbilirubinemia in the term and near-term newborn or, in other
language, the current state of medical practice with regard to management of
neonatal hyperbilirubinemia and the potential role for new drug therapies in
the prevention and management of jaundice in this population.
We
have a very, very full and interesting agenda, and we are particularly honored
to have speakers today, both scheduled and in the open public hearing, who have
contributed so much to and for some their life's work to this issue.
I
also have to remind myself that Agency doesn't bring issues with
straightforward answers to the Advisory Committees. The complexity of today's topic is an example
of the kind of issue that they do bring to advisory committees.
Before
asking Dr. Murphy to begin the meeting, I wanted to make two comments. The first is because it is a very full
agenda, I would request that all the speakers adhere as closely as possible to
their allotted times.
If
anyone goes 10 minutes over their allotted time, Tom and I may have to
intervene, which is very uncomfortable for us, so if we do intervene, please
know that we are sympathetic to your wanting to share everything you have with
us.
The
second issue is that many, if not all of you, in the room know that there is a
closed meeting tomorrow on a subject related to today's discussions.
In
order to protect the privacy of tomorrow's meetings, we ask the speakers and
particularly the committee members and the invited consultants who have had
material which they have read in great detail for tomorrow's meeting not to
comment today on the content of tomorrow's meeting.
Finally,
I wanted to thank all the members of the Pediatric Division and the Division of
Gastrointestinal and Coagulation Drug Products for all the work they have put
into today's meeting and to thank Tom Perez, our Executive Secretary.
Our
first speaker is--my apologies--we have to do conflict of interest statements.
Tom.
Meeting Statement
MR.
PEREZ: Thank you and good morning.
The
following announcement addresses the issue of conflict of interest with regard
to this meeting and is made a part of the record to preclude even the
appearance of such at this meeting.
The
topics to be discussed at this meeting are issues of broad applicability. Unlike issues in which a particular firm's
product is discussed, issues of broad applicability may involve many industrial
companies and academic institutions.
All
special government employees participating in this meeting have been screened
for financial interests as they may apply to the general topics at hand. Because Dr. David Stevenson has reported
interests that could be affected by today's discussions, the Food and Drug
Administration has granted him a waiver under 18 U.S.C. 208(b)(3) that permits
him to participate. A copy of the waiver
statement may be obtained by submitting a written request to the Agency's
Freedom of Information Office, Room 12A30, of the Parklawn Building.
Because
general topics could involve so many firms and institutions, it is not prudent
to recite all potential conflicts of interest, but because of the general
nature of today's discussion, these potential conflicts are mitigated.
With
respect to FDA's invited guest speakers, Susan Sheridan would like to disclose
that she is president of a consumer advocacy and educational group called PICK,
Parents of Infants and Children with Kernicterus. PICK receives charitable contributions from
industry, however, all members of PICK are volunteers and receive no
compensation for their activities.
With
respect to all other participants, we ask, in the interest of fairness, that
they disclose any current or previous financial involvement with any firm whose
product they may wish to comment upon.
Thank
you.
DR.
CHESNEY: Thank you, Tom.
Dr.
Dianne Murphy is going to speak to us to give us a very brief overview of the
topic for discussion today. As you all
know, Dr. Murphy is Director of the combined Office of Counterterrorism and
Pediatric Drug Development, and the Director of the Office of Pediatric
Therapeutics at the FDA.
Opening Comments
DR.
MURPHY: I wanted to take a moment and
first thank the committee, the Pediatric Advisory Subcommittee, who now has
built quite a formidable experience in pediatric drug development for being so
loyal and consistent, and being here when we have these meetings. I know that we have them fairly regularly
scheduled for you all, and it is a demand on your time. We want to always express to you how
sincerely we appreciate your ongoing effort because I think in the arena of
pediatric drug development, we need to have a very consistent core of people
who can address the myriad of issues that are going to come forward as we
continue to develop products for children.
I
wish to also thank--when I looked at the list of invitees and speakers, I am
always impressed at the commitment of people to put time and effort in what I
know are extraordinarily busy lives to come and advise us. Again, our sincere thanks to everybody who
has taken that time to do that today.
Also,
the people who worked so energetically to put this together - Dr. Susan
Cummins, Dr. Shirley Murphy, Dr. Debbie Birenbaum, Rosemary Addy. They have put together I think a wonderful
package that articulates for you what the issues are. They made one mistake. They asked me to try to provide the overview
for you, so that is what my job is this morning.
I
am supposed to focus you on the fact of what the Agency does and put that in
perspective as to how to think about the questions we have asked you.
[Slide.]
This
table could be quite extensive with many variations upon the theme, but, in
general, what the Agency does when it decides to approve a product, it must
find that it is safe and efficacious for an intended population, for an
intended use, but that comes in many ways.
The
very top line here is a therapy that might be even OTC, a therapy which has
very low risk, a few side effects, and has tremendous benefit for somebody with
allergies, let's say, so you have an OTC product.
That
product is going to have a different safety profile than another product which
would have a high or intermediate risk, but also would bring great benefit to
the patient.
In
this, the number of patients who might be exposed could be anywhere depending
on the number of options that are available to the patient, any other options,
and actually the degree of these risks as to how many might be involved.
I
think today, we really are going to be talking about drug development where the
risks are in this arena, where the benefits are, and can we define a population
that would fit in this category or not, or are we not in this category.
We
are asking you to think about what is the population that would warrant
therapy, how do we identify it, and what are the things that we should be
asking for if we are going to develop a product as to its safety profile and
its benefit.
To
do that, we have to first go through many of the areas that are being brought
up for discussion today, which is what is the status of the therapeutic
interventions that we have available and what is our status of knowledge in
this area.
I
have put on these other things just because, yes, there are products that have
lots of known high risk, not a lot of benefit, but if there are absolutely no
other options, they are actually products that may get approved in this area,
too.
So,
there is a complete spectrum and what we are simply asking you today is not
simple, it is very difficult to consider drug development for therapy of
hyperbilirubinemia, what are the kinds of risks, and for what kind of
population.
[Slide.]
Right
now, these few slides summarize where we think, I will try to define that table
in graphic form. We have a very high
risk intervention for very few patients that are involved usually, and were
willing to take it because there aren't any other options when we reach this
point.
[Slide.]
We
have another intervention earlier on, more patients involved, less risk, and
where are we, is this where we want to go with drug, or is it really here,
where is it, what is the population, and what is the safety profile for that
population.
Those
are the sort of things we want you to be thinking about as you go through the
broader issue of where are we today in this field in our knowledge of
hyperbilirubinemia and how it occurs, what the prevalence is, what the
incidence is, and what the interventions are and should be.
[Slide.]
That
is again summarizing in a very simplified way, we need to be able to put these
therapies where you decide the population would be would really define what the
risks might be, because you are going to be really defining whether you are
going to expose a lot of patients or a few patients.
I
hope that hasn't muddied the water, but again, summary from a drug development
point of view, you are going to develop a drug, you want to know what is the
population that is going to receive this intended therapy and how do we define
the efficacy and the benefits and the risks of that product.
Thank
you very much.
DR.
CHESNEY: Thank you, Dr. Murphy.
Our
next speaker is going to be Dr. Tom Newman, who will give us a historical
background and selected recent research findings relative to this issue.
He
is a professor in the Departments of Epidemiology and Biostatistics,
Pediatrics, and Laboratory Medicine at UCSF.
We thank him for coming to speak with us today.
Historical Background and Selected
Recent
Research Findings
DR.
NEWMAN: Thank you.
I
think the slides for my presentation are on the lefthand side of your little
packet there. This is what I was asked
to talk about. I guess maybe I am
getting old if I am talking about history.
It is usually people who have been around a while.
You
will see that a lot of this presentation is kind of focused on my
perspective. You will see sort of an
overemphasis on research that I have done and on the history that I have
experienced myself. I am sure that as
others speak, we will be able to even that out a bit.
[Slide.]
But
I will be talking about the history leading up to the 1994 AAP guideline which
I participated in writing, the content of the guideline, what has happened
since then, and some research findings focusing on research we have done at
Kaiser Permanente, and close with some unanswered questions if I have time.
[Slide.]
Starting
in the 1950s, and, of course, I was not around much in the '50s, so this is
based on reading the literature and talking to people.
Before
the '50s, there was a lot of Rh disease and kernicterus that was mostly from Rh
disease, and in the 1950s was the first randomized trial that showed that
exchange transfusion could prevent kernicterus in children with Rh disease, but
it is interesting that in that trial, the benefit was restricted to babies who
had a cord hemoglobin of less than 11, and bilirubin was not even measured in
that trial, so the index of severity for the Rh disease was how anemic the baby
was at birth.
But,
in fact, by doing exchange transfusions and treating these very anemic and sick
babies, it was found that kernicterus could be prevented because, of course,
when the red cells were made compatible with the mothers, the hemolysis was
reduced.
The
data relating kernicterus to bilirubin were observational data sort of added
parenthetically at the end of an article in the New England Journal by Shaw, et
al., where they said that since they had started keeping the bilirubin level
below 20, they had not seen any cases of kernicterus, and that 20 mg/dl sort of
stuck for many years as the level to try and keep the bilirubin below.
The
other thing that happened in the '50s was a randomized trial, the only other
randomized trial I know of where kernicterus ended up being an endpoint, but
this was a randomized trial of prophylactic sulfisoxazole in premature babies,
and the sulfisoxazole displace bilirubin from albumen and caused kernicterus in
the intervention group, in the group that got it, and that contributed to our understanding
of kernicterus and how it is causally related to bilirubin, but especially
unbound bilirubin.
[Slide.]
Moving
quickly now into the '60s, that was when Rhogam was developed and used, which
really has just about wiped out Rh disease.
There was a lot less kernicterus.
Looking in the literature, then, there were debates, you know, when the
only intervention for hyperbilirubinemia was exchange transfusion and Rh
disease was going away, there were all these other groups who had high
bilirubin levels and it was unclear how they should be treated - should you do
exchange transfusions in babies with ABO disease and nonhemolytic jaundice and
in preemies, and that was debated. Phototherapy was first used in the 1960s.
[Slide.]
Moving
into the 1970s, the Collaborative Perinatal Project, which enrolled babies
between 1959 and 1966, a big cohort study looking at neurodevelopmental outcome
in babies that were followed from actually before birth, their mothers were
followed.
There
was some kind of worrisome data from the Collaborative Perinatal Project that
suggested that kernicterus might be the tip of the iceberg, that is, there was
some statistical difference in neurodevelopmental outcome in Bailey scores at
less than a year in babies who had higher bilirubin levels.
This
was mostly seen in low birth weight babies, but it raised this concern that
there is kernicterus, which is one extreme, but there might be subtle
neurodevelopmental problems, and the same sort of concern about lower level
bilirubin toxicity was raised by the finding of yellow staining of the brain at
autopsy in premature babies, which was also called kernicterus, so it was a
little bit unclear how much of that yellow staining was actually primarily due
to kernicterus or later event.
But
certainly in the 1970s is when phototherapy really took off partly fueled by
these concerns and the fact that the only other treatment was exchange
transfusion, we could measure bilirubin, we could treat it with phototherapy,
reduce the levels, so phototherapy became very popular.
In
the 1960s, most babies in the U.S. were bottle fed. In the 1970s, we really saw an increase in
breast feeding.
[Slide.]
That
brings us up to the 1980s where my own personal experience starts. I was a resident in pediatrics from 1980 to
1983 at UCSF, and I was taught that bilirubin is a neurotoxin, it's a brain
poison was what I was told, and that we did phototherapy when the bilirubin
level hit above 14 to 15 mg/dl, and exchange transfusions, if it got above
20. This was not a good time to be doing
exchange transfusions.
This
was San Francisco 1980 to 1983. There
was a lot of HIV in the blood supply.
So, part of my formative experience was doing exchange transfusions and
then later finding out that probably they weren't necessary and wondering if I
had given any babies AIDS and knowing that there were going to be babies who
got AIDS from exchange transfusions.
Also,
when I was a resident, this article called "Vigintiphobia," fear of
20, came out sort of a light-hearted questioning of why we were so worried
about 20 and suggesting that maybe in babies who did not have Rh disease, that
was too low a level of bilirubin to worry about.
Then,
just sort of incidentally, but a very striking result was that in a study, an
autopsy series, there was just this abrupt disappearance of kernicterus when
the benzyl alcohol preservative was removed from the bacteriostatic saline in
neonatal intensive care unit. Again, that might have been displacing the
bilirubin from albumin.
[Slide.]
Moving
into the 90s, this is when I started doing research on jaundice in babies. Jeffrey Maisels and I published a couple of
articles that were sort of a more systematic examination of the literature than
what Watchko and Oski had done, but I definitely give them credit for, at least
for me, making me think this was something worth reviewing.
Articles
suggesting that it really, that the epidemiologic term here is effective
modification or interaction, it really was not reasonable to generalize from Rh
disease babies in the '50s to well, breast-fed babies in the '90s in terms of
estimating what is the risk of neurologic damage from a high bilirubin level,
and this evidence that if 20 was the level that we need to worry about in Rh
babies in the '50s, then it surely wasn't 20 for well babies in the '90s.
This
led to the 1992 paper which had recommendations for less aggressive treatment
of jaundice in babies, also fewer laboratory tests because the laboratory tests
that were then recommended were mostly not useful.
With
Mark Klebanoff, I re-analyzed data from the Collaborative Perinatal Project,
those data were available to Mark, looking specifically at this issue of was
there really good evidence that at lower levels of bilirubin, there was
neurologic damage, and got I think very reassuring results for intelligence for
the IQ measures and for hearing, and reassuring for definite neurologic
abnormalities, but the sort of small but statistically significant increase as
bilirubin levels went up in abnormal or suspicious findings.
The
trouble is that bilirubin levels in that study were fairly low and that the
biggest burden of sort of extra abnormal or suspicious findings came in babies
who had bilirubin levels between 10 and 15.
In
that paper, we calculated that if everybody in the whole Collaborative
Perinatal Project's bilirubin level had been kept below 10, the population
frequency of these abnormal or suspicious neurologic abnormalities would have
gone from 15.1 percent to 14.85 percent, so we didn't think it was a very
important effect.
Then,
the AAP practice parameter, which was one of the first practice guidelines that
the AAP did, was in 1994. Around the same time, beginning in the '80s and into
the 1990s, hospital stays for newborns got shorter and jaundice really moved
from the inpatient problem that it was when I was a resident to an outpatient
problem and the problems of babies with jaundice needing to come back and get a
bilirubin test, and then come back again and get another bilirubin test, and
when they needed phototherapy, to be readmitted, and that really was a change
from the 1980s.
[Slide.]
The
AAP Guidelines addressed more than treatment, but I think probably the most
important difference with the guidelines was raising the thresholds for
treatment somewhat, varying them by age, and then the next version of the
Guidelines, that will even be a little bit smoother rather than changing
abruptly at 24, 48, 72 hours.
You
can see that most of the jaundice, most of the babies getting phototherapy are,
because bilirubin peaks after about three days, more than 72 hours old. Of course, if it is rising fast, you need
phototherapy sooner, but this sort of said it is reasonable to do phototherapy
at 17, but you can individualize and not all babies are the same, but you
really probably should do it if it gets above 20.
If
phototherapy fails, you should do an exchange, and if you are starting out
above 30, you really probably should just do an exchange although some of these
babies, the bilirubin drops fast and then they end up not getting one.
[Slide.]
So,
what has happened since then? Well, I
will show you some data on some of these things. One is that there are a lot fewer exchange
transfusions being done unless phototherapy, there is a concern about
kernicterus coming back, about an increase in kernicterus.
In
1996, the Newborns' and Mothers' Health Protection Act was passed, which
mandated coverage for at least a 48-hour length of stay. That became effective on January 1st of 1998.
PICK,
which has already been mentioned, Parents of Infants and Children with
Kernicterus, was formed, and I think had a major influence on bringing
attention to kernicterus as a problem.
I
guess there has been more of a focus, not so much on when we should be treating
jaundice and whether we should be doing phototherapy at 15 or 20 or when, but I
am trying to figure out who is going to need it and trying to determine that
before babies leave the hospital. We are
sort of acknowledging this problem of jaundice having shifted from an inpatient
to an outpatient problem.
Those
are some of the things also, it shows some data on.
[Slide.]
These
are some data from Israel that I think most directly address this question of
the influence that the AAP practice parameter may have had. Anyone who is the practice guideline
business, this is a totally remarkable change.
The Guideline was published in '94, the amount of phototherapy done, a
63 percent drop in these two hospitals, and an 85 percent drop in the number of
exchange transfusions just in this relatively short time period.
I
think for those who are trying to change doctor behavior with guidelines, the
key is to issue a guideline that tells the doctors to do what they want to do
anyway, and that they don't have to do something that they didn't want to do
anyway, and then you get very good adherence to the guideline, because most of
us never I mean really liked to do an exchange transfusion, and to sort of be
given permission not to have to do that, that is the way you get good adherence
to your guideline.
My
guess is that this has happened elsewhere, as well, that nobody really liked
doing exchange transfusions, and phototherapy, readmitting a baby to the
hospital and putting them under the lights is not much fun either, so people
were happy to be kind of I think be given permission not to do as much.
[Slide.]
These
are data from Kaiser Permanente, even more remarkable. These show adherence or lack thereof to the
AAP Guideline, just published in May of this year in Pediatrics.
Just
to orient you here, these are 11 different hospitals in the Northern California
Kaiser Permanente system. You can ignore
the green bars for you and just look at the red bars.
The
red bars are the proportion of babies who received phototherapy for whom the
Academy of Pediatrics said it was recommended.
Remember that slide showed you before of the Guidelines, the AAP said
that for over 72 hours, consider it at 17, and do it at 20. Well, the green bars are the percent for
consider, the red bars were the bilirubin, most of these babies had bilirubin
levels over 20, what percent of them got phototherapy.
You
can see that it ranged from about 27 percent in hospital 9, up to about 75
percent in hospital 10, so a huge inter-hospital variation, but overall, almost
half of babies at Kaiser with bilirubin levels between 20 and 25 didn't get
treated with phototherapy in 1995-96.
We
don't have data from before that. My
guess is this is somewhat of a drop, but also talking to many of the doctors at
Kaiser Permanente, they were never as worried about bilirubin as we were at
UCSF, I think. So, big differences by
hospital and many babies not getting phototherapy.
We
did look at the lab tests and the vast majority of babies who didn't get
phototherapy with bilirubin in the 20's did have their bilirubin repeated, and
it was documented that it went down, so maybe it was 21 and then the next day
it was 19, and it just went down by itself.
[Slide.]
The
next point I was mentioning was the increase in concern about kernicterus, and
this is kind of a raggedy slide because I scanned it from a photocopy of cases
in the pilot kernicterus registry.
I
show this because this sort of slide has been used to raise concern about
kernicterus, and I think kernicterus is a problem, but the methodology of the
registry isn't sufficient to answer the question about whether there has been
an increase because kernicterus wasn't being looked for, for the registry early
on, so the method of ascertaining cases which involved asking people to report
them would lead to an increase or to a picture like this, probably whether or
not there had been an increase, so I think we think we just have to be careful.
The
issue I don't think really is has kernicterus increased as the issue is, is it
there and can we reduce it.
[Slide.]
In
terms of again the Kernicterus Registry, these are the definitions from the
recent paper in Journal of Pediatrics, the criteria for case eligibility. I think one of the things we are going to
come back to, a central question really in deciding whether to treat
hyperbilirubinemia with drugs is how bad is hyperbilirubinemia, how dangerous
is it, how many cases of kernicterus are there.
The
problem that we are going to come to is that kernicterus is not always a yes or
no definite thing, and there is going to be a tradeoff between sensitivity and
specificity.
The
criteria to be in this registry included either acute symptoms of kernicterus,
which are listed there, or chronic sequelae abnormality in at least two of the
following including extrapyramidal movement disorder, gaze abnormalities,
auditory disturbances, intellectual deficits, enamel dysplasia of deciduous
teeth.
Although
many or most or maybe all of the kids in this kernicterus registry may have
kernicterus, I don't think we can say that.
We don't know that, certainly not from these inclusion criteria, because
these are nonspecific. There are many,
many children who have intellectual deficits and auditory disturbances who
clearly do not have kernicterus.
Many,
many kids with cerebral palsy have enamel dysplasia of their teeth. Many kids with hearing loss have teeth
problem, so these may be sensitive criteria for kernicterus, but they are
certainly not specific, and it makes it hard to interpret data from the
kernicterus registry.
[Slide.]
So,
what do we know about how common kernicterus is, because I think that is a key
question. In the recent publication, 90
cases in 15 years in the U.S., if they had complete ascertainment, which I
think is not possible, not even close, that would be an incidence of 1 in
700,000, so there is both way underestimation from underreporting and possibly
overestimation from non-specificity of the case definition.
We
have been looking for many years now for cases of kernicterus of Northern
California Kaiser, where there are about 28,000 births per year in term and
near-term babies, and in 111,000 cases, we have looked very closely because we
have all the bilirubin levels, and looked at all those with very high bilirubin
levels.
In
this month's Pediatrics, we have a paper describing the 11 children who had
bilirubin levels over 30 out of those 111,000, so 1 in 10,000, and none of them
got kernicterus.
We
have also started looking in earlier years.
We don't have the lab data, so this is relying on discharge diagnoses,
but I am working with a neurologist, Dr. Yvonne Wu, who is studying cerebral
palsy, and she has reviewed the charts of all the kids with cerebral palsy
diagnoses in this cohort, and we still haven't found any cases of kernicterus
in this now about 230,000 babies.
In
the California cerebral palsy project, this is a personal communication from
Susan Cummins who was involved with that study.
They had 1 case in 155,000 out of a total of 192 cases of cerebral
palsy, so a small proportion of cerebral palsy.
One
other population-based report comes from Denmark where there is a report of
increasing kernicterus between 1994 and 1998, 5 cases, but with a denominator
there, that would be about 1 in 65,000.
That
is kind of hard to interpret because it is hard to know whether this is the
right denominator, 94 to 98, or it should include a few years before or a few
years after, but that would be an increase.
The
trouble is that we don't have that sort of data in the U.S. because it's a much
bigger country and we don't have an easy way of knowing how many cases there
are.
[Slide.]
So,
the problems in trying to figure out how common kernicterus is--and I am sure
you will hear more about these later--there is no uniform surveillance, there
is a trade-off between sensitivity and specificity in case definition. If you don't want to miss anything that might
be kernicterus, you will include a lot that probably aren't, and the diagnosis of
kernicterus is often delayed and uncertain and contentious.
This
is especially true if the baby didn't show symptoms in the newborn period, and
it is very hard to tell someone who has some of the symptoms of cerebral palsy
or kernicterus from someone who just happened to have a high bilirubin and had
those anyway.
My
best estimate is that it is probably somewhere between 1- and 200,000, or 1- in
500,000, which would be between about 8 and 20 cases per year in the U.S., and
just to mention that people should be very careful about extrapolating from the
U.S. to other countries because kernicterus appears to be much more common in
some other countries, especially in Africa.
I
was just struck at the Pediatric Academic Society's meeting just last month,
the report from Southern Nigeria, where they described kernicterus in 9 of 20
infants admitted with bilirubin levels over 15, or 40 percent, and this is
because they were putting camphor on the umbilical cord stump, probably in some
kids who had G-6 PD deficiency. So,
kernicterus is definitely a problem some places in the world, a much bigger
problem than in the U.S.
[Slide.]
So,
moving on now to the selected research findings, and I think the things that I
talk about are jaundice in the first 24 hours, how much does that tell you that
this is a baby who is at very high risk and needs bilirubin measurement and
close, careful follow-up, using bilirubin measurements before discharge to
predict who is going to develop hyperbilirubinemia, end-tidal carbon monoxide,
and a risk index sort of as a placeholder for just the idea that the history
and physical gives you a lot of information about the risk of developing
hyperbilirubinemia.
Just
most recently last month we presented the idea that combining clinical
information with bilirubin measurements is probably the way to go.
[Slide.]
This
first slide, there is a tendency I think in the medical-legal cases especially,
and this actually I think comes up not infrequently to sort of paint a picture.
Here
is a baby who was jaundiced at less than 24 hours and no one checked the
bilirubin level, and now the child has kernicterus and there is this very clear
causal relationship and the doctors messed up, but if you actually look at
studies to say, you know, is jaundice at less than 24 hours really pathologic,
you first have to say, well, there has only been, as far as we know, one study
that looked at babies at less than 24 hours to see whether they were jaundiced
or not systematically, and that was by Davidson in the '40s, and they compared
that to bilirubin levels, and I think it is generally accepted that when the
bilirubin level gets above 6, most observers can observe jaundice, but there is
quite a few data about how many babies have bilirubin levels more than 6 at
less than 24 hours, 41 percent at a mean of 72 hours in Alpay's study, 25
percent at a mean of 21 hours, 47 percent at 24 hours, so to say that anyone
with any jaundice at all in the first 24 hours automatically has pathologic
hyperbilirubinemia probably wouldn't fit most people's definition of pathology.
[Slide.]
We
looked at this at Kaiser because we reviewed charts for a nested case control
study trying to predict which babies would develop bilirubin levels of 25 or
more, so we had charts on just a random sample at birth.
These
are not the cases, these are mostly controls, babies who never developed high
bilirubin levels, and we just looked at when jaundice was first noted in the
chart.
Of
course, having something noted in the chart and having it be there are two
very, very different things. Presumably, the ones that are noted in the chart
are a subset although sometimes people noticed jaundice at nighttime and then
in the daytime, it seems to be gone when the light is better and babies are in
the sunlight, but this shows the percentage of babies in whom jaundice was
noted in the chart at Kaiser almost always by the nurses up to about 6 percent
at 24 hours.
So,
that is few enough that you would think that it would be pretty abnormal and
taken seriously.
[Slide.]
But
then what we looked is, okay, so how soon after this supposedly pathologic
jaundice was noted in the babies at less than 24 hours, how soon did bilirubin
levels get done, and these are cumulative, so within six hours in 19 percent,
within 12 hours in 38 percent, less than half actually had a bilirubin level
measured within 24 hours of when they were noted to be jaundiced, if they were
noted to be jaundiced at less than 24 hours, and two-thirds eventually got a
bilirubin level.
So,
one of the themes here is that, number one, we have had very little or no
kernicterus at Kaiser Permanente in many years and with a couple hundred
thousand babies; and, number two, it is hard to say it is because jaundice is
managed very aggressively or according to guidelines there.
The
phototherapy slide and this slide suggest that this is true, that the low
frequency of kernicterus at Kaiser I think is due mostly to the fact that at
Kaiser, we have a denominator, it is not due to extraordinary efforts to treat
jaundice.
I
think in the interests of time I will skip that one.
[Slide.]
So,
continuing with free discharge risk assessment, and everyone will be familiar I
think with this graph from Bhutani, et al., looking at bilirubin levels over
time, showing how important it is to know the baby's age in hours when
interpreting a bilirubin level, but again for pre-discharge risk assessment, I
want to emphasize that babies are going home between 24 and 48 hours.
These
points, the points between the 40th percentile and the 95th percentile are not
all that far apart, and this I think is very relevant for predicting jaundice
using transcutaneous measurement, so just keep these numbers in mind - 5 mg/dl
is the 40th percentile and 8 is the 95th percentile at about 24 hours.
[Slide.]
This
is one of the instruments that is used.
It is wonderful not to have to poke babies and do heel sticks for
bilirubin levels. It costs $4,000 and
$7.00 each time you use it.
[Slide.]
These
are data looking at how accurate that machine is compared to HPLC. What I just want to call your attention to is
that, you know, it is pretty good especially when the bilirubin levels are
between or less than about 10, but that the error range is really plus or minus
about 2, 2 or 3. It says it is up to
plus 3 or minus 2 would be the 95 percent range. What is being plotted here is the difference
between the HPLC and the transcutaneous measurement.
So,
if, for example, you measure the value and it's 7, then, it means, well,
probably it's between about 5 and 10, but if you remember that 5 was the 40th
percentile and 8 was the 95th percentile, the ability of a transcutaneous
measurement at about 24 hours to predict who is going to develop subsequent
jaundice is probably going to be pretty imperfect.
[Slide.]
This
is another technology which it had been hoped would help determine who was
hemolyzing and therefore how much bilirubin was being produced and who would be
at risk of subsequent severe hyperbilirubinemia.
It
turns out that for each molecule of bilirubin that is made, a molecule of
carbon monoxide is made, so as long as you have a non-smoking mother and not a
bad air pollution day, you can measure the carbon monoxide in the baby's breath
and get a direct index of bilirubin production.
[Slide.]
The
good news is that it is better than a direct antiglobulin test, better than
Coombs' test of predicting who is going to get jaundice, but a Coombs' test is
really not very good, and it is not as good as a total serum bilirubin measure,
which is not too surprising because the bilirubin measurement sort of reflects
both production and excretion, and the carbon monoxide only reflects
production, and it is kind of pricey - Herschel pointed out it is cheaper than
a Coombs' test, but the machine costs about $20,000 and about $14.00 each time
you use it.
[Slide.]
A
low tech approach, which just involves a history and physical, we suggested,
and again at the Pediatric Academic Society's meetings a year ago and last
year, validated this for another two-year birth core.
This
was developed for babies born in '95 and '96 to predict who would develop a
bilirubin level over 25, which actually should be easier. It should be easier to predict who is going
to get over 25 than over 17 or 20, because it should be a higher percentage of
kids who have risk factors.
Without
going through it in detail, these are the risk factors - exclusive breast
feeding, having had a family history of jaundice, bruising, Asian race,
cephalhematoma, and so on, and those give you a lot of information about who is
subsequently likely to run into problems.
[Slide.]
I
know the AHRQ folks will be talking about this later, so I will be very brief
here, but if you use the area under the ROC curve to estimate how well can we
predict who is going to develop hyperbilirubinemia subsequently, there is a
range. Most of these values are in the
0.8-something range.
This
is the original study that used that graph that I showed you, that used the
bilirubin percentile group, came up with a high area under the ROC curve, but
probably the babies with lower bilirubin levels were less likely to get a
subsequent one, so that it is probably biased a bit towards being high, and
this is probably the better estimate of the accuracy of the bilirubin level
measured at 24 to 36 hours because Stevenson, et al., used the same Bhutani
groups, but this was in a multicenter study, it wasn't just in Philadelphia,
and this was calculated by me from their data.
The
area under the ROC curve, by the way, 1.0 would be perfect and 0.5 would be
worthless. This was the estimate for the
end-tidal carbon monoxide. It was quite
a bit worse. The risk index, this is
actually the 0.83 is when we validated on a separate group of babies, but again
it is trying to predict much higher bilirubin.
What
we did most recently is we just showed that by combining the bilirubin and
information from the risk index, this was done all with computerized data, so
we didn't have breast feeding, but we had a substantial increment in the
ability to predict bilirubin level by saying now only what was your bilirubin
when you were 36 hours old, but what was your gestational age, which turns out
to be key. Babies who are 36 weeks, 37
weeks, much higher risk, how old was your mother, what was your race, and so
on, that enhanced prediction.
[Slide.]
Moving
on to the long-term effects of hyperbilirubinemia, what are the bad things that
it can cause, and certainly at the top of the list is kernicterus, it turns out
the next most bad thing that hyperbilirubinemia can cause is probably exchange
transfusion. We really would like to
avoid doing that. It is a risky
procedure and especially people have less practice with it than they used to.
Phototherapy,
phototherapy is something we would rather not do. It is not totally benign. It probably doesn't have long-term effects,
but it involves separating the mother from the baby, and it's costly and
disruptive.
Then,
I want to address this issue of more subtle neurodevelopmental effects. I know other people will be talking about
this, as well. There are definitely
transient effects on brain stem responses and on behavior, and one of the
questions is are there any long-term effects on hearing or motor or cognitive
outcomes or behavior.
[Slide.]
I
just want to tell you a little bit about a study that we are just finishing
year 4 or 5 of this study, looking at babies with very high bilirubin levels,
bilirubin levels of 25 mg/dl and up.
There
is another case group, which is babies who were readmitted with significant
dehydration and randomly selected controls, all born within a defined cohort
1995-98 Northern California Kaiser Permanente Medical Care program hospitals.
What
we are doing is bringing these children back when they are 5 years, 1 month,
and having full neurodevelopmental evaluations by psychologists and child
neurologists who are blinded to whether the child is a dehydration case, a
bilirubin case, a control, or both. We
have a few who were both dehydrated and had hyperbilirubinemia.
I
am going to go ahead and show you some data for this, but they have to be
regarded as preliminary. The data
collection, if everything is on schedule, will end in February 2004, when the
last of the babies born in 1998 turn 5 years, 1 month.
[Slide.]
The
outcome variables for this study are a standard neurologic exam by a child
neurologist. These are IQ tests, the
Wechsler Preschool and Primary Scale of Intelligence for children and Visual
Motor Integration test all done by a psychologist.
A
Motor Performance Checklist, which was developed by an Australian occupational
therapist for five-year-olds, turns out to be just the sort of thing that we
were interested in because it is very practical items with a lot of face
validity like jumping, throwing, hopping, catching, you know, using scissors to
cut out a square, and we measure how well they follow the lines, putting beans,
how many beans can they put into a bottle in 20 seconds, and so on.
These
are all blinded, and then the Child Behavior Checklist and Parent Evaluation of
Developmental Status by the parents.
[Slide.]
Here
is where we are as of a few months ago.
Of the 140 babies who had bilirubin levels over 25 in a four-year
period, we were able to get 86 of them to agree to this study. We would have liked to do more, but this is
pretty good considering this involves the family taking basically a half a day
off to come to a site to get all these tests done, and we have done about 70
percent of the exams completed, so I am going to be showing you data on done
and entered 60 babies who had bilirubin levels over 25, about twice that many
controls, a lower consent rate from the controls. You know, we tried very hard, but there just
isn't too much way that we can get the controls to be as interested in the
study as the parents who have experienced a dehydrated or very jaundiced baby.
[Slide.]
This
slide shows, I will try to show now just a description of the patients in the
study. These are the bilirubin
levels. Of course, the cases all had
bilirubin levels over 25, but I have to say this is mostly a study of babies
with bilirubin levels between 25 and 28.
We already have reported on these babies who had bilirubin levels over
30.
Remember,
there were 11 babies with bilirubin levels over 30, but a number of them
weren't in the study or hadn't been examined yet.
Some
of the controls had bilirubin levels in the teens, even a couple over 20, the
vast majority never had a bilirubin measured.
[Slide.]
As
expected, there were differences in the maternal race and ethnicity with an
excess of Asian moms among the cases and a fewer than expected Blacks and
Whites and Hispanics about the same.
[Slide.]
Not
much difference in education. The trend
toward the bilirubin cases being a little bit better educated.
[Slide.]
No
difference in family income. This is 28
or 27 percent had family income more than $100,000, so this was not an
impoverished group. This is what you
have to make to live in the Bay area.
[Slide.]
As
expected, the gestational age was quite a bit younger among the cases. See this big excess of 38, 37, 36 weeks. We added the 35-weekers later, so we actually
recruited additional controls at 35 weeks.
[Slide.]
This
one sort of surprised us, the duration of breast-feeding because we thought
this would be a big confounder we would have to worry about, that the cases
would much more likely to have been breast-fed for longer. This wasn't the
case.
The
big risk factor was exclusive breast-feeding, exclusive breast-feeding during
the birth hospitalization, which is what was associated with being the case,
but not any breast-feeding, not just whether you had any breast milk or not,
and not duration of breast-feeding.
[Slide.]
So,
now some results, first unadjusted and then I will show you adjusted. The short answer is that there is only one
statistically significant finding so far, I will show you on it. It goes in the direction of favoring the
bilirubin cases.
The
verbal IQ, the trends were towards higher IQ's and the unadjusted verbal
performance, and this is the test of visual motor integration, nothing
statistically significant, all higher for the cases.
[Slide.]
Adjusting
for race, ethnicity, parental education, income, and so on, nothing is
statistically significant, and generally, the two numbers move a little bit
closer together and usually the bilirubin is still a point or two higher
although for performance IQ, they did switch directions, but not statistically
significant.
[Slide.]
Remember,
this is that test, the Motor Performance Checklist which when it was developed,
it was considered that scores above 4 were abnormal, and this is also not
statistically significant. These are,
you know, you get a point, that is, higher scores are worse, you get a point
you fail if you can't throw or catch a ball, or stay within the lines when you
are cutting out a square, and so on. So,
no difference there.
[Slide.]
This
is kind of unexpected. The blinded
neurologic exam, which we had the neurologists rate from normal, normal
questionable, which is a child that they still thought was probably normal, but
there was just something a little bit iffy, you know, maybe a little bit
hypertonic or brisk reflexes or not too great at the tandem walk or something
that they didn't think was abnormal, but that in order to maintain a high
sensitivity, they were just going to say questionable.
Abnormal
was where they felt that this was a child who definitely was abnormal, but
minimal means there was minimal or no functional disability, so that it didn't
really affect the child, but they could see that there was a pattern of maybe a
very slight hemiparesis or something, and then there were very few who had
anything more severe. This came out
statistically significant in favor of the bilirubin group. They had fewer questionable to minimally
abnormal neurologic exams.
[Slide.]
I
will close with some unanswered questions.
I think we still don't know what the incidence of kernicterus is. We know that it's not common, but given that
we have very few large series with denominators, it is quite possible that
something other than treatment of bilirubin is what makes Kaiser Permanente
better that average, and it could be higher than I think.
What
we really need to know is not just what is the risk of kernicterus, but at what
level of bilirubin, what the risk is at different levels of bilirubin, is there
any risk at all between, say, 25 and 30, or 20 and 25, and, if so, what is it
because what we are going to have to do is balance risks and benefits in
treating. As you get above 30, 35, it is
very hard to make guidelines about things like exchange transfusion if you
don't know these numbers.
What
factors modify these risks? I think this
is key because two different babies who have a bilirubin level of 30 may be at
enormously different risks of kernicterus depending on other factors, such as
other illnesses the child may have, you know, hemolysis being best
demonstrated, but I think there is at least good anecdotal evidence that babies
who are septic have a much higher risk of kernicterus, and so on.
We
need to know what are the risks and costs and efficacy of treatments. We don't really have a good feel for that,
large series of exchange transfusions, careful looking at long-term effects, if
any, of phototherapy, and certainly any new treatment, this would be key.
Ultimately,
I am afraid we are going to have to come up with some sort of decision about
how many tests and treatments it is worth doing to prevent one case of
kernicterus because there is always going to be uncertainty. Kernicterus is
very rare, you can't always predict it.
It is always going to involve treating many, many patients who aren't
going to get it anyway in order to prevent one who does, but how many that
should be, I think that is an unanswered question.
[Slide.]
To
close, the problem I think is that it is going to very hard to show that a new
drug or any other treatment will improve neurologic outcome in children with
jaundice because the bad outcomes are just too rare.
So,
we are faced with effects on bilirubin levels, which is really a surrogate
outcome, and not knowing for sure whether if we lower bilirubin levels, we do
anything except avoid the treatment.
So,
we end up treating with a drug to avoid phototherapy and exchange transfusion,
which are both things that we choose to do at certain levels. So, it is going to be a difficult decision, I
think, how much data on safety we need to approve a drug intended to prevent
treatments like phototherapy and exchange transfusion for a risk factor, which
is a high bilirubin given our current uncertainty about when those treatments
are indicated.
I
think I am out of time, so thank you.
DR.
CHESNEY: Thank you very much.
We
will have time for discussion of the presentations after the next group of
presentations, and the next group of presentations have been allotted one hour.
Just
by way of introduction, in February of 2003, the Agency for Healthcare Research
and Quality published an evidence report on several question with relevance to
the issues being addressed today.
We
are going to be hearing from three authors of this report, and the first
presentation is by Dr. Lau, who is Professor of Medicine at the Division of
Clinical Care Research at Tufts-New England Medical Center, Director of one of
the AHRQ evidence-based practice centers, and Director of the Boston Office of
the New England Cochrane Center.
He
is going to first discuss the methods that were used to develop the report.
Agency for Healthcare Research and
Quality Report
DR.
LAU: Thank you.
[Slide.]
My
colleagues and I will be talking about the evidence report that was produced
under the Agency for Healthcare Research and Quality's evidence-based practice
center program.
I
would like to acknowledge other investigators on this report.
[Slide.]
The
evidence report process involved a rigorous, comprehensive synthesis and
analyses of relevant scientific literature.
It uses explicit and detailed documentation of the methods, rationale,
and assumptions.
The
scientific syntheses may include meta-analyses and cost analyses, and a broad
range of experts is included in the development process in formulating the
research questions and the peer review process.
What
is important is that the reports do not make clinical recommendations, we
primarily summarize evidence.
[Slide.]
A
systematic review process involved initially formulating well-focused research
questions because this is a very broad topic, and we cannot do all the
questions.
They
involve forming a technical expert panel and through several rounds of
iterations of teleconferences, and we finalized a set of research questions.
We
established the evidence-based practice center protocol for this review,
establishing inclusion and exclusion criteria, and then we perform a
comprehensive literature search, screen the abstracts and the full articles,
and finally abstract data and perform critical appraisal of the literature, and
then perform the analyses, summarize,
and interpret the results.
[Slide.]
The
key questions that were formulated along with the technical experts are listed
here. What is the relationship between
the peak bilirubin levels and/or duration of hyperbilirubinemia and
developmental outcome?
What
is the evidence for effect modification of the results in Question 1, the
previous one, by gestational age,
hemolysis, serum albumin, and other factors? My colleagues will not be talking about this
due to time, but you can refer to the evidence report that has been published
and available on the web site.
[Slide.]
The
third question. What are the
quantitative estimates of efficacy of treatment for: reducing peak bilirubin levels, for example,
the number needed to treat--I will define that later--at 20 mg/dl to keep total
serum bilirubin from rising; reducing the duration of hyperbilirubinemia, that
is, the average number of hours by which time total serum bilirubin greater
than 20 mg/dl may be shortened by the treatment; and improving the
neurodevelopmental outcomes.
[Slide.]
The
fourth question is what is the efficacy of various strategies for predicting
hyperbilirubinemia, including hour-specific bilirubin percentiles? This will be address later by Dr. Stanley Ip.
The
last question is what is the accuracy of transcutaneous bilirubin
measurements? This will be addressed by
Dr. Rebecca O'Brien.
[Slide.]
The
medical literature search involved searching the Medline and Premedline
databases in September 2001. This
yielded over 4,000 citations.
We
also consulted other experts and reviewed the bibliography of relevant review
articles for potential additional studies.
Also,
in 2002, we also performed a supplemental search for case reports of
kernicterus.
[Slide.]
The
general inclusion criteria for the studies were all human English language
literature, newborns between birth and one month, healthy, full-term infants
equal to 34 weeks of EGA or about 2,500 grams, and also each study must have at
least 20 subjects per arm except for Question 1 and 2, which we lower the
number to 5.
Additional
criteria were also applied to specific questions.
[Slide.]
The
total number of full articles retrieved based on screening of over 4,000
abstracts were about 663. The number of
studies included in the report, 138, although there was some overlapping in
number.
The
specific number addressing each of the questions is listed here. For Question 1 and 2, there were 37, and then
also there were 28 kernicterus case reports; Question 3, 21 studies; Question
4, 10 studies; and Question 5, 46 studies.
[Slide.]
In
summarizing the evidence, there are several parameters that are generally
recognized that are important to sum up - the methodological quality of the
study, that refer to the internal validity, the study design, conduct, and
reporting of the study.
Then,
also the applicability, how well the study can be generalized, sometimes also called
external validity about the patients, population and setting.
The
study size is also important to capture to represent the weight or the
precision of the evidence. Then,
finally, the effect or the results, associations, or the test performance.
[Slide.]
In
evidence reports, it is typical to also provide some measure of the
methodological quality, but the quality is something that is difficult to
measure, so this is some caveat that needs to be interpreted.
It
generally refers to the design, conducts, and reporting of the study. Because studies may be from a variety of
types of design, we generally follow three-level classification, and then apply
to each type of study designs.
There
is Grade A, B, and C, least potential bias to C, which is significant bias that
may invalidate a result, and B is somewhere in between.
[Slide.]
We
also generally use the applicability scale although not directly applied in
this report, which also is Category 1, 2, and 3. Category 1 will be a study that is representative
of the target population.
So,
instead of using this scale, we just report the report in the tables, the
country of origin of the study, as well as the racial composition of the
population.
[Slide.]
Now,
I am just going to describe some of the quantitative methods used in the
evidence report before I turn it over to my other colleague to describe the
exact results.
[Slide.]
For
Question 3, there was a question about the NNT or the number needed to treat,
and that is what are the quantitative estimates of the efficacy of the
treatment for reducing peak bilirubin levels.
[Slide.]
The
definition of the NNT is that if you have a clinical trial, this is a typical 2
by 2 table, the treatment and no treatment arm, and the event and no event. In
this hypothetical example of this trial of treating bilirubin level at 15 mg to
prevent it from rising, so rising is the outcome.
In
each of the arms, there will be 100 patients, and in no treatment arm, let's
say 20 patients out of 100 will rise beyond the 15 mg, and if you treat at this
level, only 10 patients will rise, so therefore, one way of estimating the
benefit of this treatment will be the risk difference or the absolute
difference, so it will 10 over 100 in the treatment group minus 20 out of 100
in the control group or minus 10 percent or 10 percent reduction of absolute
event rate.
NNT
is defined as an inverse of the risk difference or 1 over 10, or 1 over 0.1 is
an error, or equal to 10. What that
means is that you need to treat 10 patients in order to prevent one baby,
bilirubin from rising.
So,
some believe this is a useful metric for understanding the benefit of the
treatment for clinicians.
[Slide.]
For
Question 5, collection of the study reported several measures of diagnostic
performance. The most common one is the
correlation of two tests or the r value, and one can also then combine study
that address similar question, however, combining the correlation value is not
the ideal approach in examining the agreement between two test methods, and the
Bland and Altman method, already Tom Newman has shown earlier, is the preferred
approach. I will describe that in a
little bit.
[Slide.]
This
is the Bhutani paper, that I am sure you will see repeatedly over and again,
showing the result of the HPLC versus the BiliChek, and has reported an r value
of 0.91, so sound like a fairly decent r value.
[Slide.]
But
a problem with the correlation that is shown n this slide is that its black
diagonal line's identity, that is, this is an exact matching, the 25 mg measure
on the device being investigated is equal to the same value by the reference
standard, but any other highly correlated line or this shown to have
correlation of 1, will be maybe misinterpreted as being a perfect test where a
substantial bias may be so, that is, some study may consistently overestimate
the actual level.
So,
correlation is one of the conditions of being a measure of a test, but not
sufficient.
[Slide.]
The
limitations of the correlation in assessing the methods are summarized
here. It provides a measure of the
strength and directionality of the association, but not agreement.
The
correlation measures ignore bias, and the coefficient does not provide
information as to the clinical utility of diagnostic test, and also the
correlation is dependent on distribution of the serum bilirubin, as Tom also
mentioned earlier.
I
already mentioned the last point.
[Slide.]
Now,
the Bland and Altman method assumes that the true value is unknown. It takes the average of the paired measurements
as the best result, the pair of the reference standard and the device being
investigated.
It
plots for each pair of the measurement, the difference in result between the
device against the average results, and this also removed statistical artifact
of plotting the difference against either of the measurement as long as the
built-in correlation problem.
This
magnitude of the bias can also be estimated as well as the standard deviation
of the difference. So, this is again,
Tom has shown you this slide showing the mean of the reference standard and the
device being investigated on the x axis, and on the y axis, plotted difference
between the two devices, and midline is the average of all the scatter plot,
which is slightly above zero, suggesting there is a small bias in the device
being investigated, and then also you can establish the distribution of what is
known as the limit of agreement. Tom
already mentioned some of the other issues.
But
then also out here in the high bilirubin end, you can also see that there are
more underestimation by the device being investigated, so you could then also
better appreciate the how the new device being compared performs.
[Slide.]
Other
methods we used in our report is for diagnostic performance combining test
performance or sensitivity and specificity.
There is a number of ways that this can be done, not always used, such
as combining sensitivity and specifically independently, but there is some
problem with that, but sometime may be useful.
The
most common method is the summary ROC curve, and I will just describe this very
briefly.
[Slide.]
This
is a meta-analysis method to combine multiple study diagnostic performance when
study address similar issue. An
assumption is that studies differ because of different thresholds being
reported. The solution is to fit a
receiver operating characteristic curve that best describe the data, and I am
just going to show you very briefly what this means.
[Slide.]
This
is a standard diagram showing the population, the certain value on a horizontal
axis, for example, the bilirubin value from the very low to high, and in health
population, there is certain distribution of the bilirubin level and in
the--well, I guess this is the high bilirubin level, the label is disease, and
different thresholds may then be applied to define what is important or high or
low.
The
different threshold would then produce different sensitivity and specificity,
and as shown here, using a low threshold will result in high sensitivity and a
high threshold will result in the lower sensitivity, but higher specificity, so
there is an inherent trade-off.
Similarly,
in the summary, SROC method, this is some examples of it with the ellipsis
representing the individual studies performance, sensitivity and specificity,
and when we fit this curve around, we can then describe this collection of
studies. The X there is the
independently combined sensitivity and specificity to give you an idea where
this average overall what this performance may be.
I
think I will stop right here.
DR.
CHESNEY: Thank you. Dr. Lau, for those of us who are uninitiated,
could you just say once again what does ROC stand for and what does SROC stand
for?
DR.
LAU: The ROC stands for receiver
operating characteristic curve, and SROC just adds Summary on top of that. ROC describes the trade-off of the threshold
effect in the individual study. The
Summary ROC is a meta-analysis method to combine multiple studies.
DR.
O'FALLON: Would you explain the
different shapes of those studies? Some
of them are oval, some of them are--
DR.
LAU: The oval shape represent the weight
of the study, and they are not in x and y dimension, it is not the same,
because in the disease arm and the non-disease group, it is different number of
patients in the different groups, so they are proportional. It is just to give you a visual impression of
the disproportion.
DR.
CHESNEY: Thank you. I am sure we will have more questions for you
in the session after this.
Dr.
Ip is our next speaker. He is an
Assistant Professor of Pediatrics at Tufts University Medical School, and he
will be presenting findings of Question 4 from the AHRQ Report on
bilirubinemia, and I assume you will tell us again what Question 4 is.
DR.
IP: Question 4 is asking what is the
efficacies of the different strategies for predicting hyperbilirubinemia. Tom Newman actually did most of my talk for
me, so I will just go over some of the details.
[Slide.]
When
we reviewed the studies, there are a total of 12 different studies and 10
publications. Some of the publications
combined two different methods into one paper.
In
terms of the methods, as listed here, there are cord bilirubin, serum
bilirubin, the first 24 hours, the ETCOc, the carbon monoxide predischarge risk
index, and the predischarge risk zone by Bhutani.
[Slide.]
As
you can see, these studies, they are very, very variable. They are from like seven different
countries. The subjects ranged from 50
to almost 3,000. Some study subjects
consist of term babies, some consist of term and preterm babies. The proportion of breast feeding varies from
like 4 percent to 90 percent. Some of
them include ABO incompatibility, some of them don't. Some received phototherapy, and some don't.
[Slide.]
The
other issues with these group of studies, out of the 12 studies, there are 8
different definitions of hyperbilirubinemia, so it almost makes it impossible
to compare is one strategy better than another strategy.
As
you can see, there is even one study that use clinical jaundice as an
endpoint. In other words, the way they
define hyperbilirubinemia is just by looking at the baby. If the baby is yellow, they say, yes, that
kid is hyperbilirubinemic.
On
the other hand, after they have identified it, when they measure the bilirubin,
the range went from 6.4 to 19.3.
[Slide.]
I
am just going to go over several different papers in terms of each method and
just highlight certain points. The first
method in terms of the cord bilirubin, Carbonell in the 2001 paper and the 585
nonhemolytic babies assessed--that little sign should be greater than or equal
to--2.2 mg/dl in the first, in the cord bilirubin, it will predict total serum
bilirubin greater than or equal to 17 on day 3 to day 4. The sensitivity of this test is only 22
percent.
In
Knudsen's paper, when he changed the definition from 17 to 11.7, you notice the
sensitivity went up to 71 percent.
In
the very last paper, in Risemberg, his subjects only consisted of ABO
incompatible babies, so it is a highly selected population. He also raised the threshold of
definition. You can see the sensitivity
and the specificity went up quite a bit, 92 and 100 percent.
[Slide.]
This
is just to show you more of the ROC curve we discussed earlier by Dr. Lau,
showing that this is from the Knudsen studies, and so you can pick any point
you would like to set up as your test threshold, so if you use 2.05 as the
threshold, then, you get certain amount of sensitivity, like about 70 percent, and a false positive
rate of about 20 percent.
[Slide.]
The
other methods is basically measuring the early serum bilirubin level. Some of these papers actually included
transcutaneous bilirubin as part of their study. The first one was done in India out of 274
subjects, and basically, they find that if you use 3.99 as a cutoff point, this
was drawing sometimes between 18 to 24 hours of life, it will predict to a TSB
of greater than 15. The sensitivity is
69 percent, the specificity is 66 percent.
The
author noted that these are acceptable figures for the India population, but
they said it needs to be validated, and they said they are happy with that
result and using that population.
In
the Carbonell study, out of 1,500 and some babies, he says the TSB at 24 hours
greater than 6 predicts to a TSB greater than 17. The sensitivity is like 100 percent, and if
you combined with a 48 hours TSB, greater than 9 predicts like 17.
Carbonell
also did transcutaneous measures using the same threshold. The numbers are comparable. They don't look as high both in terms of the
sensitivity and the specificity.
Seidman,
in Israel, 1999, out of 1,100 babies, he calculated odds ratio using multiple
logistic regression analysis, predicted that if you have a TSB greater than 5
at 24 hours of age, it is high significant to predict a day 2 TSB greater than
10, day 3 greater than 14, and greater than 17 later on.
The
other factors that he looked at, you see at the bottom, the odds ratio for day
1 TSB is 36.5, which is high predictive of high bilirubin later on.
[Slide.]
Anyway,
the other significant factors are the day 1 TSB measurement and apparently you
can calculate, depends how high it goes, and it gives you a certain odds ratio,
maternal blood type, maternal age, and so forth. To, this is one method of predicting high
bilirubin is looking at risk factors analysis.
[Slide.]
Tom
Newman did the same. He mentioned
earlier the Kaiser studies, and these are the original data from his
paper. He showed that if you have early
jaundice the first 24 hours, your odds ratio of having high bilirubin is like
7.3, which is like the highest.
So,
what he did in his paper was he wanted to know if you can predict high
bilirubin after discharge, so he used the other factors, not the early
discharge because they are already in that group, and then he basically
combined them into an index score and see if you can predict extreme bilirubin
of greater than or equal to 25.
[Slide.]
This
is the ROC curve from Tom Newman's study.
You will notice that you can see the risk index of 10, which is at the
upper lefthand corner, the most upper lefthand corner, which is the preferred
point if you use that as a cutoff point.
Just
to talk about that risk index of 10, Tom did a calculation. If you use risk index of 10, because it's the
low prevalence of the disease, your positive predictive value at that setting
is like 0.027 percent, which is very, very low.
So, what he concluded is you are going to have to treat like 370 kids
with a risk index of 10 to prevent one kid from reaching greater than 25, so
that is a huge number of patients to treat to get at one kid.
[Slide.]
The
other method is basically to use ETCOc as a predictor of high bilirubin, which
has been done by Stevenson back in 1997 on kids with hemolytic jaundice. Also, Okuyama, in Japan, decided to use the
same technology to see if it will work for kids who don't have hemolytic
jaundice, and he finds that if you have a ETCOc greater than 1.8 ppm at 48
hours, it's a good predictor that that group will have TSB greater than 15.
Notice
the very high positive predictive value of 40 percent in that particular
population.
[Slide.]
Now,
we talking about the Bhutani paper from '99, where he had started out with
13,000 infants who fulfilled a criteria, and out of the 13,000, only roughly
2,800 who had two TSBs done at the same institutions, so those 2,800 were the
subjects for his study.
[Slide.]
What
he did was he basically did a bunch of different bilirubin at different time,
and you can calculate 95th percentile from each group.
[Slide.]
This
is an early curve that Tom showed, that you can have different curves and
giving different percentiles.
[Slide.]
So
what Bhutani did was depending on where you were at the predischarge area, you
can predict to whether or not you are going to stay at the greater than 95
percentile, which is how he defined hyperbilirubinemia.
So,
for instance, if you look at the upper lefthand corner in A, you will see that
if you start off at greater than 95th percentile, roughly 40 percent of that
population stays in that zone, so he considered that would be a high risk.
On
the other hand, if you look at the lower righthand corner, in D, if you start
off with less than 40th percentile, none of those kids went on to be in the
high risk zone in the greater than 95th percentile.
[Slide.]
This
is the Bhutani curve where Tom showed the calculated area under the curve of
0.93.
[Slide.]
So,
if you use the 75th percentile as a cutoff point, as shown by this ROC curve,
you get a sensitivity of like 90 percent, a specificity of 85 percent, and a
positive predictor value of about 21 percent.
So, what that means is you are going to have to treat roughly 5 kids who
have greater than 75th percentile to prevent 1 kid from reaching greater than
95th percentile in his population.
[Slide.]
It
is of note that Bhutani's study population is very different from a typical
U.S. population. As you can see in his
study, he had 41 percent African-American while the national population is 15
percent. He had 4 percent Hispanics, and
the national population is 21 percent.
[Slide.]
Stevenson
decided to look at both ETCOc and TSBc to see if it will improve the
prediction. As Tom mentioned earlier, it
really didn't improve the prediction of the accuracy of hyperbilirubinemia.
[Slide.]
The
interesting thing about the Stevenson study, because it was done over in like
nine different multinational centers, he actually used the raw data from the
Bhutani population and see where the 95th percentile is for his study
population.
As
you can see, the 95th percentile varies anywhere from 38 percent to 6 percent,
so it's very, very highly variable.
On
the other hand, if you just look at the ones with the study size greater than
100, the variability is not too bad, and then it's from like about 5 percent to
about 10 percent, but nevertheless, it is not really comparable to the Bhutani
population.
[Slide.]
In
summary, it is not possible to directly compare the accuracy of various
strategies for the many reasons we have stated before. It is also very apparent that the higher you
have the TSB at an early age is associated with hyperbilirubinemia three to
four days later. In fact, that is probably a better prediction than if you try
to say that if you have a low TSB, you won't get a high hyperbilirubinemia
later.
The
hour-specific nomogram looks promising.
It has a high AUC, but further validation in different populations
should be done.
DR.
CHESNEY: Thank you.
Our
next speaker, and then we will have a question and answer session, is Dr.
Rebecca O'Brien, who is an Assistant Professor of Pediatrics at the Floating
Hospital for Children at Tufts-New England Medical Center, and she is going to
review for us the accuracy of the transcutaneous measurement of bilirubin.
DR.
O'BRIEN: I have 10 minutes, is that
right? I will try to do my best to get
through this.
DR.
CHESNEY: Actually, you have plenty of
time. I don't mean two hours, but you do
have 20 minutes.
DR.
O'BRIEN: I will go through some of it
quickly, though.
[Slide.]
I
am addressing Question 5, which was looking at the accuracy of transcutaneous
bilirubin measurements in our evidence report.
I think these terms are familiar to all of you, but I will use TcB to
reflect transcutaneous bilirubin, TSB to reflect total serum bilirubin, and
HPLC, which was used in some of the newer studies of the BiliChek device as
either high performance or high pressure liquid chromatography.
[Slide.]
We
had 47 qualifying studies in 50 publications that actually looked at the test
performance of the transcutaneous bilirubin instruments to predict total serum
bilirubin.
The
four devices that were included in these studies included the Minolta
AirShields bilirubinometer, and clearly this has been the most studied
device. At the time of our review, there
were three studies on the BiliChek device with 809 subjects, the Icterometer
was in 4 studies, and 1 study reflected the Colormate III.
[Slide.]
We
will start with the AirShields bilirubinometer, which is in 2002 called an
AirShields jaundice meter. This is a handheld
device, I think similar to the picture you saw with the BiliChek. It uses fiberoptic techniques that
illuminates the skin and subcutaneous tissue, and then you analyze the
intensity of the yellow color spectrophotometrically.
This
particular instrument requires development of an index, and it appears to be
institution dependent, and their correlation curves have different intercepts
on the y axis, and we will talk a little bit about that, and it does require
daily calibration of the instrument.
[Slide.]
It
has been studied for over 20 years. It
has been studied in diverse patient populations. In about half of the studies we looked at,
they actually looked at test performance generally reported as a sensitivity
and specificity of the transcutaneous instrument to predict a threshold of
interest of total serum bilirubin.
Measurement
sites were generally performed in most of the studies at the forehead and
mid-sternum, and several of the studies reported on other sites.
[Slide.]
Again,
challenges of combining these studies for meta-analysis include that authors
use different total serum bilirubin thresholds of interest. Some used 10 and some used 12, some used 15,
and it does limit a little bit of our ability to perform meta-analysis.
The
studies that we were able to combine, we combined three studies that used total
serum bilirubin of about 11, 11 studies we are trying to predict total serum
bilirubin over 13, and in 3 studies over 15.
[Slide.]
The
studies predicting TSB greater than 11 were 500 paired samples. They were done at the forehead. Using a random effect model, the pooled
estimates of sensitivity and specificity, as you can see, were in each study
individually here, and then the pooled sensitivity of about 76 percent with a
specificity of about 80 percent.
You
can really see the variability, though, of this index that is developed at each
institution and where Maisels used an index of 20, Knudsen used an index of 9.
[Slide.]
Then,
to predict total serum bilirubin of 13, there were 11 studies, so I didn't show
you a table, but I will show you this summary ROC curve for this particular
predicting total serum bilirubin over 13.
There
were 1,560 paired measurements. Again,
the cutoff index ranges in the various studies anywhere from 13 to 24, and we
will show you the summary ROC curve that while it isn't quite a clean threshold
effect as we will show you, so there does appear to be some heterogeneity in
the way this performs.
Using
a pooled estimate, however, of all of these 11 studies, we have a sensitivity
of about 85 percent, a specificity of about 77 percent.
[Slide.]
So,
this is the summary ROC curve. Again, I
guess the perfect test, all of these gray points would all be kind of right
along this line, and this would be the lowest levels of the transcutaneous
measurement, and then you would lose sensitivity as you went to higher levels
of the index.
It
sort of fits. This is 15 index, this is
a 22, this is a 21, but there is a lot of scatter over here, this is 20. So, it is not a totally neat fit as a test.
[Slide.]
Then,
for predicting total serum bilirubin over 15, again, there were only three
studies that could be combined here.
Overall, they actually looked pretty good with a sensitivity of 95
percent and a specificity of 67 percent for the Minolta AirShields.
[Slide.]
Now,
looking at just how well does the transcutaneous measurement from the Minolta
AirShields correlate with the total serum bilirubin, and again with all the
limitations that Dr. Lau spoke of, this was really what most of the studies
actually do talk about and do present as data.
It does help us when we look at some of the factors that may affect how
well this device works though.
[Slide.]
So,
in these studies, the r values ranged from 0.52 to 0.96. When they were pooled, the correlation is
about 0.84. There is details in the
evidence table on page 241 for those who are interested later.
[Slide.]
Again,
he spoke about the limitations, I will skip this slide.
[Slide.]
But
when we were looking at the factors that affect the test accuracy of the
Minolta Airshields bilirubinometer, again the study designs varied. Some of these studies were screening all
infants, some were screening only jaundiced infants. They varies as to racial background,
measurement sites, age at measurement, and then what was their reference or
gold standard, which particular lab method did they use.
There
was, however, some subgroup analysis done, and we attempted to look at some of
these factors in the slides coming up.
[Slide.]
Just
as a summary, there was higher correlation of the transcutaneous measurements
by the bilirubinometer when the sternum or forehead sites were used in term
versus near- term. It seems to correlate
better with White versus Black infants, and those who had not received
phototherapy versus those who had received phototherapy.
[Slide.]
Again,
just sort of showing, you can see the correlation sort of drop as you move to
some of the sole, the palm areas, and seem to be most highly correlated at the
forehead and sternum sites.
[Slide.]
Looking
at gestational age, there were five studies that actually gave separate
correlation coefficients. While in the
individual studies, there were not significant differences, there did appear to
be a trend lower in near-term infants, and you can see this in the results
here.
[Slide.]
Looking
at race or skin color, there were six studies that compared correlation
coefficients across race or skin color.
Half of those were at the sternum site.
There
were two U.S. studies that did find significant differences in White versus
Black infants. The other racial groups
that were studied were Malay, Chinese, Indian, and there were no Hispanic
subgroups analyzed for the Minolta device.
[Slide.]
Looking
at, as you can see, the correlation coefficient in black, there were three
studies with this sample size of 258 and pooled correlation coefficient is 0.59
compared to the White, which was 0.75.
Overall, this is how they performed.
[Slide.]
Looking
at phototherapy, there were six studies that reported on the effect of
phototherapy. All of these studies had
lower correlation coefficients if the children had received phototherapy. That was significant in two of the
studies. With meta-analysis of the
correlation coefficients, again, you can see there is a small difference in the
results.
[Slide.]
The
next device was the Ingram Icterometer, which has been around for a long
time. It's transparent plexiglas that
has five painted transverse strips or precise and graded hue of yellow
color. You press this device against the
infant's nose and the skin blanches.
The
yellow stripes are then compared and a number is applied. Most of the studies used a number, 1 to 5
used 3 as their cutoff point. It is I
think only about 7 or $8.00, so it is a low cost device.
[Slide.]
The
studies reported the correlation coefficient here. There were four studies of the Ingram
Icterometer. The reason why there is two in India, these were near-term,
preterm infants, and these were term infants.
You can see there is really sort of a variability in how it performed,
but overall, pooling the results, it appeared to be fairly highly correlated.
[Slide.]
Looking
at test performance of the Ingram Icterometer, there were three studies that
actually reported on the test performance, generally, a sensitivity and
specificity. Two of these studies were
looking at a TSB of 12.9. The threshold
of the Icterometer TcB measurement was 3, and Bilgen's study in Turkey found
100 percent sensitivity, Schumacher found an 82 percent sensitivity although,
with experience with the device, apparently this goes up to 95 percent, and
then in the Indian studies, again performing a little bit less well in preterm
versus term in terms of sensitivity.
[Slide.]
The
next device is the BiliChek device. At
the time we did this review, there were three studies. This is a device that used multiwavelength
reflectance and therefore, theoretically, can improve on the transcutaneous
measurement by accounting for bilirubin, hemoglobin, melanin, and thus things
like skin color, skin thickness,
pigmentation.
There
is a fiberoptic probe that is placed on the forehead and multiple measurements
are made and averaged together after contact.
[Slide.]
These
three studies, again, we have heard certainly the Bhutani study, it is very
similar to what he did with the hour-specific nomogram although he was trying
to use a transcutaneous measurement with the BiliChek to look at the same.
The
difference in these studies is this is the first time we sort of saw people
using a gold standard or reference standards of the high performance liquid
chromatography, and this was used in the Bhutani study and in the Rubaltelli
study.
Rubaltelli
also used lab serum bilirubin and actually compares the transcutaneous
instrument to the lab, and we will go through these in the next several
minutes.
[Slide.]
I
am sorry this is such a busy slide, but again here are the three studies,
Bhutani, Lodha in India, and Rubaltelli.
Again, very high correlation was found in the Bhutani study, and he
again using the threshold of the transcutaneous bilirubin instrument as
measured by the BiliChek, and the transcutaneous measurement at the 75th
percentile to predict serum bilirubin of the 95th percentile.
By
using this, again lower threshold of the transcutaneous instrument has 100
percent sensitivity. I think it was 23
out of the 419 actually fell into that range, so it is a small number of
infants who are falling into that 95th percentile.
The
study in India did not perform quite as well, and certainly appeared to perform
less well when you were looking at higher total serum bilirubin levels with a
sensitivity of only 20 percent.
Rubaltelli
is probably best seen on an ROC curve again because he uses multiple
thresholds, but again it sort of summarizes that as you lower your threshold,
your sensitivity is higher, and he did this at several levels, which we will
show in the next couple slides.
[Slide.]
In
the Bhutani study, again, this was a sample size of nearly 1,800 samples with
490 term or near-term infants. He had a
very low Hispanic population, I think as Stanley had alluded, he had Whites and
Blacks were represented.
There
were 11 different devices used in the study, BiliChek devices, and as noted,
his correlation was high.
[Slide.]
Again,
this sort of shows graphically, and I think that the one point, though, most of
these points are at bilirubin levels, HPLC bilirubin plotted here, and
transcutaneous, and you can see that there may be--and again it's hard to
say--a little bit more variability at the higher levels.
[Slide.]
Again
looking at this as a Bland/Altman or error distribution plot, I think Dr. Lau
sort of pointed out that maybe there is a little bit more variability at high
levels, but you are dealing with sort of a plus or minus 3.23 and 2 negative
here, the BiliChek does appear to slightly underestimate, so that the mean is a
little bit higher, the HPLC value.
[Slide.]
Rubaltelli
again was a multicenter study. It was in
six different European hospitals and it used infants who were going to have a
TSB done as part of their care. There
were multiple users. He was trying to
look at how this might actually perform in real life, multiple users of the
BiliChek. There were multiple lab
measurements of serum bilirubin, and then all of these were compared to a gold
standard of the HPLC serum bilirubin.
There
was one single lab that did the HPLC measurements, and he found that the
correlation of the transcutaneous measurements with HPLC were high, although
not quite as high as the laboratory, they were fairly close.
[Slide.]
This
is sort of graphically looking at correlation, this being the BiliChek
versus--I am sorry you can't see this--but BiliChek versus HPLC here, the lab
versus HPLC here. They again both had
very high correlation, perhaps a little bit more variability with the BiliChek.
[Slide.]
Then,
again, looking at an error plot, again, this is the BiliChek device. I know you can't really read this. This is
plus or minus probably about--this 2 standard deviations here--I think this is
about plus or minus, probably 3 positive, 3 negative here, and again looking at
the HPLC serum bilirubin versus the lab serum bilirubin, perhaps a little bit
narrow, but again these are sort of comparing these two. He also compared the BiliChek to the lab, but
sort of, of interest, how those two compare.
[Slide.]
Then,
looking at how they perform as a screening test. Again, we see these ROC curves and looking at
how this is an ROC curve here to predict a bilirubin over 13, again by the HPLC
method, predicting bilirubin over 15, and again predicting bilirubin over 17.
In
this, the solid line represents the treatment measure, and the dotted line, the
serum bilirubin as measured by the lab.
While they seem to operate closely, it is probably maybe here we can see
that the lab and the dotted line probably performs a little bit better than the
transcutaneous. Again, anything, the
perfect curves are going to be as high up into the lefthand corner as you can
be, and that is why people use sort of the area under the curve, although at
this higher level, they seem to perform very comparably, if not a little bit
better with the transcutaneous instrument.
[Slide.]
Then,
in this final study by Lodha, there was 109 jaundiced Indian infants with serum
bilirubins of 8, showed fairly high correlation, but the subgroup with higher
bilirubins appear to perform less well with a correlation only of 0.64.
[Slide.]
There
was one study that compared the Minolta to the BiliChek, and it does appear to
perform better, at least by looking at correlation coefficients with the
BiliChek correlation coefficient of 0.94 and the jaundice meter or the Minolta
AirShields jaundice meter of about 0.7, and skin color was significant for the
jaundice meter, but not for the BiliChek.
[Slide.]
Again,
this just shows you sort of graphically, again with this Bland/Altman error
plot, there is a lot more variability using the jaundice meter as opposed to a
lot tighter fit here using the BiliChek.
[Slide.]
Finally,
just one other device, there is only one study, and it only reports on
correlation coefficients. It is the
Colormate III, and I guess for the sake of time, I will kind of just go quickly
with this, that it requires a baseline measurement prior to the development of
jaundice, so it requires sort of all infants to have some measurements done and
then it is done by computer analysis to correct for some of the color
luminosity, redness and yellowness.
It
does appear to have a very high correlation, they are reporting 0.956. Again, it has only been studied up through
about serum bilirubins. It tends to
underestimate again, and only up to serum bilirubins here probably of about 15.
[Slide.]
This
is the only other interesting thing in the study. They sort of actually compared how does
visual inspection do compared to this transcutaneous device, and you can see
that the transcutaneous device does appear to improve with a better correlation
than our visual inspection for detecting jaundice.
[Slide.]
I
think this is looking at phototherapy.
[Slide.]
Just
to kind of finish up here, just to say that it appears that the transcutaneous
bilirubin measurements by all three devices definitely appear to have a linear
correlation to total serum bilirubin, but as noted by Dr. Lau, the correlation
coefficient alone doesn't really provide us information on how well this
particular diagnostic test works, however, many of these studies did not really
report performance data. At least half
of the Minolta studies only reported correlation.
It
is going to be highly dependent on where you are measuring your distribution of
serum bilirubin. It appeared that the
devices may perform less well as screening tests at higher levels of bilirubin,
but I think we need more information and more study there.
Again,
the Minolta AirShields tends to perform best at the sternum or the forehead,
less well in Black infants versus White infants, did not appear to perform
quite as consistently across the studies when we look at the summary ROC curve.
I
think the limitations with the Ingram icterometer, there really were a small
number of studies that evaluated that, and it does have some observer
visualization, some issues around objectivity.
It does seem that it performs better after people have used it for some
time.
There
is a new BiliChek device that theoretically corrects for the effect of melanin
and hemoglobin that may be an improvement over the older devices, and I think
we recommend future research to confirm these findings in larger sample sizes
with more diverse populations and really look at the effects of phototherapy.
Thank
you.
DR.
CHESNEY: Thank you very much.
We
now have some time for questions and discussion of the presentations by Drs.
Murphy, Newman, Lau, Ip, and O'Brien.
Dr.
Fost.
Discussion of Presentations
DR.
FOST: Two questions. One I think is for Dr. Ip, and the second for
Dr. Newman and Dr. Murphy.
It
seems to me negative predictive value would be more helpful than positive
predictive value. That is, if we had a
number at discharge that could confidently tell us that this child will almost
certainly not develop a worrisome bilirubin level, that that would be very
helpful.
I
just want to make sure I understand your slide on page 9 of your handout,
called "Predischarge Risk Zone."
Do
I understand that to say that if a bilirubin around discharge is less than the
75 percentile, that has a 99.5 percent negative predictive value of a worrisome
bilirubin?
DR.
IP: That's correct. Basically, the symbol is wrong. It is greater than equal in 75th
percentile. What that says is if you
have a child who is less than equal to 75th percentile, then, that kid is not
going to get in trouble according to the Bhutani population.
DR.
FOST: Thank you. Then, a question for Dr. Newman and Dr.
Murphy.
There
has been a lot of discussion of risks and benefits, but not much about
cost. You just alluded to it in your
last slide. I am wondering if you or any
of your colleagues are doing any studies or estimates of cost-benefit or cost
effective analysis of various interventions.
That
is, suppose there were a drug that was completely safe and could completely
reduce the risk of serious hyperbilirubinemia, are there any estimates of what
the cost per case of kernicterus averted would be?
My
question for Dr. Murphy is what do you see as the FDA's role in those sorts of
policy question, that is, suppose there were a drug that were 100 percent
effective and completely safe, but it cost a million dollars to prevent a case,
does that have any role to play in the approval process?
DR.
MURPHY: I think I can answer that pretty
quickly, which is our job is to assess whether a product is safe and
efficacious. We don't determine the
price, and that other agencies would determine the utilization of that
product. It clearly is a concern to us,
but really our mandate is to make sure it works and how to describe it, so it
would be safely used, and then work with other agencies in trying to integrate
that information with any decisions that they make.
DR.
NEWMAN: You ask I think an excellent
question, one in which we don't have enough data. It is actually the next grant I am planning,
which would be if you add up sort of all the bilirubin levels, all the extra
days in the hospital, all the extra outpatient visits, the home phototherapy,
the hospital phototherapy, the exchange transfusions, all of the money we spend
to try to prevent kernicterus, and even then we are not successful, so there is
still cases of kernicterus.
So,
if there were a magical, totally safe drug that would just basically eliminate
all that or a whole lot of it, it would be worth a lot. I can't give you a cost per patient of what
it would be worth. I am sure the company
making it would figure out a way to price it, so that it would make them money,
but it could conceivably save a lot of money.
What
happens is that there are some cases of kernicterus, there are some kids who
are destined to develop jaundice, who are easy to find and obvious in
preventing kernicterus and the ones who present early with jaundice or who have
all the risk factors, who are easy to follow.
It
costs a lot less money than trying to prevent those last few, sort of
unpredictable cases that show up without risk factors, so that it will be
unless you are going to give the drug to everybody, there will some sort of
incremental cost-benefit thing where the cost per case prevented and the cost
efficacy is much better in the higher risk kids and eventually it tails off to
where it might just not be worth it.
But
if the drug were completely safe, you would give it like vitamin K to
everybody.
DR.
CHESNEY: Other questions? Yes.
DR.
MATTISON: In the evidence report, you
commented on the relative lack of information in a single bilirubin value, and
spoke about the need to think about other strategies for measuring bilirubin,
so it brings to mind sort of a common theme in developmental toxicology, which
is to try to understand mechanism and then relative value of peak concentration
versus area under the concentration curve.
I
imagine that as we talk more today, we will get at some of this, but I wonder
if you would like to comment a little bit on strategies or ways of thinking
about improving strategies of measuring bilirubin, single versus multiple
values, frequency of sampling, and so on.
DR.
IP: Dr. Mattison is referring to our
conclusion on a separate part of the evidence report, which we did not
discuss. Basically, it is what happens
to the majority of the kids who gets high bilirubin, but they don't have
kernicterus.
When
we reviewed the studies, there were a very limited number of studies that
actually address that question. In fact,
most of the other studies, they all had kids who are preterm, term, they are
sick, they have comorbid factors. It is
very difficult to sort out if those factors are not responsible, if they have
any kind of detrimental incomes, so our conclusion was using one single
bilirubin is really insufficient to predict what is going to happen to these
kids seven, eight, 10, 12 years down the line.
The
problem that I see is, first of all, way that the peak bilirubin is measured,
the way it is even reported in the literature,
it seems to me a lot of times it is not necessary, the peak bilirubin
level. That is one problem. I glanced at some of the kernicterus case
reports. They have peak bilirubin done
like 24 hours before something happened, you don't know what happened 24 hours
later, it could be higher, it could be lower.
The
other thing is everybody talks about there is a huge variability of bilirubin
measurements between laboratories, so when you are comparing studies across
different nations, across time, that it is not really a good predictor model.
So,
as you said, maybe we can use the time of exposure, how long have these kids
been exposed to under certain bilirubin and see what happens in the long run,
or maybe have to look at other factors.
The
other issues, we can discuss this at length, is how we define kernicterus in
the first place. The problem that I see
is the terminology is that we always say if you have neurological impairment
with a history of hyperbilirubinemia, that is how you have kernicterus, so what
that means you can't really say that it is the bilirubin causing it because you
define it that way, so it gets involved.
DR.
CHESNEY: Yes, Dr. Oh.
DR.
OH: I have a comment and a question for
Tom Newman. I would agree wholeheartedly
that a key outcome for any intervention in hyperbilirubinemia is
neurodevelopmental outcome, and yet as you pointed out, the kernicterus
incidence is so low, and we don't quite know the new developmental outcome of
hyperbilirubinemia, so it brings up he issue of the follow-up that you have.
Ideally,
compliance rate of 80 percent or greater is desirable in any follow-up study,
with 60 percent, I was just wondering if you had a chance to compare the
variables of the 40 percent that you didn't follow with those that you
followed, particularly with reference to the bilirubin level and the
socioeconomic status.
Can
you comment on that?
DR.
NEWMAN: It's an excellent question. The biggest concern we have, I mean, of
course, we would like to have 100 percent in both groups, but the potential for
bias is that we have a higher percent participating in the bilirubin group than
in the control group, and the concern is what if the controls who choose to
participate are those who are a little bit more worried about their child, and
therefore, they want this free neurodevelopmental assessment.
We
haven't looked at these data yet, but the ways that we are addressing that is
that all the data I showed you are in what we call the full participants, but
when people say no, then, we still ask them, well, will they at least fill out
the questionnaires for us.
One
of the questionnaires I didn't show data on is called the PEDS or the Parent
Evaluation of Developmental Status, where we specifically ask the parent, do
you have any concerns about your child, and there is 10 questions, you know,
how your child understands speech, how your child speaks, how he uses his hands
and fingers or arms and legs, and so on.
What
we at least will be able to do is besides the socioeconomic variables and race
and other variables, see whether we do see evidence of increased participation
in the control group according to whether the family was worried, and then, of
course, we can stratify in those variables and just compare among both the
cases and the controls.
We
do know that most of these parents of these
five-year-olds think their kids are fine, and most of the kids are fine,
so if we stratify just on whether the parents said they had any concerns, and
we started the study before, so we have whether they had any concerns at age
three, age four and five, and so on, we can address that, but we haven't looked
at data comparing participants to non-participants yet.
DR.
CHESNEY: Dr. Ebert.
DR.
EBERT: A lot of your information was
directed towards specifically looking at identifying individuals with high
bilirubins, but yet you also mentioned earlier that because the risk of
kernicterus is so low, perhaps we should look at more the risk or the need for
therapy.
Is
there a way that we can overlay the AAP guidelines for treatment with some of
these risks to look at what would be the predictor for the need for
phototherapy or the need for exchange transfusion?
DR.
NEWMAN: I am not positive I understand
your question. I mean I think we can
look at predictors of bilirubin at a certain level, and that I think has the
advantage that since phototherapy is, as you saw in the slide of the different
hospitals, varies a whole lot from doctor to doctor or hospital to hospital.
I
think we are better off trying to predict bilirubin level above 15, 20, 25 than
trying to predict something like exchange transfusion or phototherapy, but even
then, these are retrospective observational studies and we are restricted by
whether the doctor chose to do a bilirubin or not, and if you have doctors who
don't believe jaundice is a problem and don't choose to measure bilirubin, all
of our data from Kaiser on sort of incidence of bilirubin at different levels
are all minimal estimates because when we get up above 20, 25, we just assume
that if it wasn't measured, they didn't have it, so there may be slightly
higher estimates.
I
am not positive if that answered your question.
DR.
EBERT: That really was what I was
getting at, but looking at the ultimate outcomes and the issues on impact on
health care and the things that we need to do to treat patients effectively, I
guess the end result, the true treatment is a lower incidence than it is of
finding that elevated value.
DR.
NEWMAN: Yes, and again, I think if you
allow as an outcome, doing less phototherapy, then, of course, another way to
achieve that outcome is to change your guideline. One of the problems with the surrogate
outcome of bilirubin is that given that the bad outcomes are so rare, you know,
we could less phototherapy. We could
say, well, we are going to do 22 instead of 20.
That
would have a big impact on cost on phototherapy. Actually, in one study looking at comparing
hospital and home phototherapy, and looking at the cost, the biggest
determinant of cost wasn't whether you did it in the hospital or whether you
did it at home, it was whether you decided to do it at all, because there was
so much variability, and the variability results from the rarity of the outcome
and the lack of data.
DR.
CHESNEY: Dr. Gorman has a question, but
if I could ask one first. Dr. Newman, do
we know anything about autopsies of premature and normal infants today in terms
of how much bilirubin staining there is?
DR.
NEWMAN: David may know this better than
I do. There was sort of a flurry of activity in the '80s about autopsies in
preterm babies, and then I haven't seen much more of that, that it went away
when they took away the benzyl alcohol, but I do bigger,
"weller"--more well babies, so if any of the neonatologists here
knows that--I haven't followed closely autopsies in preterm babies.
DR.
CHESNEY: Dr. Gorman, do you have a
question about "weller" babies?
DR.
GORMAN: I was going to let the
neonatologists with expertise try to answer that question first.
DR.
STEVENSON: I am not aware of any large,
systematic review of autopsy data that would address that directly, at least
recently, and I am not sure what your experience is, but anybody else who knows
anything about it could comment, as well.
DR.
HUDAK: I think that is correct. I think the literature shows that basically,
premature babies who die because they were very sick had bilirubin staining of
the basal ganglia at relatively low levels, and I think that is sort of
uninterpretable information, and it certainly doesn't address the broader
issue, and it doesn't say anything about whether premature babies are more at
risk for kernicterus at lower levels although it was certainly interpreted by
neonatologists for many years that way, but there is nothing recent.
DR.
CHESNEY: Thank you.
Dr.
Gorman.
DR.
GORMAN: This question is to both Dr.
Newman and to whoever reviewed the 38 case reports of kernicterus. I also had
several formative experiences. One was
measuring theophylline levels in the thought that it might help people with
asthma for many years.
I
have that same deja vu all over again while I look at all this chasing of
bilirubin levels. I am going back to the
question of causality of bilirubin and kernicterus.
I
will ask the question in a reverse way.
We have talked about the confounders and the potentiators for bilirubin
or in bilirubin and kernicterus. In that
series, has there ever been a well child who has developed--a well infant--I
ask this question at the risk of offending my neonatology colleagues--a well
infant, term, at any bilirubin level, who has developed kernicterus?
DR.
NEWMAN: I would say yes. Some people say, but if developed
kernicterus, you must not have been well, so there is a little bit of
circularity there. There are children
who, at the time they were discharged from their birth hospitalization, looked
perfectly fine, who are readmitted with very high bilirubin levels, who have
what looks like the kernicterus that babies in the 1950s with Rh disease used
to get.
To
me, the causality is more convincing if they started out well and come in
symptomatic. I mean they come in with a
high-pitch cry, arching, and opisthotonos, maybe seizures, and there are some
of those kids who then, you know, they get an exchange transfusion, and some of
those acute symptoms seem to get better, and if they are left then with the
classic sequelae like used to be seen with Rh disease, to me, that is pretty
convincing.
It
is much harder when they don't have that acute picture or when they end up with
something which is sort of a partial syndrome.
They have cerebral palsy, but it is spastic, and not athetoid, and they
don't have the hearing loss, so they have just the hearing loss, but otherwise
they are fine.
The
courts often end up settling these or they lead to lawsuits, and it's people
arguing about is it kernicterus or not, because the child has something which
is abnormal, which in the parent's mind may be very much associated with the
jaundice and the treatment for it, because treatment for jaundice, especially
when it involves exchange transfusion, is a very salient and frightening event,
but what the child has, it becomes unknowable.
The
MRI findings of the increased T-2 signal and the globus pallidus would be very
suggestive, but I haven't seen enough studies that looked at kids who have
athetoid CP, who never had a high bilirubin, to see how often they have similar
basal ganglia findings on MRI.
DR.
GORMAN: So, in your review of the case
reports, you think the answer is yes, well babies with high bilirubins and no
other disease, trying not to be circular, develop kernicterus?
DR.
NEWMAN: Yes, apparently well babies,
babies who have nothing else wrong with them that we can identify, but it's rare.
DR.
GORMAN: Well, always placing the most
emphasis on the most recent data, Pediatrics arrived on my doorstep yesterday
and because of this meeting today, I actually scanned the titles and saw your
article on bilirubin without kernicterus in several babies.
I
know everybody in California is above average, your IQ scores are all above
average despite whether they were high bilirubin'd or not, but I will leave
that as it is.
I
had a second question which I am now blocking on completely, but it will come
back to me.
DR.
NEWMAN: Just commenting on the babies
over 30, it was only 11, so the quick rule of 3, if you observe zero out of 11
or zero out of 10, because one of them did die of apparent SIDS, you know, the
upper limit of that could be a kernicterus rate of 30, 40 percent in babies
with bilirubin levels over 30.
There
is no question in my mind that it occurs, but probably somewhere in the range
of 1 and 2 in 500,000.
DR.
GORMAN: If you had to predict, and this
is the other question, which of the potentiators or confounders are going to be
most difficult to sort out, which would you point to? I will use that to any of the group that
presented. Is it the hemolysis, is it
the sepsis, is it the gestational age, is it medical intervention?
DR.
NEWMAN: Oh, that's a tough one. I would say medical intervention is going to
be very hard to sort out, because babies who have symptoms, you know, that is
one of the indications, that is one reason they would be more likely to get an
exchange.
In
reviewing some of these case reports, I mean that come from medical-legal
consultation, I have seen ones where the child came in with a high bilirubin
and seemed to be okay, and the exchange transfusion seemed to make them worse,
you know, they either had a seizure during the exchange or something happened,
because it's kind of, you know, it's a big thing to do, so I think that would
be--I was looking through the cases on the plane that I have reviewed, you
know, there is several of them that have this sort of iffy infection.
They
have a little bit of a fever, but people say you can get fever from
kernicterus. They have staph epi or
something in their blood culture, maybe a little low platelet count, it is just
not stuff where you can tell, maybe there was an infection. A lot of them have some white cells in their
urine, but negative urine cultures, but they got antibiotics, so I would say
sorting out infections, some have like a little CSF pleocytosis, you know,
sorting out those things has also I think been hard to say, was this just a
well baby or was this a baby who maybe had an infection.
DR.
CHESNEY: I think, as always, infections
are the most important thing, but I would like to take a break for 10 minutes
if we could, and we are going to have more discussion after the break. It's about 10 of 11:00, if we could come back
at 11 o'clock and then we will address Question 1, which really is general
enough that we can continue some of this question and answer.
Thank
you.
[Break.]
DR.
CHESNEY: For the next 10 to 15 minutes,
although there was an initial and very general question, what we would like to
do is two things. One is to allow people
to continue to ask questions of the speakers, but also please raise any issues
which you feel have not yet been discussed about this area, that have not been
raised by this morning's speakers.
Any
questions, any issues that haven't yet been raised? Dr. Danford.
DR.
DANFORD: I have a question primarily
addressed to Dr. Newman. It has to do
with that multiple logistic model for predicting people who end up with total
serum bilirubins greater than 25.
I
was wondering about the methodology of that because the performance of a risk
index like that is generally better when you assess that performance in the
cohort in which it was derived than it would be if you took an independent
sample afterwards and tried to apply it.
I
don't know, is the kind of encouraging looking ROC curve for that index on the
derivation cohort, or is that an independent sample?
DR.
NEWMAN: That's an excellent
question. In fact, it hasn't been
published yet, but the derivation sample is babies born in '95 and '96, and we
validate it for '97 and '98, and it performed just about as well. The area under the ROC curve went from 0.84
to 0.83, and 0.83 was the one that I showed in my table there.
That
is higher than what Stanley showed because that is using all of the data, and
anytime you categorize it, as he did, the ROC curve that he showed from our
study only I think had four points, you know, more than 15, you know, cutoffs
at 10, 15, 20, and so on, but when you look at the whole data, you, of course,
get additional credit for information that is contained between values that are
in between there.
In
fact, this would be true of the total serum bilirubin measurements, as well,
which is that the area under the ROC curve for those, which when Bhutani said
was replicated, was about 0.84, in the study by Stevenson, 0.4, 0.85. If instead of categorizing it, they actually
looked at the actual value, that would probably go up a little bit, as well.
DR.
DANFORD: Thanks.
DR.
CHESNEY: Dr. Stevenson.
DR.
STEVENSON: This is a question for Dr. Ip
or maybe Dr. Newman. I think Dr. Law and
I think Dr. Ip mentioned that they were not going to be commenting about
hemolysis although it has been mentioned several times, also infection is
associated with up-regulation of the hemoxygenase gene with increased
production of the pigment, and oftentimes hemolysis occurs in that
context. Empirically, jaundice is
associated with infection.
But
I wondered what the quality of the data are with respect to the issue of risk
for not so much bilirubin level, but injury in association with
hyperbilirubinemia between hemolysis, anything on that at all, what is the
state of the evidence.
DR.
IP: We didn't really review specifically
to address the hemolysis, but from what I gather, at least our task was to
review healthy term/preterm, near-term babies without any kind of diseases, and
all the kids with Rh, we excluded that from our analysis.
On
the other hand, there are quite a large number of kids with ABO. There is no way you can exclude them because
they are part of a lot of the studies.
As Dr. Stevenson knows well, the Coombs' test is not the best predictor
of hemolysis, and a lot of times we just have to look at the raw data and say,
well, some authors assume that if mom is O, baby is A, they must have an ABO
problem regardless of what the Coombs shows, and some authors say no, you have
to have the Coombs, so it is difficult to say what the end result should be.
DR.
NEWMAN: I agree. I think the data here are in the form mostly
of case reports. There are some studies
where here is a series of babies who had high bilirubin levels and what percent
got damaged, and clearly, those series of Rh babies in the '50s and the series
of G-6 PD deficient babies, another group that seemed to have a higher risk of
kernicterus in series at a lower bilirubin level.
The
other things are case reports and sort of informally looking at case reports
when you say here is a baby that looks like he or she might have kernicterus,
and the bilirubin level is only 28, and then you say, yes, but the baby had a
urinary tract infection or some other infection or something else that if you
look at the kernicterus cases where it occurred, say, at bilirubin levels less
than about 30 or 35, children with other problems are overrepresented. I think that is about the best I can do.
DR.
CHESNEY: Dr. Luban.
DR.
LUBAN: I think we can't underestimate
the number of children that have G-6 PD deficiency or have G-6 PD deficiency
combined with sickle cell disease who are FS on screen, but eventually become
children with sickle cell disease at a rate of 1 out of 400 African-Americans,
and that is a group that I know we are not concentrating on with this data, but
we shouldn't underestimate.
DR.
CHESNEY: I have a question. Dr. Newman, I will address it to you, but
maybe other people know of. We keep
talking about hemolysis as being a high risk factor. Is there anything about the hemolytic process
per se as in liberation of lipid red cell envelopes that enhances blood-brain
barrier access for the bilirubin, do we know anything about that, are there any
animal models where lipids have been given along with the bilirubin?
I
realize this is a far-out thing, but we just sort of accept that hemolysis is
more likely to give it, and we assume it is because there is more bilirubin,
but I wonder if there isn't some other issue.
DR.
NEWMAN: I don't know the answer to that
because those are sorts of studies I don't have the expertise to evaluate very
well, the ones, you know, with animals, so I defer to any of the other people
here who know those studies better.
I
don't think it is clear why babies with hemolysis are at higher risk, but part
of it is, you know, they were born in the 1950s. Mostly now, I mean our data is coming from
the 1950s. Many of them, labor was
induced, they were electively delivered prematurely.
You
know, there are so many things different between Rh babies in the 1950s and
babies now. We don't know what the risk
of kernicterus is with babies with severe arch disease or hemolysis now when
they get a very high bilirubin because we don't let them get a very high
bilirubin.
It
has become very, very hard to study.
Other people may know the animal data, I don't.
DR.
CHESNEY: Yes, Dr. Freeman.
DR.
FREEMAN: I am just revealing my
ignorance, but there is a recent paper out on bilirubin as a cytoprotective
agent, picking up as a scavenger molecule.
Is there any level of bilirubin in the newborn which is good?
DR.
CHESNEY: We were discussing that during
the break. It is sort of like
fever. I mean fever is actually a very
good thing. Maybe bilirubin is a
desirable thing in those infants who have lower levels.
Dr.
Stevenson, you were going to answer that.
DR.
STEVENSON: There is considerable data
that demonstrates conclusively that bilirubin is a naturally occurring
antioxidant. At levels that occur in
circulation after birth within what would be considered the physiologic range,
although we are still debating what that range might be, it will confer that
kind of protection.
You
can even thing about the teleology behind having a naked ape exposed to
sunlight and oxygen, having a naturally occurring antioxidant in circulation
temporarily while your other antioxidant systems up-regulate after birth.
One
of the comments that I will make later is that everything is dose dependent,
and if there is a level at which bilirubin is safe and may be essential, there
is also a level which bilirubin is toxic, there is no question about that from
the animal work. Clearly, from our
experience clinically, there are conditions in which bilirubin is associated
with injury, there is no doubt about that.
DR.
CHESNEY: Dr. Oh.
DR.
OH: I clearly agree with Dr. Stevenson
on that. My own gut feeling is that a
little bit of bilirubin may be okay as an antioxidant, but too much is bad I
think. That is my own feeling.
DR.
FREEMAN: What is that range, Bill?
DR.
OH: We don't know that. That is the question that we need to know.
DR.
CHESNEY: That is comparable to fever - a
little bit is good, too much is not so good.
Other
questions? Dr. Glodé.
DR.
GLODE: I had a question for Dr.
Newman. I realize that he was kind
enough to just share with us his preliminary information, but it was really a
comment and a question.
The
comment would go to potential bias in the study. You already brought up the issue that perhaps
the control families would be more likely to enroll although I think you could
also argue that the families of the children with the high bilirubin might bias
the study in favor of enrollment because they were concerned about neurologic
development.
But
my question refers to the one area, neurologic exam area, where it was
statistically significantly different in preliminary analysis, favoring the
children with the high bilirubin.
I
was just interested if you knew of those 86 children who had been enrolled at
least, could just give us some sense of the interventions that were done. Do you know what percent had phototherapy or
exchange or anything else?
DR.
NEWMAN: I know that for not the 60 who
have had exams, I showed data on, but
for the whole group of about 140 who had bilirubin levels over 25. I think four of them got exchange
transfusions, and all but one got phototherapy.
The one that didn't get phototherapy, you know, was like at 25.2, and
they repeated it the next day and it was lower.
So,
not very many exchange transfusions, a lot of phototherapy. In terms of the bias, you are right that
families of jaundiced babies who are worried about what effects it might have
had might be more likely to participate in the study.
I
am focusing on the other bias because that would bias us in the direction of
finding that jaundiced babies did worse, and since our trend is that they did a
little bit better, the concern I have is that the controls selectively enroll
who are more worried.
DR.
CHESNEY: Thank you.
We
have two presentations over the next hour.
The first is by Dr. Oh, who is a neonatologist and Chair of the
Department of Pediatrics at Brown Medical School. He is also the pediatrician and Chief at
Rhode Island Hospital, and the Sylvia K. Hassenfeld Professor of Pediatrics at
Brown.
He
will be discussing the safety and efficacy of phototherapy for treatment of
hyperbilirubinemia in the term and near-term infant.
Dr.
Oh.
Phototherapy
DR.
OH: Thank you very much, Dr. Chesney.
My
job is to review the intervention for hyperbilirubinemia, which is actually the
standard of care today, in the next 35, 40 minutes or so.
[Slide.]
What
I will do is just briefly discuss the historical event that led to the
introduction of the phototherapy for the treatment, spend some time on the
mechanism, in other words, how it works, and some data on the efficacy and
acute side effects, as well as some long-term outcome.
[Slide.]
The
first paper actually was published in 1958, in Lancet, by Cremer and others,
showing that when they exposed infant with jaundice to sunlight, it has a
reduction in serum bilirubin, and actually that was based in laboratory, in
vitro observation that when they exposed the serum to light, the bilirubin
level actually goes down.
So,
they used this in vitro experience to perform a clinical trial that shows that
in vivo, by sunlight, it also reduced the bilirubin, as well.
[Slide.]
Subsequent
to that report, there were several clinical studies including some that were
done here and some in South America in the '60s, which confirmed the efficacy
of phototherapy in lowering the serum bilirubin level, which then made
phototherapy a standard of care up to today.
There
is also some trials showing that the efficacy is somewhat more than the full
term in terms of the low birth weight infants, and the reason for that is
actually unclear.
[Slide.]
In
terms of mechanism, we know that it works on the basis that bilirubin absorbs
photon from the light at certain spectrum, light spectrum, which is at 400
nanometer in vitro. Following the
absorption of this photon, it results in a series of photochemical reaction
with the formation of three major products, and these are the isomeres that are
different physical properties that allow for elimination of the bilirubin
without going through the conjugation system in the liver.
[Slide.]
This
is the spectrum of the absorption spectrum for the bilirubin, which is
somewhere between 400 and 500, the peak being around 450.
[Slide.]
But
the in vivo absorption of spectrum light for bilirubin is actually a little
different from the in vitro, because the in vivo setting, the bilirubin is
bound to the albumin, and the albumin has some fatty acid that might change the
spectrum of maximum absorption from 450 to somewhere around 475, 480 nm.
That
explains some of the reason that the different kinds of light has variable
results when the infants are exposed to this light.
[Slide.]
This
is the series of photochemical reactions that are known to occur when the
bilirubin is exposed to light. When the
photon is absorbed by the bilirubin, it makes the bilirubin sort of excited. It excites the bilirubin, that then produce
photo-oxidation. That is one of the
byproducts.
It
also has a change in the structure in another reaction that will form
lumirubin, a substance called lumirubin, and then there is also a process
called configurational isomerization, in other words, the structure is not
changed, but the isomere was formed because the configure was changed, the
bilirubin structure was changed, forming three different photoisomeres - 4E,
15Z, 4Z, 15E and 4E, 15E, and I will get back to that in a minute in terms of
what those numerical numbers mean.
[Slide.]
One
of the interesting observations is that for 20 years or so, since Cremer's
report of the efficacy of light, of phototherapy introducing bilirubin, the
assumption was that the major mechanism was through photo-oxidation, and not
until the early '80s, when the other mechanism was discovered or described,
that people began to realize that it is not the photo-oxidation product that
accounts for the major route in the elimination of the bilirubin, but it is
rather the other two formation of the isomeres.
[Slide.]
One
of them is the change in configuration that I talked about earlier. This is a molecular structure of
bilirubin. On your left is the native
bilirubin. You will note that the carbon
4, the two double band bridging the two pyrroles on the left and on the right.
Just
look at the carbon 4 on your left, which is a Z, and the carbon 15, also Z, on
the right. What happens is that the
change in this particular model occurs in the carbon 15, so that the Z, the
double band, is rotated 180 degrees, allowing for the hydrogen ion to be
essentially "exteriorized," quote, unquote, that change the polarity
to make this molecule more water soluble than the native bilirubin.
The
water solubility or the less lipophilic characteristic of this molecule will
then allow for the particular product to be excreted through the bile and also
through the urine.
[Slide.]
Now,
this is a situation where the change is occurring in the structure itself, it
is not the configurational change. There
is an actual change in the structure.
Again, on the left is the native bilirubin. You notice the 4Z and 15Z bilirubin. In this particular case, the left pyrrole
ring, the structure is changed, so that again, the hydrogen ion is exteriorized
and allows for the bilirubin to become water soluble and be able to be
eliminated through the bile or through the kidney.
[Slide.]
The
major issue here is that the native bilirubin, the 4Z, 15Z is hydrophobic and
lipophilic, in other words, they are not water soluble, they cannot be
eliminated through the bile or through the kidney in the urine because of the
physical property of the molecule.
The
only way that the native bilirubin can be excreted or eliminated is by
conjugation in the liver with the glucuronyl-transferase, the enzyme
responsible for glucuronide of this particular bilirubin.
But
when the bilirubin is exposed to light, the isomeres are formed, and they are
less lipophilic and less hydrophobic, in other words, they are more water
soluble, and therefore, it enhances elimination through the bile and the urine.
[Slide.]
The
studies have shown that in terms of formation of this various product, the
formation of the 4Z, 15E isomere, meaning the one that occurred through
configurational isomerization, is greater than the structure change, the
lumirubin, and those, in turn, are much greater in amount than the
photo-oxidation products.
But
the important thing is that in terms of elimination, the rate of excretion is
far greater for the lumirubin than the photo isomere 4Z, 15E, and over the photo-oxidation
product, so that the rate-limiting process in terms of elimination is actually
the lumirubin and therefore it is very important to remember that lumirubin is
the key isomere in terms of the elimination of the bilirubin when they are
exposed to light.
One
other important phenomenon that one needs to keep in mind is that once the baby
is exposed to the light, the formation of the various isomeres is almost
instantaneous and they maintain a level that maintain a fairly good
steady-state in the bloodstream. The
rate-limiting state, as I said, is the elimination process, and that is what
takes time.
That
might explain some of the reason why the so-called continuous versus
intermittent phototherapy has no difference in terms of the ability to reduce
bilirubin, because the rate-limiting step is not the amount of lumirubin being
formed, but the way it is being eliminated through the kidney and through the
bile.
[Slide.]
This
cartoon summarizes what happened to the various products of the bilirubin. The ZZ that you see here is the native
bilirubin in the center. As you can see,
they are transported to the liver by binding to the albumin, and because of the
nature of this molecule being lipophilic and hydrophobic, they cannot be
eliminated unless it is conjugated by glucuronyl-transferase.
On
the other hand, when they are exposed to light, it forms the either ZE by
configurational change or lumirubin by a structural change that again are bound
to the albumin, and for the ZE, it gets excreted through bile into the
intestine, where then it's a reversible process, as well.
Once
it's in the dark, once it gets into the intestine, it reverts back to the
native bilirubin, ZZ, and recycle it to the blood.
On
the other hand, lumirubin, or LR, again is bound to the albumin, gets to the
liver, excreted through the bile into the intestine, and part of it is also
excreted through the kidney through urine, so there are two ways that lumirubin
can be excreted from the body, either through the bile into the intestine or
through the kidney through the urine.
The photo-oxidation product is primarily excreted through the kidney.
So,
I think we have a fairly good knowledge to date in terms of the mechanism of
how light works. It involves the
formation of the isomeres and the photo-oxidation product, but the major route
of excretion is through the formation of the lumirubin, the structural change,
and excreted through the bile and through the kidney.
[Slide.]
Now,
what are some of the factors that might affect the efficacy of
phototherapy? It all boils down to four
major factors. One is the type of light
used, either blue or green or white.
Those are the three major light sources that are used clinically
today. The light intensity itself, the
surface area of the skin exposed to the light, and then the distance of the
light to the baby.
So,
all of this boils down to the irradiance that the baby receives, and that
irradiance is dependent on the light intensity, the type of light used, the
surface area being exposed to, and the distance from the light to the
baby. Today, in clinical practice,
although we don't use equipment to measure irradiance in most cases, the ideal
setting will be to try and achieve an irradiance of approximately 15 to 20
microwatt per square centimeter per nanometer.
That
is the setting where the maximum degree of reduction of the bilirubin takes
place.
[Slide.]
Let
me just walk through a few types of phototherapy devices available clinically
today. One is generic fluorescent tubes,
which can come in three different kinds of light - daylight or white light,
which is the usual fluorescent light that you see in the household, a blue
light, and then the green light.
Then,
there is halogen lamps also used, fiberoptic system, and I will go through this
in detail, and then more recently, a gallium nitride light-emitting diodes has
also been developed and used clinically.
Again, as I said, I will go through each one of these in detail.
[Slide.]
Now,
in terms of the fluorescent light, this is a comparison study done by KL Tan in
Singapore, published in 1989, comparing the percent reduction in serum
bilirubin when the infant was exposed to either special blue or green light or
daylight.
What
he found is that the special blue is more effective in reducing the serum
bilirubin by about 33 percent compared to green and daylight, which is about 20
percent reduction over a period of time, or the duration of exposure are all
constant.
Now,
what he concluded was that it is preferable to use either daylight, because it
provides enhancement of clinical observation and adequate efficacy, or blue
light because it has a better efficacy, but the green light is not recommended
by him because it provides neither.
[Slide.]
I
have to make a note here in terms of what the blue and the green light ends up
with when you do a clinical care in this baby.
The blue light makes the baby cyanotic and the green light makes the
baby sort of, you know, somewhere between cyanotic and being under-perfused, so
it is very difficult for the nursing staff and the physician to evaluate these
babies when they are under blue or green light.
So,
today, in most settings, the white light is the most commonly used because it
produces efficacy very similar to the green light although less effective than
the blue light, but it has the advantage of a better clinical assessment
compared with the other two lights.
[Slide.]
The
halogen light, also called a spotlight, is advantageous in the sense that it is
more compact, but the problem is that you cannot bring it too close to the
baby. It has some significant amount of heat emitted that could sometimes burn
the infant if you get it too close.
[Slide.]
The
fiberoptic system, also called Wallaby light,
is essentially a blanket wrapping around the baby, also called a
Biliblanket. It has some advantages in
that you don't have to use eye patches since the eyes are not exposed to the
light. It is more portable, it is more
convenient for mother and baby in case the mom wants to breast-feed the infant,
it becomes more advantageous in the sense that you could simply have the
blanket wrapped around the baby, and the mom can continue to breast-feed the
infant while under phototherapy.
It
is also used quite often in the home phototherapy setting. The disadvantage is that it has much lower
spectral power.
[Slide.]
In
fact, the study by Dr. Gale and Holtrop comparing the fiberoptic versus
conventional, in this case they used halogen lamp as a conventional therapy,
showing that there is less decline in bilirubin. The yellows are fiberoptic and the black bar
are the conventional. You will see the
decline in serum bilirubin is much greater particularly in the Holtrop study,
which has a p-value of 0.05, in the conventional therapy versus fiberoptic
system.
So,
one of the disadvantages of the Wallaby is that because of the lower spectral
power, it has less efficacy in terms of reducing the serum bilirubin level.
[Slide.]
The
most recently developed system is called light emitting diodes, which employs a
narrow band of light spectrum, and the commercial company in this particular
setting used the blue-green combination.
It is power efficient is one of the advantages, and also has a low heat
emission, but the one disadvantage is the fact that it is a very eye-irritating
system. In fact, we just brought two of
them into the nursery recently, and I have already got nurses at my office door
saying take those away because it is very irritating for them to watch the baby
under this LED phototherapy light.
[Slide.]
This
is the light spectrum of LED, and as I said, the company that developed this
particular device used the blue-green spectral system.
[Slide.]
Again,
in terms of efficacy, this is the study by Seidman, published in Journal of
Pediatrics a couple of years ago, comparing the efficacy of LED versus halogen
lamp, and you will see that the yellow bars are the bilirubin level of entry,
the black bar is bilirubin level during the therapy, and you will see that
there is no difference in the decline of bilirubin between the two methods of
treating the baby.
[Slide.]
Now,
let me just say a few words about the different modes of phototherapy.
[Slide.]
One
is the continuous versus intermittent phototherapy. The reason why this was studied is the
attempt to demonstrate that there is no difference in the ability to reduce the
bilirubin level and allowing for the caretaker or the mothers to breast-feed
the infant on an off-phototherapy setting.
So,
this is a study by Caldera where they compared the percent reduction in serum
bilirubin of those that were treated with continuous phototherapy versus those
that were intermittently treated, two hours on, two hours off strategy, and
showed no difference in the ability of these two modes of therapy to reduce the
serum bilirubin level.
As
I said earlier, knowing the kinetics of how the bilirubin is excreted or
eliminated, the fact that the level of the various isomere goes up
instantaneously and maintains a steady state, and that the rate-limiting step
is the elimination phase, it is not a surprising finding that there is no
difference between continuous versus intermittent therapy.
[Slide.]
This
is another study by Rubaltelli and Lau showing that although the numbers were
small, there is no difference again in terms of the continuous versus
intermittent therapy. This is the basis
for our clinical practice of allowing mothers to feed infants on phototherapy
because the infant can be taken out of the crib or the isolette and be fed a
certain period of time, then go back to phototherapy setting.
[Slide.]
The
other mode of therapy that I would like to just touch on briefly is the
difference between single versus double phototherapy. This is three studies that are put together
in one graph, showing that the yellow bars are single phototherapy, and the
double phototherapy in black bars. You
will see that in all three studies, there is a significant difference in the
decline in serum bilirubin between single versus double phototherapy.
Again,
it is not surprising to see this in terms of a more effectiveness in terms of
double phototherapy because you increase the light exposure of this baby. This is actually the basis for the AAP
guideline calling for so-called intensive phototherapy. Essentially, it is recommending that if you
have a level in the high range, that the intensive phototherapy using either
double or some unit even used triple phototherapy, because of the greater
efficacy in the double bank or triple bank phototherapy setting.
[Slide.]
I
just have one slide on the home phototherapy.
I noticed someone is going to speak about this issue. For several years, the committee of the AAP
was very vague about whether home phototherapy is desirable or should be
recommended or not until the most recent guideline, which was just published a
few months ago.
This
is the statement set in that guideline that I essentially put together
here. It says that home phototherapy is
an acceptable alternative, but the institution for the home phototherapy
company should set up criteria for eligible infant that will be treated with
this mode of phototherapy, and that there should be an appropriate follow-up of
bilirubin levels.
This
is one issue that I think is important, and that is to make sure the serum
bilirubin level is done in the same institution, in the same laboratory to
maintain a good consistency, and that if the bilirubin level does not decline
appropriately, then, it should be admitted for more intensive therapy.
So,
the AAP has decided to endorse this particular mode of therapy, but has some
suggestion in terms of the guideline of how this particular mode of therapy be,
not regulated, but supervised by a person within the region.
[Slide.]
Now,
there are a number of side effects known of phototherapy. Many years ago I actually did a study using
fairly crude methodology to document that the insensible water loss is about 50
percent higher in the infants who receive phototherapy. It is probably related to the heat emitted by
the phototherapy and the increased respiratory rate, which is also a finding
that we documented in order to maintain heat balance. In fact, if heat balance is not maintained
appropriately, the infant may develop fever or elevation of body temperature.
There
is also some documentation that these infants may have loose or watery stool,
and that the mechanism is not clear, but this has been confirmed by a couple
other anecdotal studies showing that there is a change in the gastrointestinal
tract in terms of a more frequent and loose, watery stool when the infant is
under phototherapy.
I
should point out that although insensible water loss is an issue, and it has
been confirmed by two subsequent studies, Paul Wu and Ed Bell have confirmed
this observation, that it is probably more relevant in the low birth weight
infant because the insensible water loss is so high, the insensible water loss
is indirectly proportional to gestational age, so that an infant who is in the
26-, 28-week range, the insensible water loss can be three times higher than
the full-term infant, so the change in the 50 percent would need to be
accommodated in the fluid balance, otherwise, the infant may get dehydration.
But
in the term infant, the subject that we are talking about today, the insensible
water loss is much lower, it's in the range of 20 ml/kg/day, so if 50 percent
increase is 10 cc, all you need to do is make sure that the infant has enough
fluid intake to maintain water balance, so it is not a huge issue in the term
infant from this particular standpoint.
[Slide.]
Now,
there is also some concern about toxic effect on the optic nerve. This was demonstrated in animal study, but human study actually has not confirmed
this. There was one control trial
showing very elaborate visual assessment, infants who had received phototherapy
versus those who did not, and showing no difference in terms of the visual
performance, but since eye patch is such a benign, non-invasive procedure, our
current practice is still to use eye patch for babies under phototherapy.
[Slide.]
Just
a few words about low birth weight infants.
Although this is not the subject of our discussion for this particular
committee, I just wanted to point out the effect of phototherapy on low birth
weigh infants is probably more, to me, is more worrisome than the full term and
near-term infant.
The
NICHD study done in the early '80s suggest that there is a higher mortality
among the infants who are enrolled in the phototherapy group, and there is also
some suggestion that phototherapy may have some influence on the patent ductus
arteriosus, a common problem in the low birth weight infant, not in the full
term infant, and that there is some concern about association with increased
incidence of blindness due to retinopathy of prematurity.
Again,
these are all related to low birth weight infants, but let me show you a couple
of slides on the second and third bullets here.
[Slide.]
This
is a study by Warren Rosenfeld showing that the infants--these are low birth
weight infants who were subjected to phototherapy--the incident patent ductus
arteriosus is lower when they shielded the chest with aluminum foil,
essentially, that is what they did, compared to those that were not shielded.
They
didn't quite explain why, the increased incidence of patent ductus arteriosus
was not as clear as it should be. Also,
the other problem of this particular study is that this is not a blinded study,
obviously, because they had to put the aluminum foil on the baby's chest. Also, the assessment of the PDA was not done
by echo in those days, it was done primarily by clinical assessment, and that
may have some bias involved in terms of documenting the incidence of PDA.
This
had never been confirmed one way or the other, so this remains a question. To me, it is not as serious as it seems to
be. Also, we now have a very good way of
treating these infants using the indomethacin in terms of PDAs. It is not a concern in terms of morbidity.
[Slide.]
There
is also some concern about the effect of phototherapy on blindness due to ROP, retinopathy
of prematurity, and this is the data from Yeo, published in Pediatrics about
three years ago, showing that the OR, the odd ratio for greater incidence of
blindness due to ROP is 4.48 with a p-value of 0.03 when the peak serum
bilirubin level is less than 160 micromole/liter, and that the same thing is
true for the duration of phototherapy.
So,
what they are saying here is that if you are aggressively treating these
infants, these are very low birth weight infants, with a longer duration of
phototherapy and bring the bilirubin down to a lower level, you have a higher
incidence of blindness due to ROP.
[Slide.]
The
problem with this data is that it is a retrospective analysis, this is a small
sample size, relatively small sample size, and that the eye exam was not done
uniformly. Again, the results have not
been confirmed. So, this is some lingering concern that people have in the low
birth weight infants from the standpoint of phototherapy itself.
[Slide.]
Briefly,
it is very difficult to assess the effect of phototherapy per se on
neurodevelopmental outcome because you always have the co-morbidity of
bilirubin. You use phototherapy only for
bilirubin, so there is no way you could compare the phototherapy in itself in
terms of outcome because by virtue of the use of this intervention, you use it
when the bilirubin is high, so you need to be able to separate out the effect
of bilirubin versus the effect of phototherapy itself.
Let
me just show you a study that Dr. Scheidt did in 1990 using the cohort from the
1980s NICHD trial where they enrolled a group of infants into the group that
received phototherapy when a certain level of bilirubin is reached and those
that were not treated with phototherapy.
[Slide.]
What
they found is that at one year, the MDI and PDI scores were similar between the
two groups. These are all full term
infants.
[Slide.]
Then,
when they assessed the six-year-old outcome, they combined both pre- and
full-term infants, again, it shows no difference in terms of the verbal
performance between the two groups at six years of age.
[Slide.]
Again,
in the low birth weight infants under 2 kilograms, they did a separate
analysis, and again showing no difference between phototherapy and the control
group in both one- and six-years of age in terms of neurological finding--they
were using cerebral palsy as the endpoint--and in developmental performance.
Now,
as I said, it is not clear whether this is truly a negative outcome from the
standpoint of phototherapy itself because you have so many confounding
variables particularly with respect to the low birth weight infants. Many of
these infants are sick, they have a certain bilirubin label, and we don't know
what the bilirubin level dictates, I mean dictate the neurodevelopment outcome,
in a much larger study, it is very difficult to assess the phototherapy itself
with reference to the population that receive this treatment because of
hyperbilirubinemia.
[Slide.]
So,
my summary is as follows. Phototherapy,
there is no question it is an effective treatment for jaundice. There is so many data over the last 40, 45
years, showing that it is an effective intervention and that the mechanism is
well defined. There is no question about
how it works.
There
are some acute effects that are known, and if you are talking about full term
infants, it is a manageable problem, in other words, the increased insensible
water loss, the watery stool, and the increased respiratory rate, those are
minor, to me, a minor effect that could be managed without significant concern.
At
least in term infants, at least in that one study, there is no real significant
adverse outcome in term infants. I went
through the Medline and I couldn't find any long-term follow-up. It is amazing, in a therapy that has been
on-board now for almost 45 years or 50 years, and yet I didn't see any
clear-cut outcome study comparing directly phototherapy versus no phototherapy.
But
I need to point out, in the last bullet, that there are some lingering concerns
about low birth weight infants because I think, not only that there are some
concerns about a PDA, the blindness, and the one set of data which I did not
present today because it really pertained more to the low birth weight infant
is the data I just put together, will be published in Pediatrics sometime in
the next few months, documenting the association between relatively low levels
of bilirubin in extremely low birth weight infants--I am talking about infants
below 1,000 grams--between serum bilirubin, much lower level than we are
talking about with a two-year-old neurodevelopmental outcome.
There
is significant association. The higher
the bilirubin is, there is almost a linear relationship between serum bilirubin
and the number of infants with neurodevelopmental impairment including hearing
loss. So, there is some concern about
low birth weight infants, but probably not in the full term infant. That is my conclusion.
Thank
you very much.
DR.
CHESNEY: Thank you, Dr. Oh.
We
do have a few minutes if anybody has questions for Dr. Oh before we have our
last presentation.
Dr.
Freeman.
DR.
FREEMAN: Bill, when you measure
bilirubin, do you also include the measurement of biliverdin? I mean are they separable by the standard
techniques that we talked about earlier?
DR.
OH: No, I think it is bilirubin that we
are measuring although, yes, biliverdin is not measured, it is bilirubin
primarily.
DR.
FREEMAN: Okay, but biliverdin doesn't
show up in those--
DR.
STEVENSON: No, it doesn't.
DR.
FREEMAN: The second question is do we
know anything about the neurotoxicity of biliverdin?
DR.
OH: I don't think we know. Do you?
DR.
FREEMAN: No.
DR.
OH: I don't think we know. If you don't measure it, we wouldn't know
what the effect that molecule would be.
DR.
CHESNEY: Dr. Newman, you had a question?
DR.
NEWMAN: You didn't present any data on
this, but from my own experience, I am probably one of the few general
pediatricians here. To kind of paint a picture of what phototherapy is like,
some of the problems with it that you didn't mention are that a lot of the
babies just don't like it because they are unwrapped, they have to be unwrapped
and many babies are much more calm if they are wrapped up, often this involves,
you know, the baby is in an isolette or away from the mom, and unwrapped, which
they don't like, so they start crying, but you can't pick them up and comfort
them because they are under phototherapy.
Then,
the mothers start crying, and, you know, the mothers, they are three or four or
five days post partum, it doesn't take very much to make them cry, and it is a
very--I think hospital phototherapy, that aspect of it, which is that it is
upsetting, I would just add that to what you mentioned about physiologic
effects.
DR.
OH: California may be different, but I
don't see that often in my nursery.
DR.
CHESNEY: It is clearly a California
phenomenon.
Dr.
Stevenson.
DR.
STEVENSON: Well, being from California
where it is always sunny, we don't have to worry about jaundice that much. One of the comments I wanted to make in
response to what Bill said is that light, it is a drug in the way that it is
being used for this purpose, and yet it has not been really handled in the way
that we handle evaluations for particular drug applications.
In
other words, there are dose ranges recommended, but no one is really
monitoring, as Bill mentioned, the doses that are being applied, so given all
the different light sources and all the different ways in which they can be
applied in the nurseries, the range of doses is considerable, and it is hard to
know what, in fact, is happening in those environments related to this
particular medicine, and much more can be done in that regard.
I
know that is not the topic of this group's concern right now either, but the
other thing I would like to mention from work that we have done, we have
published it in the abstract form, but not published the paper yet, is that
clearly, with the cool white lights, in applications in the range that we would
expose human neonates to, you can see photo-oxidation in translucent small
animals.
The
expectation is that in translucent human beings like these small infants that
Bill was talking about, they also would probably be accessible to that light,
and there could be, in fact, photo-oxidation going on in those infants
independent of the predominant pathways that have been described biochemically,
that is, the generation of lumirubin in that mechanism.
So,
I think there is considerable concern about the use of light as a medicine
particularly in the smaller infants, and it probably has some impact on the
larger infants which is just not measurable with current technology.
To
give you a hint about the patent ductus, again, this would be a hypothesis, but
we know from the work that we have done that one of the potential alternative
sources of CO, carbon monoxide, is, in fact, photo-oxidation. That has been confirmed in the absence of
heme.
So,
if you apply light to small translucent animals, you can generate carbon
monoxide, not only at the surface level of skin, but probably in tissues, in
sufficient amounts that you could actually influence the vascular behavior of a
vascular tissue. CO works through the
same pathways.
So,
that is a hypothesis, but it shows you that light, in fact, does have an impact
and probably needs to be considered is not entirely understood with respect to
all of its effects in certain categories of infants.
DR.
CHESNEY: Very interesting. Any other questions?
All
right. We will move on to our last
speaker before lunch. Connie Schomann is
a nurse supervisor with the Medstar Visiting Nurses Association, and she is
going to demonstrate for us how phototherapy is administered in the home, and
she will review how home visiting nurses instruct parents in the proper use of
this therapy.
Outpatient Phototherapy
MS.
SCHOMANN: Good morning. My name is Connie. I am a registered nurse with Medstar and I
have been doing pediatric home care for seven years now. A large part of our pediatric population
consists of babies that are being followed for hyperbili.
Occasionally,
we get babies that are discharged from the hospital with phototherapy. Maybe they have had phototherapy for a couple
days and they are sent home with a blanket to continue their therapy at home,
but the greatest portion of them are babies that were discharged from the
hospital between 24 and 48 hours of age without any evidence of significant
jaundice and the jaundice is picked up after they were home.
It
might have been an initial pediatric visit, maybe if they had risk factors and
the doctor wanted to see them in a day or two, and then they would pick up the
jaundice, or maybe when the visiting nurse would go for an early maternity
discharge visit, I know in Maryland, a lot of insurers provide for a home
health visit from a nurse their first day or two at home, and we pretty often
pick up jaundice at that time.
The
important thing here I think is that most parents do not recognize jaundice in
their infant unless they have experienced it before. I had had parents tell me, oh, gee, I just
thought he had a little suntan going, thought he had good color.
I
have walked into some homes and could tell from across the room that the baby
was jaundiced and started thinking about where is the closest STAT lab, and the
parents didn't have a clue. So, you
can't always depend on their assessment of the baby's skin color because they
just don't have the experience with that.
So,
typically, what happens once the baby gets a blood level drawn for serum
bilirubin, it might have been at the doctor's office or in a morning visit,
hopefully, in the morning. It takes
several hours before the report comes back from the lab, and a decision might
be made that the baby needs phototherapy at home.
Then,
you have to contact the DME company, sometimes several of them, to find an
available blanket, and you also have to talk to the insurance company and get
authorization for the home phototherapy, so it can be day long process just
getting this started.
It
usually ends up with a phototherapy blanket being delivered to the home 9:00,
10 o'clock at night, so the parents are generally exhausted anyway.
Most
companies--this blanket here came from Medstar Medical Services--most companies
manage their Wallaby equipment or phototherapy equipment along with their
oxygen supplies and equipment, so that the delivery to the home is actually
made by a respiratory therapist, who will give the parents some instruction on
how to set up the blanket and then leave them on their own for overnight until
the visiting nurse arrives in the morning.
I
have Baby Billy here. I had a little
girl who very willingly let me borrow her baby for demonstration purposes. He is kind of small, he is not very
jaundiced, but he is a very willing participant, and he doesn't complain too
much, so I will show you how it gets set up and what some of the limitations
are.
There
are some limitations and problems with phototherapy in the home, but generally,
parents are very happy to learn that they can have this treatment at home and
not have to go back into the hospital.
That is not what they want to do and especially when they realize that
readmission to the hospital means the pediatric unit, and not that nice, big
family centered care room with the TV and the VCR and the separate sleeping
accommodations, but it might be a room for two with a lounger for mom to sleep
in or something like that. So, they are
very willing to do whatever it takes to be able to stay at home with their
baby.
When
they get the blanket delivered, this is what it looks like. This is called a blanket. It is not very soft, it is a little pliable,
but this is your fiberoptic pad and it's a light, a light source if it works,
the light comes right from this pad.
It
needs to be applied with the correct side to the baby. It needs to be applied to the baby's skin,
not on top of their clothing. It is
wrapped around the baby's middle, so that as much of the baby's abdomen is in
contact with the light.
They
send these pieces of tape that are absolutely worthless to tape it together, so
I usually tell parents to use masking tape, electrical type, or duct tape. Everybody has duct tape these days,
right? It works very well to help hold these
in place. They tape it around the baby
with just enough space that the fingers can go in, so that it is not too tight
and constricting.
The
baby needs to be dressed over top of that. Normally, you wouldn't turn the
light on until they were dressed, which means that a T-shirt can over top or
they can be wrapped in their blanket.
The
fiberoptic pad itself does not produce heat, it is cool, so that parents need
to be instructed that they still need to dress their babies or they are going
to get cold if they don't dress them appropriately.
Once
they are wrapped, then, you have your baby receiving phototherapy. It looks pretty easy, right? But this baby is tethered to this machine, it
is not very portable. The directions
will tell you it needs to stay on a firm, flat surface, so you have got this
much room to move.
It
can be awkward, if the mom is learning how to breast-feed, she is not very good
at it, and then all of a sudden she has got all this to deal with, too. It makes it a little bit more difficult.
Basically,
they are just tethered to one spot for a few days. I usually instruct parents to expect three to
five days of phototherapy in the home.
It does take a little bit longer than when they are in a hospital under
lights. That way, if it's less than five
days, they are happy.
Basically,
that's it. Then, when the nurse arrives
the next morning, her visits consists of head to toe assessment, she weighs the
baby, and the biggest part about assessment has to do with feeding issues. As Dr. Oh talked about, a lot of these babies
are breast-fed, and when the nurse gets in there and assesses the baby, may
find out that the baby has lost a lot of weight, maybe 10 percent or more.
If
the baby's urine output is not very good, maybe the baby hasn't had any stools
since they have been home or last stool was still meconium, then, feeding
issues have to be addressed. So, a lot
of times the pediatrician will order supplementation with formula or even
withholding breast-feeding for 24 hours and using formula instead.
It
sounds really easy, but when you have a mom who has been prepping herself for
breast-feeding her baby for the last six months, and you tell her to stop, that
can be pretty upsetting. It also can be
difficult for them to manage because they are usually not prepared for formula.
Lactation
consultants, they do a great job in the hospital preparing their patients, but
one of the implementations that they have made in recent years is they have
stopped giving formula samples to breast-feeding mothers because they feel that
it encourages them or sets them up for failure, "Here, you are going to
need this when you can't breast-feed."
So,
they no longer send this home with them, so that means that somebody has got to
go out and get formula for the baby, they have got to get bottles for the baby.
They have got to figure out how to make the formula.
Then,
on top of all that, the mother has got to get a breast pump and hook herself up
to another machine for 24 hours, every two to three hours, to maintain her milk
supply So, the visiting nurse plays a
very large role in helping the parents with that process, to get through that,
so they can maintain good lactation and meet their goals with the baby, and
continue to care for their baby at home.
Generally,
they are very successful. Occasionally,
a baby will turn around and have to be admitted because the bilirubin is just
not responding. Usually, it's because of ABO or some other factor, but for the
most part, we have very successful outcomes with this, but a major part of that
success, it's not just the machine.
I
think, if I can put in a plug for visiting nurses, the support and teaching and
education that the nurses provide are really a major factor in the success of
this treatment.
Thank
you very much for having me.
DR.
CHESNEY: Thank you.
MS.
SCHOMANN: Any questions?
DR.
CHESNEY: Dr. Fost.
DR.
FOST: I am trying to get a ballpark idea
of the total annual cost of home and hospital phototherapy. Can anyone tell me what a typical charge for
hospital/home phototherapy is, and the approximate number of babies a year that
get phototherapy.
MS.
SCHOMANN: I can tell you that this
machine, the rental costs about $100 a day.
The visiting nurse, the initial visit for my company is $150 for the
initial visit and then $115 for revisits.
They usually do visit on a daily basis.
And then the lab costs. The
nurses usually draw a lab each time and transport it. There is usually STAT fees at the outpatient
lab, usually run around 35 to $40 for a total bilirubin.
DR.
FOST: Does anyone have an estimate of
the total number of babies a year?
DR.
NEWMAN: For hospital phototherapy, it is
a few percent, it varies a lot from place to place, but I don't know for home
phototherapy.
DR.
FOST: So, like 3 percent of 4 million,
so 120,000 a year roughly.
DR.
NEWMAN: Yes. It might be higher than that. It is 2 percent
at Kaiser, but they do I think quite a bit less phototherapy maybe than some
other places.
DR.
FOST: And the charge for a hospital's
phototherapy?
DR.
NEWMAN: Figure a few thousand dollars a
day, a couple of thousand dollars a day probably. But at least when we do a hospital
phototherapy, it is short, it is about a
day. We use three lights, we figure just
get it over with quick, so it is typically about a day. It is much shorter in the hospital, it is not
three to five days. It is usually a day
or two in the hospital.
DR.
FOST: Thank you.
DR.
CHESNEY: Dr. Nelson.
DR.
NELSON: I guess this is for Dr. Oh.
Have
there been any studies on the intermittent versus continuous issue using the
home blanket phototherapy?
DR.
OH: I was going to comment that I am not
aware of--the studies that have been done were all using the fluorescent lamp,
the white lamp--I am not aware of any comparative study between the Biliblanket
with intermittent versus continuous exposure.
It
is probably not an issue because as she demonstrated, the mom can breast-feed
the baby, so there is no need to discontinue the phototherapy.
DR.
NELSON: Well, there may not be a need, but from the
inconvenience I suspect that intermittent therapy is probably the norm.
DR.
OH: I suspect if somebody does a
comparative study, it will probably show the same result as the others, I mean the principle is the same. The mechanism of excretion and the
elimination is very similar.
DR.
CHESNEY: Dr. Stevenson and then Dr.
Ebert.
DR.
STEVENSON: The mechanism is the same,
but I think one of the points that Bill made would make you suspect that the
differences would hardly be noticeable, the reason being is the dose that you
are receiving is quite limited, so it is not a very potent way to treat
hyperbilirubinemia.
So,
most of us who believe that phototherapy is required as an intervention would
be more inclined to use it intensively in the rating flux range where you are
going to have demonstrated efficacy.
The
difficulty here is not so much that fiberoptic blankets can't generate an
intense light, it's the surface area of application, which you could see is
quite limited, and if you think about the total surface area, you are only
dealing with part of it, so you are going to have a very limited impact on the
person.
Also,
you say, well, why not get a longer and more convenient tether, but then you
are farther from your light source and once again you are going to lose your
power, so there is a limit to how long that tether can be, and there is also a
limit with respect to surface area as to how you can actually apply it.
So,
there is going to be not much advantage or difference between either having it
on or having it off, and that leads some people to say if you need
phototherapy, use phototherapy and not home phototherapy.
I
am not being critical of these options.
These are only the only technical options right now available in a
uniform way.
DR.
CHESNEY: Dr. Oh, could you clarify for
the uninitiated, when you talk about double and triple therapy, is that two and
three banks of lights or two or three colors?
DR.
OH: Double is typically what you do is
you have an overhead and then you put two side, you know, sort of exposing the
baby to three. Is that what you do in
California?
DR.
NEWMAN: We just use the halogen
spotlight. It makes a circle of light on
the baby, and the more of them you have, the more of the baby's surface area
you can get covered by one of those circles from the spotlight.
DR.
OH: There are many ways you could do it,
but we use overhead and two sides, and sometimes one over one side and one
spotlight, so any combination would work fine.
DR.
CHESNEY: I read somewhere about having
the baby lie on this kind of bed and the do it over. Would that be called double?
DR.
NEWMAN: We typically will have a blanket
underneath the baby and two spotlights up above.
DR.
CHESNEY: Triple?
DR.
NEWMAN: We call that triple, yes.
DR.
OH: The problem with the blanket and
then the light is that you already covered the surface, so the light on the top
is not going to work. You know what I
mean?
DR.
NEWMAN: We have the blanket. The baby is lying flat on top of the blanket.
DR.
CHESNEY: Dr. Stevenson.
DR.
STEVENSON: One quick comment. You can begin to see the complexity of the
application of this medicine. You can imagine the shadowing with numbers of
halogen lamps and also these different devices.
So,
if you look critically at the light exposure and the shadowing on a particular
infant when people are doing their intensive phototherapy, tremendous variation
across the surface of the individual and differences between institutions in
terms of where the lights are relative to the individual.
So,
dose is very hard to control unless you are measuring precisely, and then it is
only good for where you measure it.
DR.
CHESNEY: Dr. Nelson.
DR.
NELSON: Just a follow-up question. Have there been no head-to-head comparisons
controlled for starting bilirubin level in the absence of any other condition
that would increase production of looking at in-hospital intensive phototherapy
short of duration against home less intense, longer duration, had there been
any head-to-head comparison at all?
DR.
OH: I don't think so. That would be a good study to look at, I mean
a good issue to address, home versus hospital setting. I had the same kind of strategy in our place,
and I don't use home phototherapy a lot.
Once the kid needs the phototherapy, they get admitted for phototherapy,
very intense, and they stay one to two days and go home.
DR.
CHESNEY: Dr. Oh, would you comment on
the rebound? I think I read in our
materials that there has been a question of rebound in bilirubin. If you do just a one day intense, do you get
any rebound or more than you might with a prolonged?
DR.
OH: Typically, what we do with the
rebound issue is once we stop the phototherapy, we generally keep the baby in
the hospital for another 6 hours and do a rebound bilirubin, and if that
doesn't go up, then, we send the kid home, or if there is a good follow-up
system, we would do a rebound 12 hours, 24 hours later.
DR.
CHESNEY: How significant is the rebound?
DR.
OH: Actually, not very much. Most of the kids will be down to between 12
to 15, 10 to 15, and then once you get the rebound, to maybe 15's. Usually, the age also is much older and we
have less concern on the kid who is two days old versus 6 days old.
So,
even if the kid rebound to the 15's, we are not as concerned as if it were to
be two days old.
DR.
CHESNEY: Is doing a rebound level
standard of care?
DR.
OH: I don't think so. David?
DR.
CHESNEY: Dr. Stevenson.
DR.
STEVENSON: Just Maisels has actually
done recent work on this and made the case that for the otherwise well term
infant who has this application, it is not required because it's such an
infrequent event.
The
one caveat that I would suggest is that if you have a hemolytic condition where
you need to reduce the pigment at a very high rate, it's in those contexts
where you might see a rebound if your conjugating capacity is not
improved. That is typically what you
see.
If
you make the mistake of doing an exchange transfusion on a child who has been
breast-feeding, that is really the cause of their jaundice, you will not see
any rebound whatsoever. If you do an
exchange transfusion on a baby that has
been producing bilirubin at a high rate with this large amount, not only in
circulation, but also in the body, you will see a rebound that can be quite
dramatic in that context.
So,
I would say in the context of increased production, you are more likely to have
a rebound, but for the general population that is not hemolyzing, which is most
everybody, then, it should not be a problem.
DR.
CHESNEY: Thank you.
It's
12:15 and I am collecting a list here if any of you would like to add to it of
interesting phrases, so this morning we have "weller" babies and we
have "excited" bilirubin, and we have another use for duct tape.
I
think we could break for lunch now and if everybody could please be back at 1
o'clock, we are going to hear from the mother of a child who has kernicterus on
behalf of her organization.
Thank
you.
[Whereupon,
at 12:20 p.m., the proceedings were recessed, to be resumed at 1:00 p.m.]
A F T E R N O O N P RO C E
E D I N G S
[1:00 p.m.]
DR.
CHESNEY: Our first speaker this
afternoon is Sue Sheridan, who is president of PICK, the Parents of Infants and
Children with Kernicterus. Susan is the
current president and the co-founder of PICK.
She is going to present the perspectives of her organization and of a
parent of a child with kernicterus. I
understand she is going to have a short video, as well as a PowerPoint
presentation.
A Parent's Perspective
MS.
SHERIDAN: Thank you. I am David Stevenson. I am glad to see you made it back because I
notice you have 45 minutes, and I have 20, so I would like to ask if I could
borrow 5 minutes of yours. Thank you.
Also,
Tom Perez, when I was coming up here, asked me if I was nervous about today,
and typically, I really don't get nervous when I speak about this because I am
so passionate about preventing kernicterus, but if I am nervous today, it is
because I want to make a difference, I want every word that I say today to
influence you on helping prevent kernicterus.
I
am very grateful and honored to be included in this and to be quite honest, I
am relieved that this dialogue is taking place today. I have been following this debate for almost
a decade.
I
look at kernicterus and, well, the prevention of kernicterus as actually a
patient safety initiative rather than how to manage jaundice. I am passionate about patient safety, not
only because my little boy suffered brain damage from kernicterus, but I also
lost a husband last year because of a medical error.
He
had a cancer that was diagnosed properly as a sarcoma, but it was communicated
to us as a benign tumor, so while the pathology was lost for six months in the
mail, the tumor grew into my husband's spine and it eventually killed him.
So,
I hope that my words today can reorient you to a patient safety focus because
there are a lot of things that we can do to prevent harm to babies and daddies.
As
you know, my name is Susan Sheridan. I
am from Eagle, Idaho. I have two
children. My little girl McKenzie, is 5. She had severe hyperbilirubinemia from AO
incompatibility. She got a TSB, she was
tested, she was diagnosed, she was treated, and she is fine today.
I
have a little boy Cal, Cal Patrick, who is 8.
He was born a well baby--somebody asked a question about well
baby--almost 38 weeks gestation. He was
visually assessed at 16 hours to be jaundiced, at 23 hours to be jaundiced, at
33 hours to be jaundiced with no TSB taken.
He was discharged head-to-toe jaundice, no TSB with the words that
jaundice is normal, don't worry, put him in the sunlight if you are worried
about it.
I
took Cal back two days later to the pediatrician. He was becoming lethargic and his suck became
weak with breast-feeding. I took him to
the pediatrician. He was board
certified, he's an AAP fellow, was familiar with the AAP guidelines. He sent us home to wait 24 hours.
Again,
no worry, no indication that anything abnormal was going on. Well, we chose not to wait those 24 hours
because our son was deteriorating, and we took him to the hospital. When Cal was admitted, his bilirubin was
34.6.
Again,
there was no concern. We were told that
kernicterus did not happen anymore in the United States, and they chose not to
do a blood exchange transfusion because he was close enough to 30, they
recalled, which was the new benchmark that the AAP had indicated for an
exchange transfusion. This was their
interpretation of the AAP guidelines.
So,
we watched Cal. Twenty-four hours after
readmitting Cal--and this was a hospital that delivers 5,500 babies a year,
this is a JCAHO-accredited, Level 3 NICU hospital, so this was not a country
hospital--we sat there for 24 hours. At
24 hours, Cal began arching his neck backwards, and he developed a high-pitch
cry that sounded kind of like a cat, it was very disturbing.
I
indicated to the doctor something was happening to my son, and the nurses of 20
years experience on the pediatric floor, neurologists, ENT, and pediatrician,
we all watched Cal suffer brain damage before our eyes, and we didn't know it. Nobody knew that these were the classic
indications, these are the classic symptoms of the onset of bilirubin
encephalopathy.
They
used phototherapy, a double phototherapy for Cal's treatment, and it failed
him. Like 25 other babies in the pilot
registry that I think Tom was talking about earlier today, Cal has kernicterus.
Actually,
Cal likes to be a part of my presentation sometimes and he was helping me
prepare a presentation a couple weeks ago, and he knew his sister when she was
born, when she had severe hyperbilirubinemia and was treated, and he asked me,
"Mom, why doesn't McKenzie have kernicterus?"
I
thought that was an excellent question, and that is precisely why I am here
today. I am also here today, as they
mentioned, as co-founder and president of PICK.
PICK stands for Parents of Infants and Children with Kernicterus.
We
formed about two and a half years ago, right after I was invited to testify at
the AHRQ First National Summit on Patient Safety and Medical Errors. My son Cal was highlighted in a USA Today
feature article, and then that day I received all day phone calls from parents
throughout the United States.
So,
we got together and we formed PICK, and PICK's mission is to eradicate this
preventable devastating condition by partnering with the healthcare system, by
implementing a universal systems-based approach. We believe that by implementing a universal
bilirubin screen with the use of the Bhutani nomogram, we can significantly
reduce kernicterus.
To
demonstrate our partnership, PICK's partnership, I want to show you a video
that we produced just this past January with a generous grant from Partnership
for Patient Safety. This will show eight
moms who have children with kernicterus, two kids with kernicterus are on this
tape, and then what we refer to as our dream team. These are all the government agencies that
have joined PICK, partnered with PICK, to eradicate this condition.
[Videotape
shown]
MS.
SHERIDAN: In preparing my remarks for
today, I was inspired by the mission of the Health and Human Services
Department, which reads, "To protect the health of all Americans and
provide essential human services especially for those who are least able to
help themselves."
I
think newborns would fall under that category.
Much
of the debate today has been about prevalence on kernicterus, and I guess it
all depends on perspective - is the glass half empty or is the glass half full.
Frankly,
the answer to what is the prevalence of kernicterus is we have no idea how much
kernicterus is out there. Anybody who is
guessing is doing just that, you are guessing.
We know of 125 children in the pilot kernicterus registry that has been
shared voluntarily by doctors, families, and attorneys.
That
is like I think Tom said the tip of the iceberg. These are kids that are so severely affected
that they are hard to miss although my son wasn't diagnosed until he was 18
months old because either the doctors wouldn't or they couldn't. It's a tough diagnosis to give.
But,
you know, I was actually somewhat disturbed that in the binder, it referenced
prevalence at 1 in 250,000 because that is a guess. What about the rest of the kids in that
spectrum? No one will argue with me that
when there is any kind of disorder, you have got the very severe down to the
very mild. We are not capturing the rest
of that population. We have got the very
severe in this pilot registry.
But
even if we accept the guess at 1 in 250,000, I ask you, is that
acceptable? You know, I ask you, what is
rare, what is rare? It is not acceptable
in other industries. It compares to the
number of children that choke and died on toys in 1998. Twelve kids died because of choking on
toys. Yet, millions of dollars were
spent on recalls, labeling, and the reengineering of toys because of those deaths.
It
compares to the number of children that died annually from strangulation from
venetian blinds, yet 800 million of those were recalled because of that.
There
was a popular toy made by Playschool that was called the Klackeroo. I actually saw a big poster in my
pediatrician's office about the recall, how dangerous this was for children,
that we call this 1-800 and we could get reimbursed for this toy, so I called
the number, and it was the National Product Safety Commission.
I
asked about the history of this toy, and there was a web site for me to go to,
everything about this Klackeroo, millions were being recalled, and I asked
about the deaths and injuries. They had
12 reported complaints from parents, no deaths, on injuries, 2 pieces were
found in babies' mouths.
So,
12 in the other industries is intolerable.
Millions of dollars are spent to protect our babies. Why are our babies and our children safer in
other industries than they are in the healthcare industry? It doesn't make sense to me.
So,
when we talk about rare, even though 1 in 250,000 kids, I think it tragically
underestimated. In other industries, it
would be outrageous.
Action
by our regulatory agencies, the FDA, the National Consumer Product Safety
Commission, their actions, their bans, and even their fines on industry is not
due to prevalence, it is due to the perceived risk. It is due to the potential harm to Americans.
So,
nobody knows the prevalence, but let's, instead of trying to make the number 1
in 500,000, 1 in 700,000, why aren't we looking at the other way around?
Instead of saying of those 125 kids in the pilot registry, you know, some of
them may not be, well, some of them may be, and what about these other kids
that have mild auditory neuropathy and mild cerebral palsy, instead of saying
well, it is probably not due to kernicterus, why don't we turn that around and
say, gosh, that could be due to kernicterus, and the reason is because
bilirubin is a toxin.
Bilirubin,
like Tom said, is a brain poison. It's a
naturally occurring neurotoxin. Sure,
there might be some antioxidant benefit, but, you know, a glass of red wine to
end the day is also good for you, but two bottles a day is too much. So, you know, bilirubin hurts babies.
This
morning I heard the AHRQ evidence-based report, and I read that report, and
something in that report, it talks about that the preponderance of kernicterus
cases occurred in infants with serum bilirubin levels over 20. This is evidence. This was in the AHRQ report.
Yet,
the AAP recommends exchange transfusion at 25 and even 30. I must ask this committee, why is the
healthcare system complacent about the dangers of hyperbilirubinemia, the documented dangers of
a neurotoxin? How can we knowingly and willingly take these babies into a known
and documented danger zone?
And
like it was expressed earlier, how do we know what the long-term effects of
this exposure of hyperbilirubinemia is now that kids in the 1990s to present,
they have been exposed to hyperbilirubinemia at higher levels for longer
periods of time? We do not know the
effect of this on their long-term development.
As
a matter of fact, I feel that Cal, Cal was born in '95, the AAP guidelines came
out in '94, the kinder, gentler approach, and, of course, the AAP had no
intention of the reemergence of kernicterus.
But
how did this complacency, how did this complacency happen, and now, from this,
I have always felt that Cal was an in an undisclosed clinical trial, nobody
knew what was going to happen to our children with these longer duration and
higher bilirubin values.
I
don't believe there is evidence of safety at the level of 25 and 30. Sure, some kids don't get kernicterus, but
there are a lot of kids who do get kernicterus.
As
a mom, the complacency about hyperbilirubinemia is very concerning. In comparison, other toxins, such as lead,
get a lot of attention, financial support, and vigilance.
I
looked at the comparison with lead because I wanted to see what industry does
with other toxins. They are both not
good for children, they are preventable types of brain damage, and there is no
known threshold for the toxic effects of either.
Right
now in the United States, it is estimated that 800,000 children have elevated,
what they call BLLs, blood lead levels over 10 mg/dl. By contrast, 2.3 million children develop
elevated bilirubin levels each year, and 1 in 700 develop bilirubin over 25,
which is well into the danger zone.
There
has been 1 death from lead poisoning in the past decade. That was issued in a MMWR put out by the CDC.
There have been 6 documented deaths that we know of from kernicterus. As we know, they don't do routine autopsies
on newborns, so we don't really know the full number, but we do know that 6
have died in that same period of time.
So,
why is it more important to focus on lead, and not kernicterus? I think we need to raise the level of
awareness on the toxicity of kernicterus, it hurts babies. Also, the CDC has
announced or they have determined that BLLs over 80 can cause hearing loss and
brain damage.
So,
as a response to that, the HHS's Healthy People 2010 Initiative has set a
national goal of eliminating BLLs in excess of 10, a level far below the danger
zone.
This
illustrates the need to institute a goal for eliminating bilirubin levels over
20 when exchange transfusions and vigilance in testing were used and kept
bilirubins below 20 historically, kernicterus effectively disappeared.
I
want to tell you a little bit about my son Cal. He is a bright and happy little
boy. He loves Pokemon. He loves playing with his sister. When asked what he would like to do when he
grows up, his answer is to be the best daddy in the whole wide world.
He
also aspires to be a film maker. Sadly,
however, Cal is trapped in a body that simply doesn't work. He has athetoid
cerebral palsy. He has uncontrolled
movements of his arms and legs. He can't
walk. His speech is very impaired. He has neurosensory hearing loss. His eyes crossed when he was 10 months old
that were surgically repaired. His front
teeth have enamel dysplasia problems. He drools. When he gets sick, he is reduced to the
functional level of a 6-month-old.
Cal
can't go potty by himself. He is not
invited to birthday parties. He can't
tie his shoes. As a matter of fact, I
don't think he can even itch his head.
I
have titled my presentation Warning, Bilirubin is a Toxin: Who is Keeping
Newborns Safe From the Hazards of Jaundice?
I chose this title because, like the visiting nurse was saying, parents
have no clue that bilirubin is a toxin and that parents are totally unaware
that this could hurt their baby.
When
we get a toy, when we get a package, when we get wrapping paper, when we get
tape, when we get household products, when we get shampoo, they all say
warning, this could harm your baby. Why
babies don't come with this warning tattooed on them?
I
ask you who is going to keep our babies safe from the neurotoxic effects of
jaundice. I am afraid that the answer
right now is nobody.
I
mentioned that after the AHRQ testimony, USA Today did an article on primarily
my son, but how two medical errors had affected our family. It was that day that I was called by several
families throughout the United States thinking they had the only child with kernicterus. As a matter of fact, I got a call from a
daddy from a NICU in Alabama. It was
9:00 a.m. in the morning, I had just got this paper out, and his daughter was
in the NICU with a bilirubin of 33.
USA
Today got such read response that they issued this within 10 days, and they
interviewed other moms about their children and their brain injury. As a matter of fact, the day that this came out in USA Today, 6 of
us moms were on a plane headed to Chicago to meet each other, and we actually
attended an AAP preconference workshop on hyperbilirubinemia and kernicterus.
When
we were there, we decided this was an emergency. We met two other families with children with
kernicterus while we were there. So, we
formed PICK, Parents of Infants and Children with Kernicterus.
We
recruited the nation's top bilirubin researchers. We developed a mission objective, a timeline.
We actually kind of launched it like you would a small business. This is our web site which is being updated
actually today. That film that you saw
will be on our web site. There is going
to be an interactive nomogram and stories about children who suffer brain
damage from kernicterus.
We
hosted the first parent health care workshop that some of you in this room were
at. The moms invited all of the HHS
agencies that we could think of along with researchers, Boston Children's
Hospital, Harvard School of Public Health.
We showed them the problem. We
showed them videos of our kids and their medical records.
We
proposed a solution by the researchers, that was a universal systemwide
approach to make sure all babies received the same level of safety. We thought by the implementation of a
universal bilirubin screen, the use of the nomogram was the first step.
The
Joint Commission within two months issued a sentinel of an alert. USA Today again issued another article. CDC, a month after the Joint Commission
issued their alert, issued an MMWR on the return of kernicterus, and the
National Quality Forum, if you are familiar with them, they issued a list of 27
adverse outcomes that should never happen in the United States, and PICK
campaigned for kernicterus being one of them, and it is the only pediatric
issue that made the list. They defined
kernicterus as damage from bilirubin or bilirubins above 30.
The
Boston Globe covered this, as well, and several other periodicals and magazines
and newspapers.
I
wish I could tell you that Cal's story is unique. I wish I could tell you that he has the only
case of kernicterus in the United States, but the tragedy is that Cal's story
is not, as you know.
When
I met the moms all in Chicago when we formed PICK, we realized that our stories
were all the same. Our newborns left the
hospital well babies without a bilirubin test, just like 80 percent of the
babies in the pilot registry.
We
were told not to worry, we were told that this was normal. The parent education consisted of a handout
put in the diaper bag. All of our
children of the original six PICK moms were born in large, accredited
JCAHO-accredited hospitals with NICUs.
Most of the pediatricians that managed our children's bilirubin were AAP
fellow and board certified.
The
moms that I know, we all questioned our babies' symptoms - the lethargy, the
poor suck. We even took our babies to
pediatricians and to the hospital. We categorized unfortunately as
over-concerned first-time mothers.
I
am going to go off on a tangent because people earlier were asking question
about cost-benefit, and I want to share some numbers with you. When we met with the government agencies, we
did our own analysis, and actually we did an analysis on the cost-benefit of
testing all babies, doing a bilirubin test that costs around a dollar. It may
vary per institution.
The
cost of kernicterus is staggering, as you heard. My son's life care plan--and this is without
fluff--this is without powered chairs and remodeling my home to accommodate
these, is $10 million, and that is because my son needs attendant care. All of these kids will need attendant care
for their lifetime.
In
1998 dollars, for attendant care for a certified nurse assistant, that was $7
million right there. Now, some of those kids you saw up there are on feeding
tubes, they are on baclofen pumps. They
aspirate, they have to be suctioned.
They are on massive doses of drugs. They need R.N. care, and those kids'
life care plans are $25 million.
The
cost of phototherapy to our nation, if you go to the AHRQ Hospital Care
Utilization Project, HCUP, or is it the Health Care Utilization Project, they
can give rough numbers. It is not
perfect data. But the amount is what is
billed to patients. Phototherapy, they
showed I think it was '98 or '99 numbers, around 100,000 kids, primary
diagnosis, this is primary diagnosis, so other kids are coming in septic or
other problems, primary diagnosis was hyperbilirubinemia, around 100,000 kids
at a cost of approximately $700 million a year.
That is not cheap.
Our
children, the public school system, Cal, in Idaho, instead of $50,000 for his
education for 12 years, will cost the education program half a million. So, you can do the math, because they have to
use special bus transportation, special ed., physical ed., there is therapists,
assessments, they are very expensive children. As a matter of fact, they rate,
I think the highest that the CDC does on the economic burden of disability, our
kids are the most expensive.
You
saw the partnerships that we have formed.
NIH, March of Dimes, Healthy Mothers, Healthy Babies have joined
us. Of course, our mission is to prevent
kernicterus. In analyzing and just
knowing all the moms and kids with kernicterus, we are concerned that this is
not going to disappear with the status quo.
The
AAP still recommends visual assessment of jaundice. This is guesswork. And their guidelines unfortunately are not
followed. I mean Tom mentioned that
study he did I think on phototherapy, that of the kids that the AAP recommended
phototherapy, 55 percent didn't even get it.
So,
although the guidelines went through a very long thought process, pediatricians
simply do not follow them, and to change doctor behavior will take decades.
Bilirubins are not routinely taken.
Neonatal blood type and Coombs are no longer done or they are no longer
the standard of care.
Home
Health, to be honest, is disappearing because of financial constraints. Timely post-discharge follow-up doesn't
happen in the real world, and kernicterus cases are not being reported because
of gag clauses, like it was alluded earlier that kernicterus unfortunately ends
up in litigation, and parents and doctors are gagged quite often to come to a
settlement.
Our
littlest citizens are being harmed by the subjective and unscientific approach
to jaundice management. Guesswork must be eliminated. Our systems-based approach must be
implemented. Right now in the United States,
any newborn is still at risk of developing kernicterus. Newborns are not safe.
Who
is responsible for that? Nothing has
happened since my son was injured. A
reporter asked me, well, what did I expect.
I expected all hospitals to stop everything they did, implement a
universal screen, implement something like an aircraft would do if a 12-inch
screw was found faulty, they ground all planes, they change it, the public is
safe. Eight years later, nothing has
happened.
All
50 states routinely screen for PKU and hypothyroidism. Babies are screened now for their hearing.
Why aren't we screening babies, why isn't there a universal screen for
bilirubin? How many tests must be done
to prevent that one case of kernicterus as some of the data showed? I think it's a disturbing way to look at how
we need to prevent kernicterus, to be honest.
All of them is the answer. We
need to screen all of them.
I
recently read an article in Public Health entitled "A Conversation on
Medical Injury." It said that to trigger
the level of reform that is so clearly mandated here, we cannot rely on the
healthcare professional or stakeholder organizations. We, the public, must demand it.
As
parents of infants and children with kernicterus, we accept this
responsibility. We accept this
responsibility to partner with you and to trigger the reforms necessary to
eradicate this. We ask the same of you.
We,
the parents, unite to prevent kernicterus.
We unite to demand national implementation of effective understand
management standards, policies, and interventions to prevent what has happened
to our babies, and we unite for a call
to action to keep our newborns safe from the toxic hazards of bilirubin.
I
am going to start showing you a list of children in the pilot kernicterus
registry. They are not anecdotes, they
are our children. I cannot say with any
certainty how many more suffer in darkness because their condition was never
diagnosed.
I
speak for the parents of the 125 identified in the pilot registry at
Pennsylvania Hospital. I speak for the
parents of the countless children who have remained undiagnosed and for parents
of unborn infants who will soon be diagnosed with kernicterus, but most of all,
I speak for the children with kernicterus, who are prisoners of their disabled
bodies and cannot speak.
As
you deliberate tomorrow, I hope you will be inspired by the mission of HHS,
particularly the part about protecting those unable to protect themselves. You and your sister agencies have a
remarkable history of protecting children from other hazardous products and
substances.
The
time has come to apply that same commitment to protecting our babies from the
hazards of jaundice. As you read this
list, I appeal to you please do not attempt to minimize the occurrence of
kernicterus. We do not know.
Please
do not attempt to minimize the human devastation or the financial impact that
kernicterus has on babies, families, and society. Please provide the same level of safety and
protection that you would with other toxins and hazardous substances and commit
to putting kernicterus back in the history book where it belongs.
I
challenge you to ask yourself when you meet tomorrow would you allow your own
newborn's bilirubin to exceed 20?
Tomorrow will be a big day. You
will be making significant choices regarding jaundice management. I ask that you put the newborns' safety at
the top of your list, dismissing the status quo, personal agendas, professional
aspirations, and cost-cutting mandates from employers.
Statistically
speaking, what is statistically significant when it comes to a human life? What is more important than the safety of a
newborn?
I
close my remarks with a reflection of the wisdom of a child. But who knows you have the power to protect
others, he said, quite simply, like you saw on the film, prevent this. I have to tell you that I was there during
the filming, and the producers simply asked Jess if he had anything to say to
the world, what would you say, and that was his remark. It was totally unsolicited, totally
unplanned, but straight from his heart.
So,
in looking at these names and these numbers, or not the names, numbers, I ask
you how many more names do we need before we take immediate sweeping dramatic
action.
Thank
you.
DR.
CHESNEY: Thank you very, very much. You made many, many points for all of us to
consider and reconsider.
Our
next speaker is Dr. Marshallyn Yeargin-Allsop, who is a medical epidemiologist
with the Center on Birth Defects and Developmental Disabilities at the
CDC. She is going to describe for us the
CDC's kernicterus surveillance activities.
Kernicterus Surveillance
DR.
YEARGIN-ALLSOP: Thank you very much for
the opportunity to update you on CDC's activities in the area of kernicterus
surveillance. I have heard Sue speak a
number of times, and she is a tough act to follow.
[Slide.]
I
would like to just present an overview, a framework, a public health framework
for developmental disability surveillance because surveillance of kernicterus
is put into that framework of what we do in the area of developmental
disabilities.
The
first step in this process for us is to develop population-based surveillance
systems, and the purpose of those systems is to monitor prevalence rates,
trends, and prevention programs.
The
surveillance systems can also provide a registry of cases, and these cases can
be used for the purposes of service provision or provision of treatment. The
cases from the surveillance system can be used, as well, to create
epidemiologic studies, studies where the cases are compared to non-affected
children or controls in order to identify risk and protective factors and the
results from the epidemiologic studies can address public concerns.
An
example would be looking at whether there is an association between maternal
smoking and mental retardation or cognitive impairment in the children.
The
third step in this process is to design prevention programs, and these programs
promote health education and prevention strategies and also inform public
policy.
[Slide.]
I
like to compare the complexities of surveillance of kernicterus with the
complexities of surveillance of developmental disabilities, and we have about a
20-year history at CDC beginning in the early '80s. We were looking at the establishment of
surveillance for a number of developmental disabilities, so based on our
20-year experience, we think that we can speak well to the complexities, as
well as the challenges of developmental disability surveillance.
The
first point is our surveillance is based on outcomes that describe functioning
in children. However the case
definitions and the conditions are attributable to an impairment in physical,
cognitive, speech or language, psychological or self-care areas. So, we have this comparison of functioning
with a level of impairment.
The
second point related to the complexity is measurement issues. For example, we look at surveillance of
mental retardation, and our case definition for mental retardation is an IQ
test score based on a standardized test.
Now,
that is objective criteria that we used, but we also do surveillance for
autism, and when we look at autism, we are looking at a range of behaviors, so
we have more subjective criteria that may be implemented in order to look at
surveillance of autism. The behaviors
are based on the DSM-IV criteria from the American Psychiatric Association.
So,
the point is that measurement issues are not straightforward when we are
looking at outcomes related to developmental disabilities.
Our
surveillance in metropolitan Atlanta is population based, and we have tried to
implement this in other areas of the country, as well. That means that we define a geographic area
and we try to count every case within that geographic area.
Although
there may be some limitations of that, we feel that our population-based
surveillance has been informative, such as the prevalence rates of autism that
we just reported, and it is viewed as a landmark study because we don't have
any other population-based data from the United States.
In
summary, all of these issues can make generalizing results from our
population-based surveillance system difficult or impossible to interpret, so
we always issue some caution we are trying to generalize from limited
population-based data to say national figures related to prevalence.
[Slide.]
Let's
look at the complexities of kernicterus surveillance and how they might be
similar to surveillance for developmental disabilities. Kernicterus presents as a range of impairment
and associated conditions. Kernicterus
is defined as brain damage that is associated with athetoid CP, hearing loss,
vision impairment, dental dysplasia, and sometimes mental retardation.
As
we have heard and as we are probably aware, there have been changes in the
level of awareness and the use of the diagnosis over time. We believe that some of the younger
physicians may not have ever seen a case of kernicterus and may not be aware of
the dangers of high levels of bilirubin in terms of causing brain damage.
There
is also variability in how cases of kernicterus are diagnosed. We don't have a gold standard in terms of the
number of physical findings or the number of behaviors, the number and the
pattern that are necessary to establish a diagnosis of kernicterus, and that
means a clinical diagnosis of kernicterus.
Of
course, there is early onset, but often the diagnosis is delayed because these
features appear over time.
[Slide.]
From
a historical perspective, there has never been any systematic population-based
surveillance of kernicterus in place to monitor kernicterus or
hyperbilirubinemia. Sue said it
best. We don't know the prevalence of
kernicterus in this country.
We
do have some case reports from convenience samples or select populations, such
as from select hospitals, self-reported cases.
We have information from medical insurance records, but these do not
represent a systematic approach to looking at the prevalence, and there is no
accepted standard for surveillance definition, such as what would the cutoff be
for surveillance of kernicterus.
[Slide.]
Therefore,
a true population estimates are not known to date. We do have I believe now it is more than 100
cases reported from 1984 to I think January of 2002, and these are case reports
from a convenience sample. They have
been very informative. These are
numerators, they do not have denominators because these are children of
different ages from different geographic areas, and therefore, we can't really
attach a rate to the cases that have been identified. So, we can't really answer the question of
whether kernicterus is on the rise.
[Slide.]
In
summary, we have issues related to the case definition of kernicterus. There is debate about what an appropriate
cutoff would be from an epidemiologic standpoint. It is a low prevalence condition, however, it
would require a substantial population in order to detect cases.
There
is a lack of recognition because it's an acute event with specific features,
but the permanent damage and the long-term clinical features do not appear
until sometimes even years after the insult, and also the litigation may be a
possible deterrent for clinicians identifying cases.
[Slide.]
So,
what has CDC done in this area? Well, as
Sue pointed out, there was a call to action from PICK. In early 2001, there was a meeting and CDC
was invited to participate, and we became aware of the problem of the
reemergence of kernicterus.
When
we left the meeting, we thought that we could go back and establish the
prevalence of kernicterus looking at some existing datasets. So, our first look was looking at the
national hospital discharge data, and we looked at years 1989 to 1997, and
although there were many children with codes of hyperbilirubinemia, there was
no way to distinguish between those children who had severe hyperbilirubinemia
from those milder cases. We also found
that kernicterus codes were not readily used in that we found no cases of
kernicterus when we did our initial look at data from the national hospital
discharge data.
We
have an existing surveillance system in metropolitan Atlanta. It's the Metropolitan Atlanta Developmental
Disabilities Surveillance Program. We
looked at our data, and we looked at cases of athetoid CP. I think we identified eight cases, and none
of them seemed to have an association with high bilirubin levels from our
record review.
We
explored the opportunity to make kernicterus a reportable condition. We found out it is the Council of State and
Territorial Epidemiologists that is responsible at the state public health
level for determining what conditions are reported to CDC and therefore that we
get national data.
We
think that maybe our approach to them was a little premature because we didn't
have a case definition, so since there is not agreement among the experts as to
what an appropriate cutoff would be for reporting cases, we were not able to
make kernicterus a reportable condition, and that is something we hope to do in
the future.
Our
last attempt was to go to an organization of managed care organizations and to
say that if we developed a cooperative agreement, perhaps some of the HMOs
would be interested in looking at the rate of kernicterus within those
HMOs. I will just say that there was a
limited interest.
[Slide.]
But
the good news is we have a mechanism at CDC that allows for extramural
opportunities for research, and through that announcement last year, we are
able to look at kernicterus in two areas of the country.
The
objectives of the announcement were that: applicants should seek to review cases
of extreme jaundice in otherwise healthy full-term infants; provide a body of
evidence to inform why cases of extreme jaundice may lead to kernicterus and
why kernicterus may be re-emerging; to provide a forum of concerned scientists
and healthcare professionals to convene and develop a strategic plan for a
national kernicterus prevention program.
[Slide.]
Our
awards went to the University of Medicine and Dentistry in New Jersey, the
Robert Wood Johnson Medical School, and their objectives are to look at infant
mortality and morbidity related to kernicterus, to design a surveillance system
for kernicterus, to identify risk factors for kernicterus using a case control
methodology, and using this to focus on early identification and management of
hyperbilirubinemia, and to provide a support network for families affected by
kernicterus.
[Slide.]
To
date, they have submitted requests for IRB approval for their activities. There has been initial discussion and a
process for population-based surveillance with the New Jersey Department of
Health, and they have analyzed some data on infant morbidity and mortality due
to kernicterus.
They
are allowing me to share with you some preliminary results from their look at
kernicterus morbidity. They used New
Jersey hospital discharge data for 1992 to 2001. They identified 82 cases of kernicterus. The denominator is the entire State of New
Jersey, so this is population based, and their rate is 7.5 per 100,000 live
births. That is their cumulative
incidence.
They
noted that there was significant variation by race and ethnicity with the
lowest rate being among Hispanics and the highest rate among Asians.
[Slide.]
Our
second award went to Pennsylvania Hospital, the University of Pennsylvania, and
they are partnering with PICK, and their objectives are to establish
surveillance, and their surveillance activity is related to analysis of the
pilot study data that you have all heard a lot about today, to identify risk
factors for kernicterus, to establish a Prevention Task Force or Steering
Committee that would advise on the management of hyperbilirubinemia and to
launch a national prevention campaign.
[Slide.]
To
date, Pennsylvania Hospital has had a teleconference of their Advisory
Board. They met along with our other
grantee and with CDC to begin to develop a consensus on the definition of
kernicterus for public health purposes.
They
are current establishing the database that would allow them to systematically
report results from the pilot study, and with PICK, they have collaborated on
the educational video, and you saw part of the video just a few minutes ago.
[Slide.]
In
terms of future direction from the CDC perspective, we are always looking to
partner with others in our goal on elimination of kernicterus and raising
awareness of this as a public health problem.
We
are planning a forum for developing consensus on a surveillance case
definition, and the goal of that is to identify a mechanism for
population-based surveillance at the state level, as well as at the national
level.
[Slide.]
I
would like to thank Dr. Rachel Afgen, who is our point of contact for our
kernicterus activities at CDC, for our collaborative partners, as well as our
other partners, and for all of the children and families that have been
affected by kernicterus.
Thank
you.
DR.
CHESNEY: Thank you very much.
Our
next speaker is Dr. David Stevenson, who is the Harold Faber Professor of
Pediatrics and Senior Associate Dean for Academic Affairs at Stanford
University Medical School. He is going
to review for us the metabolism of bilirubin and the metalloporphyrin heme
oxygenase inhibitor drug class.
Metalloporphyrin Heme Oxygenase
Inhibitors
DR.
STEVENSON: Thank you very much.
It
is a pleasure to address you, a little bit different than the last two
presentations, but hopefully, this will add to the information that will be of
use to people this afternoon and tomorrow.
[Slide.]
Let
me begin by giving a quick primer on neonatal jaundice. This is a favorite slide of mine and some of
my colleagues in the room have seen this many times, but it is a very useful
way to begin this kind of discussion.
Neonatal
jaundice can be understood by analogy to a sink. If you let the processes of bilirubin
production be represented by the turned on spigot and the processes of
bilirubin elimination be represented by the drain, then, you can understand the
problem of transitional jaundice as a problem of an imbalance, and if the rate
at which bilirubin is produced exceeds the rate at which bilirubin is eliminated,
then, the level in the sink begins to rise.
This
is exactly what happens in period of time after birth. If there are relative increases in bilirubin
production or relative decreases in the ability to eliminate bilirubin, then,
you can exacerbate that normal transition, and it is just about that simple in
terms of the physiology although the biology is fairly complex controlling
these processes. So, neonatal jaundice
is a normal transitional phenomenon.
[Slide.]
The
turned-on spigot can be represented by this cartoon of the reactions that are
involved with heme catabolism. Some of
the most important early work on this biochemistry was done by individuals like
Dr. Kappas, many others before me.
But
this is a very ancient system in nature.
It is present in both plants and animals. It is a process which is probably essential
to life on this planet, that is, life making use of oxygen and exposed to
light.
It's
a two-step process. This is a cartoon
because there are many more oxidations and reductions that take place than
represented in this slide.
The
first step is the rate-limiting step in the process. It is catalyzed by heme oxygenase and
involves absolute requirements for oxygen and for NADPH, which is donated from
the cytochrome p450 system.
In
this first step, the alpha-methene bridge is broken, carbon monoxide, a trace
volatile molecule is produced equal molar amounts with biliverdin and iron, the
latter of which is recycled.
Biliverdin
is reduced in the cytosol. The other
reaction takes place at the microsomal level.
Biliverdin is reduced in the cytosol again with absolute requirements
for NADPH and biliverdin reductase to bilirubin, so there are actually equal
molar amounts of bilirubin and carbon monoxide which are produced.
Historically,
carbon monoxide and bilirubin have been thought of as waste products, but as it
turns out, every part of this reaction probably has some relevance in normal
biology, just to put it in context.
[Slide.]
The
point that I would like to make is that all substances are poisonous. Only the dose differentiates a poison from a
remedy, and we have had some of this discussion earlier today, but it is an
important point to make. It does not
lessen the importance of understanding, but a compound can be toxic under
certain conditions that we encounter clinically.
But
it is also important to remember that some of these compounds like carbon
monoxide, which I have used as you will see as an index for production of a
pigment because it is produced in equal molar amounts, bound to hemoglobin,
circulates in the bloodstream, and is continuously excreted in your breath, so
it is a window on endogenous CO production which mirrors bilirubin production.
We
have to remember that CO is also an important biological signaling molecule,
and a lot of people are now investigating its role in neurosciences and
vascular sciences.
[Slide.]
They
are doing that because of the fact that, just like NO, it can interact with
guanylyl cyclase and activate CGP to cyclic GMP and have a whole host of
important cellular functions.
The
relative potency of CO for doing that is much less, but the potential for the
body to make CO is much more, and I will make a comment about that later, as
well. So, even this part of the biological system is important to understand in
terms of the spigot which produces carbon monoxide, biliverdin, and then when
the second step goes to bilirubin.
Also,
it needs to be understood that carbon monoxide may be involved in the
inhibition of other enzymes with iron/sulfur centers, so its impact on other
aspects of metabolism needs to be understood, so even the CO that is produced
and is excreted at a cellular level, it may have a very important role
biologically, just like bilirubin which can serve as an antioxidant in the
intracellular environment may be involved with maintaining the redox state of
the cell and even in regulation of gene expression.
[Slide.]
So,
my world has gotten more complex. Most
people think of me in terms of bilirubin, but I have become increasingly
interested in carbon monoxide, and you will see the reason for making these
comments at the beginning because it has relevance to what I will be talking
about primarily, which will be the metalloporphyrins.
The
main reaction we have been talking about is this one right here, down in the
middle, where heme is catabolized by heme oxygenase. As you can see already there, there is an
indication that the metalloporphyrins have the potential for acting as
competitive inhibitors and can block that first step, thus putting our hand on
the handle of that biochemistry, and they can do that very efficaciously.
The
CO is produced, bound in blood, and then excreted in the breath, and you can
measure either as a continuous excretion rate or as an end-tidal carbon
monoxide concentration, corrected for the ambient exposure. This is all quantitative and mathematically
related, so they are good indices of what is going on.
But
you can see all the other possible sources. The two I will bring to your
attention, one is light, light actually can cause photo-oxidation as you have
heard, and one of the products is carbon monoxide. Also, lipid peroxidation is another source of
carbon monoxide. Both of these can occur
in the absence of heme. So, that would
be a confounding event for some of the things that I might be interested in
measuring in the newborn period.
[Slide.]
Fortunately,
the endogenous sources of CO are well understood, and this goes back many
years, and many people besides me have looked at this, but heme degradation in
the newborn period under most of the conditions that we encounter, particularly
in the kinds of babies we have been talking about today, most of the sources of
CO comes from heme degradation.
So,
from the senescent red cells, it is about 70 percent of that 86 percent, or
from ineffective erythropoiesis approaching 10 percent, then, other
hemoproteins around 21 percent.
You
can imagine what hemolysis does to these relative percentages, because if you
have an increased rate at which the red cell mass is breaking down, you will
have marked increases in bilirubin and carbon monoxide production. You can see that quite nicely.
There
are non-heme sources of carbon monoxide, as I mentioned, but they are not
really of great consequence for these estimates that we are making. Remember, the CO in the breath is an index of
bilirubin production, it is not a direct measure of the production because it
includes these other sources.
Lipid
peroxidation and photo-oxidation are variable in their contributions, but on
the average contribute roughly that amount, and they are really important in
conditions that we encounter in smaller infants where proportions might become
greater, and this would become a more important source to consider under those
circumstances.
We
were the first really to demonstrate those independent sources of CO in these
heme-free environments in vivo and in vitro.
[Slide.]
We
have been measuring carbon monoxide excretion rates in animals for literally
the last two and a half decades, and this shows you some of the systems that we
currently use for rats, mice, and monkeys, so we do larger animals, as well,
again mainly for the purpose of looking at bilirubin production under a variety
of conditions.
[Slide.]
This
is a typical diagram of a system that we would use. This is a rat in a collection system attached
to a reduction gas detector which can measure CO in parts per trillion, and
this technology actually allows us to adapt these measurements to development
of a new hemoxygenase assay which is now used by many people, a gas
chromatographic assay using that kind of detection system. Also, we can measure
over small numbers of cells and tissues, which allows us to extend the work
into those model systems, as well.
[Slide.]
We
will point out something which is important for the presentation this
afternoon. This is one of the earlier
experiments that I did literally almost 20 years ago. It is the percent recovery of injected heme
over time as carbon monoxide. Percent of
recovery of heme is along the y axis and the time is on the horizontal axis.
You
can see that when you give a known amount of heme as damaged red blood cells
and then sample the breath over an interval of time, which in this case was
about 8 to 12 hours, you can collect 100 percent of that heme as CO produced. This is the most valid and accurate way of
assessing in vivo hemolysis that exists.
This
is a little bit of history here. That
gap in the data is just because we used to have hand cranks and I had to run down
the hall to a bathroom, and I didn't get back in time for that crank. Now it is all automated, so we don't have to
worry about those kinds of things. But
this validated this approach in this system.
[Slide.]
We
also devised systems early on for studying human neonates. This is a big system for a baby, so babies
were in the same kind of systems as the smaller animals, and we were able to do
large numbers of studies. So, this is
the way the world has looked to me for over two decades.
This
world can be seen even before someone becomes jaundiced, and the points I will
make here are some important ones in the context of this discussion and about
the compounds that we are going to be talking about.
This
is the adult. This is the term
infant. This is the excretion rate of
carbon monoxide on a per kilogram basis.
You can see that all term babies on the average produce about 2 to 3
times as much bilirubin on a body weight basis compared to an adult.
So,
increased bilirubin production is in the background of all the different
patterns of jaundice that we see including pathologic jaundice in the newborn
period. That is an important concept to
remember.
It
doesn't mean that everybody who has increased production, relatively speaking,
is going to become jaundiced, in fact, many people are able to conjugate well,
so they avoid that circumstance. So, it
is not the best predictor, as you have heard Dr. Ip talk about when you use it
in isolation, but it is the best way to understand what is happening with respect
to an individual's biology.
This
is what a hematoma does, polycythemia, so a larger red cell mass breaking down
at a normal rate. Smaller preterm infants, they have shorter red cell life
spans and have increased production rates, so increased production is a part of
the near-term infant problem with jaundice.
Here is your infant of a diabetic mother. That is probably ineffective erythropoiesis
most of the time, sometimes polycythemia.
Here
is your ABO hemolytic disease and your Rh disease in which you see the most
brisk hemolysis.
So,
you can see all these things even before someone becomes jaundiced, usually by
about 12 hours of age with this current technology, or in a jaundiced infant,
you can know whether an increased production is a contributing cause to that
problem beyond what is normally the case in every baby.
[Slide.]
We
have simplified the technology and have shown that rather than having to do
things in those big chambers, which were quite cumbersome and had to have
drills to get the kids out and things like that, which was pretty challenging,
but you can now do automatic end-tidal sampling corrected for the ambient, and
you can see a very good correlation with the standard index, which is the
carboxyhemoglobin level measured by GC.
[Slide.]
This
just shows you in a recent publication that we did, and this a part of a
multinational, multiethnic study in which some people in here also
participated. This is what the
distribution of carbon monoxide production looks like as indexed by the level
in breath, so it is a mirror of bilirubin production, which is what you are
looking at, at about 30 hours plus or minus 6 hours.
You
can look at a group of individuals, and this included children with hemolytic
disease--there they are out there--you can identify the high producers of the
pigment quite easily. If you wanted to,
you could arbitrarily say, well, the part of the population that is of interest
to me, if they are having trouble with bilirubin, is the part of the population
that is, let's say, 3 standard deviations above the mean or something of that
sort, so you can actually look at production as a way of targeting your
population, but remembering that all babies have increased production to a
certain extent.
[Slide.]
Then,
you can look at this in the context of the nomogram that you have heard so much
about. We were recently looking at the
same multiethic, multinational study, and we have now learned that on the
average, since there is general impairment and conjugation in the period after
birth, that these percentiles in the nomogram are, in fact, informed in part by
production rates.
So,
if you look at the average end-tidal carbon monoxide concentrations in the
different percentiles, you will see that they go up as you go up in the
nomogram. The babies that we haven't
talked a lot about are the ones who are already outside the nomogram early on,
and they have increased production.
In
other children who are still within the nomogram and you have a hard time
figuring out what is going to happen with them, you can identify some of them
who may or may not have problems, but you will at least know who is hemolyzing,
and they will go out sometimes later.
Then,
you have kids who have normal production rates and tend to go out much later,
and those are your poor conjugators, those are your Gilberts and your G71R
mutations in the Japanese and other Asians.
So,
combining the information about production, which reflects what is happening
with the hemoxygenase in a person's body and the relative breakdown of heme,
with how a baby is actually performing with respect to that challenge, can
provide you with a lot of important information.
[Slide.]
That
is the background which establishes the rationale for what Dr. Kappas and Dr.
Drummond and Dr. Valaes, who helped him later in that series of investigations
ultimately involving human neonates, that was the rationale for getting a
handle on that spigot.
There
has been no question that over the last two decades with a tremendous amount of
systematic and exhaustive and very thoughtful work done at Rockefeller and also
over the same period of time after we were introduced to this area of
biochemistry at Stanford, we have been able to clearly establish the efficacy,
and much credit goes to Dr. Kappas and his group for making that original
observation and confirming it over many, many studies, in vitro animal studies
and ultimately human investigation.
What
you are doing when you block the step here is you are inhibiting the production
of carbon monoxide and bilirubin, and that is what we need to remember.
[Slide.]
If
efficacy is easy to establish, choosing the right drug has been a part of that
challenge. Of course, the choice has
been made, and it has been made for a lot of good reasons, and some of those,
Dr. Kappas and others may want to comment on.
It is clearly the most potent of the potential drugs, and thereby can
avoid perhaps many of the other potential side effects of these drugs by using
a much lower dose.
But
the thing to see here is there are many options. Most of these are inhibitors of hemoxygenase,
and they differ by virtue of their substitutions on the porphyrin macrocycle
and the different metals in that ring, and it is hard to predict how they are
going to behave with respect to their various properties, but without actually
evaluating each of them, there is no easy way to get a relationship between the
structure and their activity at least chemically.
[Slide.]
One
of the first things, of course, you have to ask, and I will just show this
again. The Rockefeller group showed
this, as well, and we did it after them.
This was cannulation of a bile duct in an infant treated with one of the
first drugs that was tried clinically, tin protoporphyrin, which was much less
potent than tin mesoporphyrin, and the thing that I have been asked over and
over again, and Dr. Kappas has probably been asked this, as well, don't you
just accumulate large amounts of heme.
What
happens is you convert to a circumstance where heme is excreted in bile in
approximate proportion to the degree of inhibition that you get, so you are not
going to accumulate heme in the body, at least in the aggregate.
There
may be transient elevations in specific tissues, but overall, this is not a
heme accumulation problem. This is, in
fact, a way to eliminate heme from the system and also iron if you were to give
dosing over a long period of time, but, of course, what is being proposed in
this circumstance is single, low-dose intervention, so iron loss would not be a
consequence of that kind of approach.
This
shows you how quantitative these kinds of approaches can be. It was done in a rat model in the system that
I showed you earlier. So, this can be
molar accounting for these two compounds.
[Slide.]
There
are some other effects of the metalloporphyrins. I am not going to review these in a lot of
detail, but I will mention them. We have
been able to show that some of these metalloporphyrins can inhibit lipid
peroxidation. Depending upon the dose,
many of them can inhibit nitric oxide synthase and cyclic guanylyl cyclase, but
if the dose is low enough for some of them, then, you can avoid that and they
can become much more selective with respect to their impact on hemoxygenase.
Photo-oxidation
has been something that has challenged all of us, and I think led to the
decision to use the more potent tin mesoporphyrin compound compared to the tin
protoporphyrin compound because you can get it down to a level where it will
not have those kinds of reactions or at least the chances for anything like
that happening will be minimized.
[Slide.]
So,
this is what we are talking about. A lot
of these porphyrins can be excited by light interacting with oxygen to generate
singlet oxygen, and singlet oxygen, of course, is very reactive. It can cause cytotoxicity and damaged cell
membranes. No one wants that to happen
in this circumstance. These compounds
can be used in other circumstances to take advantage of this part of their
electrical behavior.
[Slide.]
So,
we have established criteria for potential antihyperbilirubinemic drugs in this
class, and the approach that we have taken is that we can't fulfill all of
these, no drug does that, but the idea would be that you would identify a
compound with a biocompatible central metal, potent hemoxygenase inhibition,
that is the primary feature, negligible degradation, which sort of goes with
that, negligible photoreactivity, and negligible HO-1, which is the inducible
form, up-regulation of that gene.
[Slide.]
So,
our approach has been in a four-step approach. My intent here in this is not to
go over a lot of the systematic and exhaustive amounts of data that we have
produced for these many different compounds, but just to give you a sense of
how this approach is undertaken and then sort of give you a summary at the end
of where I think we are.
The
first is in vitro screening in two parts and then followed by in vivo
screening. So, the first part is really
the screening for HO inhibition, degradation to CO, that is, how do these things
serve at all as a substrate for the enzyme, which you would not expect if they
were good inhibitors since this is a competitive reaction, and then their
photoreactivity.
[Slide.]
So,
here is just an example of the kinds of data that we can get. Again, in some of these slides, the compounds
are not always the same because we were doing them in different batches, but
here is the natural substrate heme, and you can see the amount of HO activity
when you administer the substrate, and you can see that for tin mesoporphyrin
here, the second one in, it has marked inhibition.
This
is a single high dose, so you aren't able to discern among the different
compounds at a high dose like this. A
later part of the testing will allow you to look at a range of dosing, but just
to screen for their potential as inhibitors.
You
can see the naturally occurring zinc protoporphyrin, which is probably the
least potent of these compounds, but naturally occurring, and then another
example which we will track through in a few things, chromium mesoporphyrin,
because it has some interesting properties, but you can see that we can easily
see if they are serving as competitive inhibitors in this assay.
[Slide.]
We
can also then quickly look to see whether they can be degraded by the enzymatic
system, and again, these are slightly different metalloporphyrins, but some of
the same ones are included here, and you can see that we can quite definitively
demonstrate that they are not degraded, which means the ring is not broken and
the metal is not escaping.
[Slide.]
Then,
our photoreactivity determination is done using this assay. It uses cool white light at around 30
microwatts per centimeter. We take
advantage of the fact that carbon monoxide is a product of photo-oxidation and
we can actually look at the different metalloporphyrins in that context.
[Slide.]
The
system looks something like this with the vials being on top of that, and then
you can get a picture of how these compounds look.
[Slide.]
You
can see here now important features which were a challenge for the Rockefeller
group, but potency won out and they can avoid this kind of a problem. You can see the tremendous photoreactivity of
the tin compounds with zinc mesoporphyrin being in this assay, more
photoreactive, but the potency allows the drug to be used at such a very low
dose that in vivo, that is not going to be of any consequence.
In
this assay, zinc protoporphyrin also appears to have some photoreactivity in
vivo, that has not been demonstrated, but there are some compounds that appear
to be photo-inert, like the chromium compounds, for example.
[Slide.]
Here
is zinc bis glycol. This is a derivative
of the naturally occurring zinc protoporphyrin since it's a synthetic molecule,
and I show this just to show you how paying attention to these properties is
important for picking a drug.
This
is a very potent metalloporphyrin, as well, and like the tin compounds, it is
also photoreactive, and you can see that in this in vivo testing with different
concentrations of the drug exposed to light, you can see the mortality caused
by these exposures, and you will see at these lower levels, there is no
mortality whatsoever, then, there a sudden increase, and then over here on the
end, this is in the dark, so it is the light impacting the interaction of this
molecule in the presence of oxygen that can cause this kind of a problem.
This
compound can also be used in the less than 5 range, so you can avoid that kind
of toxicity in vivo. This compound has
not been used in humans and is still being investigated in animals, but it has
some other interesting properties, which I will mention at the end.
[Slide.]
The
second kind of testing is HO inhibition in a range of metalloporphyrins. Again, I know Dr. Kappas is going to say
something about the tin mesoporphyrin itself, so I will show you another one.
[Slide.]
This
is chromium protoporphyrin and chromium mesoporphyrin. You can see how in this assay, by looking at
different doses, we can characterize the relative inhibitory potency of these
compounds.
[Slide.]
We
can also look at the potency of their inhibition against the two isoforms. The HO-2 isoform is the constitutive form, is
not inducible by most of the ways in which we induce this enzyme, and then
HO-1, the one that would be regulated by exposure to heme, and things of that
sort.
You
can see that tin mesoporphyrin is the most potent compound for both HO-1 and
HO-2 inhibition, but there are some other ones that are right up near the
top. Just for people's information,
chromium mesoporphyrin and zinc bis glycol are very important inhibitors.
Then,
as you go down the list, they vary in their rankings depending upon the
compounds. You can see zinc
protoporphyrin, the naturally occurring metalloporphyrin, at the very
bottom. It still is an inhibitor, but it
is one of the least potent.
[Slide.]
The
next thing we do is we test them in vivo, and this is an example of those kinds
of experiments. This is the VeCO over
time, the control animals at the top, chromium protoporphyrin and chromium
mesoporphyrin. Both of these are done at
4 micromoles/kg, so very low dose, and you can see the relative increased
potency of the mesoporphyrin, chromium metalloporphyrin here to inhibit bilirubin
production as measured in the living animal.
So,
for each of the metalloporphyrins, you can do studies like this and see in vivo
that they are, in fact, doing what you want them to do. We also checked their tissues, and we can
confirm the patterns that we saw in vivo in the tissues.
You
can also do important things to look, like in this case, as it has been done by
Dr. Kappas at least for the tin compounds, we don't see any effect in brain, so
brain stays out of the circumstance here.
[Slide.]
The
last thing I want to show you is how we take it to monkeys. This was done for zinc protoporphyrin, which
is the first one we worked on, the least potent of the compounds. Monkeys are just like people, they have
relative increased production rates as babies.
That is in the left sort of bar graphs.
They have transient hyperbilirubinemia, and their hemoglobins are
roughly the same as the adults, they aren't quite so different as they are in
the human circumstance.
[Slide.]
This
is what their pattern looks like. It is
lower and it is shorter, but it is roughly the same kind of pattern, so they
are a good model. If you give them
undamaged red cells, you can look at a model which is almost identical to the
child with increased bilirubin production from hemolysis, and then see how
these compounds work.
[Slide.]
This
just shows you how the least potent compound works. This is carboxyhemoglobin, an index of
bilirubin production on the left, saline in the yellow, erythrocytes that are
damaged plus the solvent in the middle, and then erythrocytes plus the solvent
and then 40 micromoles of ZnPP, that is 10 times the dose you would have to use
compared to these more potent metalloporphyrins.
You
can see the marked reduction in bilirubin production.
[Slide.]
Then,
of course, bilirubin levels are not directly related to production rates, it
involves conjugation, so it is not exactly as dramatic, but you can still see
the overall impact on bilirubin in circulation in these animals in the
hemolytic condition, so it is almost exactly like you would be encountering in
the clinical circumstance.
So,
this is a very good model for what you get when you use a drug like this to
treat a human neonate who might have increased production of the pigment as a
cause of their jaundice.
So,
the efficacy has been very well established, and the potency of the current
drug that has been picked is well established and very good, and it can keep
you out of the range where it is going to cause other kinds of problems.
There
are other options, other follow-through drugs if people were interested in
developing such compounds.
[Slide.]
The
final thing that we do is we do in vivo side effect testing for HO-1 regulation
because we want to see if this impacts gene expression of hemoxygenase. Again, there are different ways to do this,
but we decided to take advantage of a new technology which is in vivo
bioluminescent imaging.
[Slide.]
Because
light penetrates tissue and it can come out of tissues, this is an example of
an internal light source, a firefly there on the right box in the upper part,
but you can also take a promoter of interest, in this case, it was the HO-1
promoter, and basically create a transgene, the HO-1 luciferase transgene, and
then under the right conditions have these animals report to you when their gene
expression occurs. So, you can see the
impact of these drugs on gene expression in living animals. It was one last check to look at safety
issues.
[Slide.]
The
way this works is you can either tag a cell or tag a gene, and you can image
them. You can digitize, quantify, and
archive, and people are using these kinds of things now for all kinds of
developmental biology. It is perfect for
gene expression, pick your gene of choice, and then build your transgene, build
your transgenic model, and you can then look at gene expression in real time
basically.
[Slide.]
The
way this works is you get a reference image grayscale, collect in low
light. You get a low light image with a
pseudocolor generated by your computer, collected in a dark box. You can superimpose them and you can see
where the light then emanates from the animal.
There are now benchtop animal imaging systems for that purpose.
We
use this system because I was interested in jaundice and the effect of these
metalloporphyrins on the system. I used
this system because there is tight regulation due to toxicity of carbon
monoxide, iron, and bilirubin, there is tissue-specific expression, it is
developmentally regulated, it is a key molecular target for therapy, and ex
vivo assays are slow and provide only a snapshot, so it's a better way to look
at the biology.
[Slide.]
We
built our HO-luc fusion and created our transgenic animals. This allows us then to also do an analysis of
about how, in fact, up-regulation occurs mechanistically. You can look at the different things that
might cause induction of that gene, and you can easily see your animals in
these systems.
[Slide.]
This
is from a homozygous mating. That is a
heterozygous mating. You can identify
your transgenic animals who make light in response to activation of their
hemoxygenase gene.
[Slide.]
Then,
we are able to study important phenomena like this one, this is an
example. HO-1 transcription early in
life in the brain. We can see that it
has a developmental pattern. That is
something important that we need to understand.
We need to make sure that medicines like this don't alter those patterns
in adverse ways.
We
can confirm these reporting systems, these optical reporting systems with more
traditional approaches looking at protein levels in the brain just to confirm
that that is happening. We can look at
any tissue. I am just giving brain as an
example here.
[Slide.]
Here
is where we use it to look at the metalloporphyrins. So, there is zinc metalloporphyrin, tin mesoporphyrin,
zinc bis glycol. You can see that there
are differences in the activation or up-regulation of the gene in response to
these compounds.
None
of them are persistent. The tin
mesoporphyrin response is slightly more protracted than, say, the naturally
occurring zinc protoporphyrin, probably because it is a more potent inhibitor,
but it is not protracted, and the zinc bis glycol has essentially no
perturbation whatsoever in this gene regulation. Just to give you some examples of how this
tool works for looking at the response of this.
[Slide.]
Using
this kind of technology, you can begin to see the differences in enhancer
involvement for that up-regulation, so you can see the differences between the
compounds. There is zinc protoporphyrin,
the naturally occurring one, which is distinct and very different from the
elements that are important for regulation of the gene in response to tin
mesoporphyrin. There is cadmium chloride
on the right side as sort of a positive control.
So,
the gene activation by different metalloporphyrins differs in magnitude and
involves different HO-1 promoter regulatory elements, which again might help
you with some drug selection issues as more drugs are developed.
[Slide.]
The
other thing we were worried about initially was that there might be an effect
on gene programming. This is what
cadmium had done. We had seen massive
responses and up-regulation response to cadmium, and then it would dissipate
and disappear like we saw with the drugs.
Then, when we retested the animals, they had an attenuated response, so
there was some kind of programming that was going on that the mechanism needs
to be fully explicated for cadmium.
The
preliminary work that we have done does not demonstrate, at least to this point
in time, for the compounds that are being considered for human use to have that
kind of a programming effect, which I think is important information. That work is still in progress, but at least
the preliminary information looks good in that regard. Another example of how we use this
technology.
[Slide.]
So,
here is my summary and my last slide.
Tin mesoporphyrin, after a lot of very systematic and exhaustive studies
conducted in vitro in animals and later in humans, is the drug of choice
currently. It is very potent and at the
dose that is being used can still achieve that kind of efficacy, and looks also
that it can be used in a way to avoid a lot of potential problems.
It
is a synthetic compound, it is non-biocompatible with respect to the central
metal. It has very high potency which
allows it to be used at a very low dose, and it is most likely not going to
affect other enzymatic systems.
It
has high phototoxicity, but that can also be avoided for the same reason. It is not orally absorbable although more
recent information we have suggests that if you can bypass the stomach, it may
be absorbable directly from the intestine, which would be a handy thing if you
package it the right way, and it is currently being used in clinical studies.
Just
for some other reference points in terms of the things we have studied, and
none of these have been used in humans yet, and haven't done anywhere near the
amount of work that has been done on tin mesoporphyrin by the Rockefeller
group, but there is a lot of information available.
Zinc
bis glycol is a synthetic compound. It
has a biocompatible central metal. It's
a derivative of the naturally occurring zinc protoporphyrin. It has very high potency comparable to tin
mesoporphyrin, very high phototoxicity comparable to mesoporphyrin, but it can
also be used at a lower dose, and also can be shown not to affect the enzymatic
systems except the one of interest, which is hemoxygenase.
This
one happens to be orally absorbable, so just a small drop could accomplish what
you want to do in the oral feeding.
Chromium
mesoporphyrin is synthetic, has a biocompatible central metal. It is very high potency again, it has no
phototoxicity, it is photo-inert, it is orally absorbable, and also may not
affect the NOS or guanylyl cyclase systems.
Finally,
the naturally occurring compound, not the greatest potency, but it does work
and it also is metabolized. It has a
naturally occurring and trace essential metal, moderate potency, very low
phototoxicity to none in vivo, it is not orally absorbable however.
So,
there are a lot of other compounds that I could talk about, but it gives you a
good sense of how I look at this biochemistry, this developmental biology, and
how it translates in terms of applicability to the kinds of choices that have
been made by my colleagues and what other potential compounds might be
available for what appears to be very powerful agents for controlling
hemoxygenase and doing pretty much what they were designed to do, which is to
get a handle on that spigot and control the production rate of the pigment.
I
will just stop at that point and see if you have any questions.
DR.
CHESNEY: Thank you very much, Dr.
Stevenson.
I
have been cautioned about the importance of a break, which I was willing to
have you all work right through the break, but I have been cautioned against
that.
As
I have to go upstairs and build a transgenic model, so I can give you a
reporting system when I return, I think we should all take a 10-minute
break. I hope this doesn't inconvenience
any of those of you here for the open public session, but if everybody could be
back in 10 minutes, we will pick up then.
Thank you.
[Break.]
DR.
CHESNEY: For the next hour we have our
open public hearing. We have nine people
who have indicated an interest in speaking.
Just two issues. First of all, as
Tom read at the beginning of the session, and I quote, we ask in the interest
of fairness that any of you who are speaking in the open public hearing,
disclose any current or previous financial involvement with any firm whose
product they may wish to comment on.
The
second point is that people in the open public hearing have been given
different intervals of time to speak, and we would really appreciate it if you
could do everything possible to stay within your time limit. We absolutely want to hear from everybody,
and we want to get as much information out of today as possible, but if you
could stay as close to your time limit as possible, we would be appreciative.
Our
first speaker is Dr. Attallah Kappas. He
is the Sherman Fairchild Professor and Physician-in-Chief emeritus at the
Rockefeller University. He is a leading
authority in metabolic and genetic disorders, and I understand won the NIH's
first annual award for excellence in clinical research.
Dr.
Kappas.
Open Public Hearing
DR.
KAPPAS: Thank you, Dr. Chesney, and I
thank David for the elegant, extremely full and really beautiful review of the
subject. It has, however, put me in a
spot. He has covered the biochemistry of it from bottom to top, leaving the
clinical part of it to me, and since I am not a pediatrician, that is not so
easy a task.
I
have had to cut and paste my presentation from a longer lecture because I had
not been scheduled for this meeting until yesterday.
[Slide.]
For
those who need addresses and so on, this slide.
My
laboratory group has for 35 years focused its research on the biochemistry of
heme and heme-dependent processes and on related clinical and pharmacological
issues. Twenty-two years ago, we
discovered the potentability of certain synthetic heme analogues to inhibit
heme catabolism, and we have intensively examined the biological and
pharmacological properties of those compounds since.
In
the course of this work, my colleagues, principally Dr. Drummond, Dr. Valaes,
and Dr. Martinez, and I developed an inhibitor which can effectively resolve,
we believe, many of the ambiguities surrounding the problem of newborn
jaundice.
[Slide.]
Heme
conversion to bilirubin is catalyzed by two enzymes, the rate-controlling
enzyme is hemoxygenase. Newborns
temporarily produce bilirubin faster than they can dispose of it. The jaundice, which is mild and transient,
which they experience, peaks at about 96 hours, well after they have left the
hospital.
In
some babies, however, the jaundice may become severe, unrecognized, and then
unmanageable, and major brain damage can occur.
More subtle neurological impairments are now being identified. It could hardly be otherwise in the fragile,
immature, and developing biological system which the newborn brain represents.
Central
issues in this problem are the unpredictable nature, unpredictable course of
jaundice in some babies, the undefined susceptibility of individual babies to
bilirubin toxicity, and the uncertain blood levels at which bilirubin is toxic
to the brain.
Phototherapy
is quite successful as you all know from personal experience. Its side effects and drawbacks are also
acknowledged.
Its
underlying medical logic in particular seems to us presents a problem. Light treatment is initiated only after the
blood bilirubin has reached a level perceived to threaten the brain. This exact level is not known for certainty,
and whatever it is, it may be reached after the baby is beyond medical care.
[Slide.]
We
focused our research on the enzyme which controls bilirubin production and we
ultimately developed an inhibitor of its activity. We named this inhibitor, a synthetic heme
analogue among the group that David presented to you, Stannic-mesoporphyrin or
SnMP for short. It is now known as
Stannsoporfin.
It
acts, as shown on this slide, to prevent heme from binding to the enzyme site
at which bilirubin production is initiated.
Its pharmacological and toxicological properties have been intensively
examined over a number of years.
[Slide.]
In
the studies along these lines which we have conducted, the inhibitor was shown
to rapidly and effectively suppress bilirubin production in all of the models
of jaundice in experimental animals, shown on the left. In clinical studies, in adult, a single small
dose reduced blood bilirubin levels by 30 to 50 percent for a period of 10
days.
The
inhibitor acted similarly in adults with liver disease associated with jaundice
and ultimately was shown to suppress hyperbilirubinemia in children and to
interdict development of severe newborn jaundice in the population shown on the
right.
[Slide.]
The
overall results in five controlled, randomized, blinded where possible,
clinical trials involving more than 400 newborns are summarized here. We had earlier determined the appropriate
dose of inhibitor in careful dose-arranging studies in several hundred
additional newborns. These studies were
funded for a very long period of time by the National Institute of Child Health
and Human Development, monitored by the FDA regularly, and closely supervised
by senior neonatologist, in particular Professor Valaes.
Treated
babies in these studies have had medical follow-ups for periods up to five
years. No side effects of treatment have
ever been observed. There were 279
combined control infants in these trials, 129, or 46 percent, needed light
treatment to suppress progressive jaundice.
A total of 443 infants received a single small dose of the inhibitor at
a suitable time after birth. In these
infants, blood bilirubin levels were significantly reduced and in 97 percent,
the need for light treatment was eliminated, and there were not cutaneous
reactions to treatment in these babies.
In
a group of 80 newborns in whom bilirubin levels had reached 15 to 18 times
normal, that is, close to the level, 19.5 mg/dl, requiring phototherapy, the
inhibitor rapidly blocked further progression of jaundice, and none of the
babies needed light treatment.
In
contrast, of 86 controls who did not receive the inhibitor, 22 percent required
phototherapy. A direct comparison of the
inhibitor versus phototherapy was made in other newborns in whom blood
bilirubins had already reached the critical level requiring light treatment.
Forty-four
babies received the inhibitor alone. In
all 44, jaundice receded and none required light treatment. These babies left the hospital about 30 hours
earlier than the 42 infants who did not receive the inhibitor, and they
required considerably less medical resources to monitor their status.
The
inhibitor entirely eliminated the need for light treatment in newborns with
G6PD deficiency, a gene defect predisposing them to severe, unpredictable
jaundice. Out of 58 babies in the control group, 31 percent became seriously
jaundiced and required lights. None of
the 225 babies receiving the single dose of inhibitor developed jaundice
requiring phototherapy.
The
interdiction of severe jaundice in these infants simplified and greatly reduced
the cost of their medical care.
[Slide.]
Inhibitor
effects in these G6PD-deficient newborns are graphically shown in this
figure. The 58 babies who did not
receive the inhibitor continued to accumulate bilirubin in their blood during
the second day after birth, as shown in the top line, and ultimately, many
required light treatment.
The
bilirubin accumulation process was blocked in the 225 babies who received the
inhibitor, and none needed phototherapy.
[Slide.]
A
more severe hereditary disorder in children results in jaundice which is nearly
always fatal. Affected children are
unable to dispose of bilirubin and survive for a time with bilirubin levels of
20 or more times normal as in this 4-year-old girl. They ultimately die of brain damage unless
they are able to secure a liver transplant.
These
children are being studied Rockefeller-Cornell joint program of research
involving pediatric pharmacology.
A
single dose of inhibitor can, as shown on the left of this slide, markedly
reduce blood bilirubin levels for about 10 days. The effects is entirely analogous to what is
observed in newborns.
Several
doses, as shown on the right, in the same child can moderate the jaundice for
many weeks. In these children, the
inhibitor can offer, while they wait for a liver transplant, protection against
the acute, severe exacerbations of jaundice which prove fatal to them.
[Slide.]
The
inhibitor can also replace the full blood exchange transfusion, a light, last
resort procedure when lights do not control severe jaundice. Seventy-five hours of intense phototherapy
could not stop the relentless progression of jaundice in this infant. Blood exchange was rejected on religious
grounds by the parents.
With
emergency FDA approval, the inhibitor was flown to the physician caring for the
baby in South Dakota, and a single dose was administered as shown by the arrow.
Blood bilirubin levels declined rapidly and the threat of brain damage was
eliminated as was the matter of taking legal action against the parents.
This
experience is well known now in the Jehovah's Witness community and has been
repeated a number of times over.
[Slide.]
Periodic
reappraisal of clinical interventions is essential if science is to advance
medical care. Phototherapy in use for 40
years could not be reappraised properly because there simply was no serious
alternative to which its advantages and its drawbacks could be compared, thus,
pediatricians have become bound to a single therapeutic option, and to the
logic that newborn jaundice can only be treated when the bilirubin level
directly threatens the brain. What this
exact level is remains elusive. This is
an unsatisfying and, as you know, sometimes dangerous logic.
The
use of an inhibitor to temporarily reduce bilirubin over production, a key
source of this problem, while the bilirubin disposal mechanism matures in the
infant, has a more secure basis in science.
It also now has a firm foundation in a clinical experience comprising
multiple successful trials for more than a decade in which more than 800
newborns to date have been treated and studied.
The
inhibitor can be used early to control jaundice in select populations, such as
G6PD-deficient newborns, or it will interdict jaundice at any time point in the
evolution of this process as the physician chooses.
Finally,
I think we need to remember that there are underprivileged societal settings in
this country and abroad in which prolonged unrecognized or untreated newborn
jaundice can, because of its prevalence and the paucity of medical resources,
constitute a serious public health problem.
The
method we have developed provides a simple and rapidly effective means for
resolving this problem.
Thank
you.
DR.
CHESNEY: Thank you, Dr. Kappas.
Our
next speaker is Dr. Bhutani, who is a neonatologist in the Department of
Pediatrics at the University of Pennsylvania School of Medicine. He is a member of the current AAP Committee
on the Management of Neonatal Hyperbilirubinemia. He has been an investigator of the BiliChek
transcutaneous bilirubin monitor and the author of the nomogram for detecting
severe hyperbilirubinemia.
DR.
BHUTANI: While we get started, I would
like to wish everybody a good afternoon.
My name is Vinod Bhutani. I am a
baby doctor from Philadelphia. I am also
an investigator and a rookie in the area of bilirubin for the last decade or
so, and as a part of that, I received mentorship from Dr. Lois Johnson, who has
been a great instrument of teaching to me personally.
In
addition, we have a grant from the CDC to look at the database for the
kernicterus registry, and I am unsalaried investigator for the WellSpring
clinical trial. I am not going to be
mentioning those things in this brief kind of set of comments.
[Slide.]
The
issue of saving babies from brain damage is something that is inherent to all
pediatricians and neonatologists and to ensure that a baby has a full safe
week, we protect babies from six-year, from hypoglycemia, from sepsis, from
intracranial bleeding as a vitamin K injection, as well as from trauma.
Ever
since a concern has been raised whether bilirubin causes brain damage, we now
know from our kernicterus registry based on the year of birth of the child the
number of cases that have been reported to the registry have increased 11-fold
from this day in 1990, and that is in the handout that is available.
The
handout is detailed, but I will just stick to a few slides and a few points.
[Slide.]
The
question that Susan Sheridan asked, and we have asked ourselves, is in trying
to prevent adverse outcomes and concerns for patient safety with newborn
jaundice, what is the level of bilirubin that is high. The one that I get stuck at is the one which
is how sure are we that serum bilirubin levels are actually safe or will be
safe.
In
an attempt to answer that question, many of our studies have focused on a
structured approach to the management of jaundice, so that we can make it
easier for the practicing pediatricians who have to implement the various
guidelines that are passed down to them.
[Slide.]
As
we review the cases of kernicterus in our registry, we have used the Institute
of Medicine matrix to analyze the care that these babies have received as their
families and at all levels related to patient safety, patient centeredness,
effectiveness of care, and more importantly, on the timeliness of care. There have been significant lapses, as you
will see in the handout.
[Slide.]
The
primary root cause analysis tell us and shows us the there has been an
underlying major loss of concern for the neurotoxic potential of bilirubin,
limitation on the visual recognition of jaundice, and the failure to recognize
the severity of hyperbilirubinemia corrected for age in hours.
In
that respect, a nomogram was meant to be of help. Many have attempted to read more into the
nomogram than there may actually is.
This nomogram represents, in the simplest form, the rate of bilirubin
rise that occurs in the first 72 hours.
It provides at the magnitude of the severity of bilirubin and then it
can be also used as a predictive strategy, but the rate of rise is important.
If
one looks at the 95th percentile track, the rate of rise if 0.2 mg/dl/hr, which
compares at the 75th percentile to 0.15 mg/dl/hr, and at the 40th percentile to
0.1 mg/dl/hr.
As
you review the cases that were reported to us in the kernicterus registry, the
readmission bilirubin values, once the babies were discharged, some being
admitted within the third day, fourth,
or the fifth day, the ranges of bilirubin on admission ranged from 21.5 to 50
mg/dl.
Clearly,
these babies had high bilirubins before they were discharged. In these babies, the estimated rate of
bilirubin rise ranges from 0.25 mg to 0.6 mg/dl/hr.
If
you compare the rate of rise of 0.25 mg/dl/hr for the 95th percentile track,
and margin of safety is extremely small given all the issues that we know about
bilirubin measurements.
[Slide.]
This
is a baby with a high bilirubin value as one can see. The babies that we worry about are the babies
between the 75th and the 95th percentile track, who have a 1 in 5 chance or a
probability of having a severe hyperbilirubinemia once they have been
discharged. The other 87 percent
generally do well, but we do not yet have better predictive strategies to
differentiate these 13 percent babies from the remainder 87 percent babies.
[Slide.]
To
this end, we look at the limitations of the visual recognition of jaundice, and
we have compared with a pooled analysis of data, babies who were screened by
the jaundice-based screening techniques and those by bilirubin-based screening
techniques, and these are again in the handout in detail.
[Slide.]
The
pooled analysis shows that with bilirubin screening, you can reduce by 50
percent the peak bilirubin values of 20 and above, as reported in the
literature. You can reduce by 50 fold,
the occurrence of bilirubin above a level of 25, and you can potentially have a
zero occurrence of the never [?] event of bilirubin value above 13 mg/dl.
[Slide.]
We
view jaundice in two simple forms for pediatricians. One, the early onset of severe
hyperbilirubinemia, a value above the 75th percentile track before 72 hours of
age when the bilirubin binding to albumin is impaired, so these babies are
vulnerable to lower levels of bilirubin and toxicity, and then the late onset
that Dr. Stevenson mentioned, the conjugation defects, who are above the 95th
percentile track and are more than 72 hours of age.
The
concern is of the baby before they go home, those who are above the 75th
percentile track.
[Slide.]
If
you follow these guidelines and this level of concern, I think we can meet the
goals of all the stakeholders and bilirubin, those of the clinicians, those of
the public health officials, those of the society, and those of the family for
a safe experience with newborn jaundice.
Thank
you very much for this time.
DR.
CHESNEY: Thank you very much, Dr.
Bhutani, and for giving us the extra slides that we can peruse tonight.
The
next speaker is Dr. Murray Goldstein.
DR.
HATLIE: Madam Chair, I am actually not
Murray Goldstein. I am Martin
Hatlie. Murray Goldstein's chair was
empty next to me for the whole meeting, so I stepped up in the interest of
time.
DR.
CHESNEY: Do you want me to introduce
you?
MR.
HATLIE: That would be nice, unless
Murray is here and we just don't know who he is.
DR.
CHESNEY: I am so sorry.
Martin
Hatlie, Esquire, is President of the Partnership for Patient Safety and a
nationally recognized authority on patient safety and medical professional
liability issues. He founded the
Partnership in 2000, which is dedicated to advancing the reliability of
healthcare systems, and he is a member of the Harvard University Kennedy School
of Government's Executive Session on Medical Errors.
Thank
you.
MR. HATLIE: Thank you, Madam Chair.
I
was given a sliding scale of time today, 5 to 10 minutes, so I will stay within
the 10 minutes and try to keep closer to 5.
I
am a lawyer. I got to patient safety
through years of being a lobbyist on litigation issues for the AMA. I am not
really going to talk too much about that today, it is not the topic, and
frankly, many of you may not care, but I wanted you to know that about me
because you will see that I come from a different perspective and had the
privilege of working with organized medicine as this notion of a systems
approach to safety and a safety kind of science has been developing really
starting in the mid-1990s although I will say that it did start in anesthesia
quite a bit earlier, probably the mid-1970s, and the CDC and the FDA were very,
very involved in partnering with the anesthesia field to make that happen.
So,
when we did start a National Patient Safety Foundation out of the AMA in
mid-1990s, it was really the FDA that probably had more system and safety
knowledge. This is out of the Center for
Devices and Radiological Health than any other part of government that we can
find.
I
am going to jump around in my slides a little bit today. You have some more material in your written
materials than you are going to see up here today, but I want to leave you with
four points at the end of my presentation and for the purposes of sort of
reinforcement and repetition, I am going to start with them.
One
is that low prevalence from a system and safety point of view is really not a
justification for inaction. A lot of
industries really are pursuing high reliability, and, Madam Chair, that is a
term of art for your list or extraordinary safety, really focus on their low
prevalence especially high severity injuries as treasures, they call them. They are essentially things that tell you a
lot about your system, if you can't prevent those high severity injuries, then,
there are some systemic things that you really need to be looking at, and every
one of these cases becomes something that industries that are serious about
safety spend quite a bit of resources on to really investigate how that could
fallen through the cracks.
The
second is that an intervention that relies on either vigilance or memory, or
both, really again from systems thinking and human factors thinking is not
optimally safe. Those are ways in which
we know human beings fail no matter how hard they try, and no matter how
competent, it is not how perfect they are.
Vigilance
including visual assessment, memory including know when and how to apply a
guideline are things that just are not going to get you again to that
extraordinary safe stratosphere that you want to go to.
The
third point is that evidence-based medicine, while a very valuable tool and
really important for a number of reasons in medicine, is not a particularly
sensitive safety tool. For a number of
reasons that have really been articulated best probably in the literature by
two pediatricians, Don Berwick and Lucian Leape, in an article, a dialogue actually,
in JAMA last summer, they really focused on a number of reasons why
evidence-based medicine isn't something that is going to be particularly
helpful to you in making safety happen.
It's slow, it's costly, it's not good at sort of targeting latent risk
or emerging risk in a system, so you need other things to complement that
certainly.
It
is not that it has no value, it has great value, but you need more. It should not be a rate-limiting step.
The
final point I want to make, really based on comments this morning, that I
really want to leave you with, although I will elaborate all of these a bit
more, is that accidents, including the kinds of stories that are captured in
registries like the Pilot Kernicterus Registry, are incredibly robust safety
tools.
The
aviation industry has spent terrific amounts of resources in really capturing
the kinds of stories that are captured in registries like this one, voluntary
registries that have a lot of narrative, a lot of richness of story telling
where you can thematically analyze and understand why things went wrong and how
they went wrong.
There
is much more emphasis from a safety point of view in that kind of data than in
counting numbers and just looking at frequencies because that doesn't give you
the kind of narrative, the kind of richness where you can really understand why
processes failed and what went wrong.
We
really are going to move through these slides pretty quickly.
I
also want to stress, though, by saying that complacency is a word that has come
up here a couple of times, and the IOM report that really brought safety into
the public consciousness at the end of 1999 did charge the healthcare system
with being complacent.
By
that, they didn't mean careless, they did not mean callous, what they meant is
that there is a sense in some industries that we are doing as well as we can do
especially where prevalence is low, that we are sort of at the best place that
we can be at, and again, organizations that are highly reliable are often
seeing that their safety initiatives, their big leaps forward in safety come
from organizations that are already leaders in the field, they are already at
the top of the game. They might be
organizations that either themselves would say or their peers would say you don't
need to be focusing on safety because you are already doing as good a job as
anyone that we know of, those organizations that again really aim for
perfection and they are often motivated by the Hippocratic Oath. That really resonates with a lot of other industries,
first, do no harm, let's aim for perfection.
Those are the organizations that are going further.
The
best case study I can leave you with, and it is not in my slides, is the Alcoa
case study. It comes out of the Harper
Business Review. It's a wonderful,
wonderful story that you will find very applicable to what you are doing here,
but really focusing on first doing no harm, looking at your processes, aiming
for perfection, and finding a lot of cost savings along the way.
This
is Patient Safety 101. I would recommend
James Reason's book which is cited in your slides, and Charles Perrow's book
which is cited in your slides, or the IOM report, you can pick up all of this
stuff.
These
are all the different places that safety science comes from. It is not just the medical literature. There
is a lot of knowledge that is being captured from other fields.
These
are the basic models. If I leave you
with nothing else today, this will be some of the things that are certainly
percolating through the safety literature right now.
This
is the Swiss Cheese model. This is
coming from James Reason's work. It
really I think is applicable in many ways to the kinds of issues that I heard
you discussing today.
One
of the basic paradigm shifts that we see in systems thinking about safety
versus the kind of thinking that I think is driven by our current liability
system, if nothing else, is that things are constantly on the verge of
happening. Accidents don't just happen
when there is a breach in the standard of care.
They are constantly on the verge of happening. You are constantly managing them and keeping
them from happening through a series of defenses that you all have in your
systems.
The
fact that the prevalence of kernicterus is as low as it is, and the fact that
you are managing hyperbilirubinemia as well as you are, suggests that your
defenses have worked pretty well.
What
we see, though, in safety thinking is a paradox, sort of the better that you do
at safety, the more you lose track of the kind of risks that are there. Frankly, if you are trained to look for a
certain kind of risk, if you are trained about the dangers of
hyperbilirubinemia, but you don't see it for 15 years, you tend to move it off
to the side of your red error screen.
So,
one of the hole to one of these defenses is just the kind of complacency or
lack of alertness that comes with not seeing something for a broad period of
time. A number of organizations, we use
different kinds of simulation training to really keep that foremost in the
minds of the people and keep those kinds of risks alert.
The
phenomenon, the human fact researchers call "the coming of
attention," we just don't look for things,
we don't tend to see things that we don't see frequently and aren't
familiar with.
Another
thing I want to mention from this slide is that certainly in Dr. Newman's
presentation this morning, he went through a number of things in history that
have changed over the course of our management of this disease.
One
of the things that we know from systems thinking is that any kind of change
introduces different kinds of risks. So,
for example, one thing that resonated very much with me today is the movement
of the management of hyperbilirubinemia out of acute care settings into
ambulatory care settings.
When
that happened in the mid-1990s, again with 20/20 hindsight, perhaps there was a
need to do different kinds of education with families, different kinds of risk
management strategies to reflect that change in the way in which we now see
this kind of risk emerging.
Frankly,
it is one of the holes that PICK is trying to fill. It is the hole in really bringing forward the
partners, the families as partners, the lay caregivers as partners, and they
have a more active role to play if this is a fact, something that is going to
emerge in outpatient care settings.
We
have talked a lot about--this is, first of all, the Sharp and Blunt Ends model,
another one of the basic models from Safety Science. We have talked quite a bit about the
guidelines that are in place here and the fact that kernicterus does continue
to happen even if the prevalence may be low.
The
purpose of this slide is to really show that
where care is given, which is the sharp end of this triangle,
practitioners are often balancing three different things, guidelines in this
case, it's their goals, what they think is going on.
Probably
in this case, a good example would be can you diagnose kernicterus, can you
diagnose hyperbilirubinemia, are you trying to balance it with other kinds of
things that you are differentially diagnosing, and also the issue of attention,
and attention is really interrupted in most healthcare settings by distraction
and by fatigue.
So,
a lot of the work that happens in managing safety involves managing that
attention, that focus of attention. It
is one of the reasons why vigilance and memory really are not good strategies
to rely on because they get interrupted by all that action at the sharp end of
the system.
The
sharp end, frankly, what happened to the sharp end is shaped by the blunt, and
the blunt end includes different kinds of systems thinking including the legal
system, including the guidelines, including the kinds of technologies we have
in place. Anything that we can do to
minimize vigilance, reliance on vigilance, or minimize reliance on memory, or
simplify or standardize are frankly things that will help people perform better
at the sharp end, and that is really the major take-away I think from this
slide in the time that we have today.
Hindsight
bias. I haven't heard it much today, I
have heard it in most situations where we have talked about this sort of thing,
and that is the statement that if doctors only followed the guidelines that
they have up there, we really wouldn't see kernicterus.
In
fact, it is a very, very well known phenomena in the literature that hindsight,
that when you look back on a situation, you tend to make judgments like that,
it's internalized blame that it was the doctor that was at fault. In fact,
because of all that complexity at the sharp end of the system, there is many
things that are going on and really focusing on whether doctors should be or
should not be following guidelines is not going to get you where you want to
go.
Again,
you want to focus on technologies, strategies, to simplify, to standardize, and
to decrease reliance on vigilance and memory.
How
do we apply safety science to optimizing the prevention of kernicterus? One of the major lessons that we know from
looking at many years of experience in safety science and other systems is that
systems never run perfectly, they are prone to failure and degradation, we
should not be relying on guidelines and protocols as our major line of defense
because that assumes optimal system performance, and the system rarely performs
optimally.
Reliance
on vigilance and memory, we have talked about already, but there is frankly
just not strategies that are going to really get you to the high reliability
sector on this issue.
How
do we apply safety science to optimizing the prevention of kernicterus?
My
time is up. Lots of people have to be
involved. Simplification and
standardization are important tools.
Many
of these other strategies are cultural strategies, we are not going to talk
about them here, but it really is a whole series of training and communication
stuff.
Evidence-based
medicine, I am going to leave you with the slides here. They include a number of quotes from Berwick
and Leape from that series of articles that I talked to you about, but
essentially, evidence-based medicine is not something that either aviation or
anesthesia has relied on terrifically in creating safety.
It
is much more of a problem-solving technique.
It is every story in the registry that can be analyzed thematically and
really looked at with the kind of problem-solving that frankly, commissions are
very good at doing.
So,
you have the steps in place to really move forward and really getting to the
next level in safety and reducing the prevalence that you have of
hyperbilirubinemia, whatever it is. It
is really just the approach that could be different than the traditional
approach that is important here.
I
am going to stop here. There is many
more things that I could say, would love to say. If you have any other questions about any of
this, I will be at the cocktail bar at the end of the day and I would be happy
to talk to any of you.
Thank
you so much.
DR.
CHESNEY: Are you sponsoring the
bar? I don't think the FDA is.
MR.
HATLIE: No, I think the hotel is, I
think it is something that they are giving us for free. Thank you very much for the extra time, I
appreciate it.
DR.
CHESNEY: We will be there. Thank you very much.
Many
of us have become devout Don Berwick fans and for those of you who have not
seen the video, Escape Fire, I think if you want to understand process and
medicine and errors, that has a very profound message to it.
Our
next speaker is Dr. Duane Alexander, who is the Director of the NICHD and has
been since February 5th of 1986. His own
personal interests and training have been in developmental disabilities, and I
was interested to learn that in his first position at the NICHD, he directed
their national amniocentesis study that established the safety and accuracy of
amniocentesis for prenatal diagnosis.
Dr.
Alexander.
DR.
ALEXANDER: Thank you all for the
opportunity to speak to this group on this very important topic.
The
study that I organized after the amniocentesis study was a phototherapy study
assessing the safety and efficacy of phototherapy for treating jaundice. I never got to finish that one because I went
on to the National Commission for Protection of Human Subjects instead, but
this is obviously an issue that has been of interest to me for a long time and
to the Institute.
During
its 40 years of existence, a major focus of our attention has been on improving
pregnancy outcome and ensuring intact survival of newborn infants and
prevention of disability. I should state
for the record that I have no financial relationships to WellSpring or other
pharmaceutical companies, nor does the Institute.
Bilirubin
encephalopathy has long been a major problem for newborn infants. The biggest advance came before NICHD was
established with the development of Rhogam, which eliminated a huge proportion
of neonatal jaundice and problems associated with it.
Then
came phototherapy. The Institute
addressed this. It took care of much of
the problem with premature infants when our collaborative study demonstrated
its safety and efficacy in reducing the need for exchange transfusion and
reducing the incidence of kernicterus, and it rapidly became standard
treatment.
Unfortunately,
it is also clumsy and complicated, it takes a long time, it interferes with
access to the infant, and it is not 100 percent effective, so we really have
needed a better intervention if one could be developed.
Sumner
Yaffe, the former Director of the Center for Research for Mothers and Children
at NICHD, came to me one day with a potential solution. Based on his conversations with Attallah
Kappas, who you just heard speak, Dr. Kappas reported on development of a new
series of compounds that they were working on that could represent a one-time
injectable drug that would interfere with the formation of bilirubin until a
baby's enzymes matured sufficiently that it could excrete it.
They
had tested several different formulations, tin, zinc, proto-, meso-, and
settled on tin mesoporphyrin as the most effective and the safest, as
well. We believed, based on the evidence
that we saw, that this could potentially be the long-sought magic bullet that
could finally end the problem of hyperbilirubinemia and kernicterus.
We
worked with Dr. Kappas to organize some clinical trials. These were done by contract in Greece and in
Argentina. They included studies of term
breast-feeding infants, G6PD-deficient infants, ABO incompatibles, term infants
with hyperbilirubinemia.
In
every study, tin mesoporphyrin administered once resulted in lower peak
bilirubins in the treated infants than in the controls, and reduced or
eliminated the need for phototherapy.
The only infants in any of these studies that have been reported who
required phototherapy after receiving tin mesoporphyrin were some very small
preterm infants.
In
addition to this, there was no evidence of any adverse effects in any of
studies. Results like this don't come
along very often. So, the number of
patients, however, in our studies, was not large, it numbered in the hundreds
rather than in the thousands, so these data have to be regarded as preliminary
certainly rather than definitive.
They
also were not reported in sufficiently rigorous way to meet all the FDA
requirements, so more studies were needed.
We urged Dr. Kappas to license this compound to a pharmaceutical
company, which he did, and the studies have begun.
The
promise of this treatment is so great that it is important that these studies
needed to provide data for a judgment on approval, need to be moving ahead
rapidly, so that tin mesoporphyrin can be studied for its preventive efficacy,
as well as its therapeutic efficacy.
We,
at NICHD, believe that this is one of the most important new drugs being
studied for pediatric use and that it is the only intervention on the horizon
that holds out the prospect of completely eliminating the problem of
hyperbilirubinemia and kernicterus.
We
are sufficiently enthusiastic about it that we have a protocol ready to
implement in our neonatal intensive care unit network to test its additional
applications of tin mesoporphyrin once it is approved for use in term infants,
so that we will know its efficacy and safety before it gets broader application
after licensure.
If
this proves useful, we will go on to evaluate other possible applications. We hope that a way will be found to move
current studies forward expeditiously, so that the full promise of this drug
for ending the problem of kernicterus will finally be realized.
Thank
you very much.
DR.
CHESNEY: Thank you.
Dr.
Goldstein is here, but I think we will give him a chance to catch his breath
and move on to Dr. Andrew Moosa, who is Director of Newborn Nurseries and the
Infant ICU at St. Francis Medical Center in Linwood, California.
DR.
MOOSA: Thank you, Dr. Chesney, thank
you, Tom Perez for allowing me to speak today.
As
an initial waiver, I want to say that I have no relationship with WellSpring, I
am not being reimbursed, I am not involved in the clinical trials, I am not
salaried, so I have no conflict of interest.
Dr.
Lucey asked me who was I representing, so I said I was representing the
practicing pediatricians who day and night take care of babies and
children. I am from Southern California,
the Los Angeles area. Somebody has to
speak for the South since Dr. Newman and Dr. Stevenson represent the North,
which is more affluent, which is more sophisticated, but I am from Southern
California.
Dr.
Newman mentioned to you the Kaiser study in Northern California. Kaiser is a very special place in the sense
that they have very good control of what goes on with both the physicians and
the patients, et cetera. It is a
marvelous system. But in those of us who
practice outside the system, I practice in a hospital of 520 beds. We have 7,000 deliveries a year.
When
we look at those numbers, and a lot of our population is the working poor, who
earn $20,000 or less a year, many of them are single parents, they don't have
vehicles to come back to the hospital.
With the new HMO systems, in spite of the federal mandate that the kids
will stay in the hospital, the newborns will stay in the hospital for 48 hours,
the mothers are sent home earlier by HMOs or they choose to go home because
they have got three or four other kids at home and they need to go home.
We
then say, well, you had better come back and get a bilirubin in two days, three
days, they don't come because they don't have transportation. Our system is very difficult. It is very different from the Kaiser system
or other systems in the west side of Los Angeles as opposed to where we
practice.
I
practice in southeast Los Angeles. Then,
we have been tracking. One of the things
I also do is I head California's program for hospital accreditation. In that role, I go up and down to California
hospitals and we survey them for accreditation.
One
of the things we are looking at now, and one of the things front and center,
both in Washington and in Sacramento, is patient safety. We are now looking at the babies who come to
the hospital or show up in the emergency room from the time they are discharged
from the hospital until 21 days of life.
In
my hospital last year, I pulled the figures out, we had close to 7,000
deliveries. The exact number was 6,987
babies. Out of that, 535 babies came
back to the emergency room in the year 2002 for jaundice and poor feeding. We have not been looking at those figures.
I
don't have the numbers of how many were readmitted to the hospital. Now, that is a major problem for us because
when these babies go home, a large number of our babies belong to parents, as I
said, that really can't afford to come back to the hospital, can't afford the
taxi fare, can't afford or do not want to come and get the kids stuck two or
three times when the bilirubin is up, and they really don't want the kid in the
hospital, they want the kid to go home.
Then,
when you say to the mother, when we call the mother say, you know, how come you
didn't bring the baby for the blood test, they say, well, my other two children
are sick or I don't have transportation, or my husband is working on the night
shift or day shift, whatever, it is a problem for us.
So,
I have 37 pediatricians. This year I
happen to be Chairman of the Department of the Department of Pediatrics, have
37 practicing pediatricians in my department.
You know, they are looking for a better way to take care of these kids
who are jaundiced. We are now using the
carbon monoxide studies for the Bhutani graphs, trying to find out which babies
the bilirubin is going to go up, et cetera, and we are having difficulty with
that, because we know these kids, it is going to go up, we want to measure the
bilirubin in two or three days. They
don't come.
So,
what I am saying to you as a practicing physician out there, the practicing
pediatrician out there, we need some help.
If there is a compound available, a pharmaceutical agent available out
there that can help us with these kids, because they are really, in the real
world, they are not going to get two and three blood tests of bilirubin to come
back.
Somebody
said, Dr. Bhutani said it costs one dollar to get a total bilirubin, Dr. Lucey
said it costs $35.00 in Vermont, so I don't know what it costs where, but it is
not cheap, and to get the thing done, we are allowing these kids to stay at a
risk that is there.
Dr.
Newman asked a very important question during his talk. He said how can we reduce the occurrence of
kernicterus. For me, as a practicing
pediatrician, my question would be how can we eliminate kernicterus.
Thank
you for allowing me to talk to you.
DR.
CHESNEY: Thank you very much.
Our
next speaker is Dr. Jerold Lucey, who is a Professor of Pediatrics and
Neonatology at the University of Vermont, and has been a mentor for many of us
with respect to his years of writing, teaching, and advocating for infants and
as the long-time editor of the Journal of Pediatrics.
DR.
LUCEY: I paid my own way. I am a friend of Dr. Kappas, but he doesn't
have to pay me for that.
Being
almost the last one on this program is sometimes an advantage. You can always say, well, everything that has
been said worthwhile has been said already, and I think I can plead that
somewhat, but I am probably the only one in the room that goes back to the
Shaw, Diamond, and Allen era in Boston when they invented the level of 20 mg
percent.
I
have done hundreds, I think I stopped counting, exchange transfused at number
500. So, let me say something about
exchange transfusions. Nobody has made
clear the fact that there is about a 1 percent mortality rate with these, and
it happens in well babies, and there have been articles written about it in the
old days, but nobody ever really solved the problem of why these babies died.
I
can remember probably every single one of the ones that died on me because they
stunned you. You went out and talked to
a mother, said we are going to do an exchange, and there is a very low risk,
and then, boom, the baby's heart stopped during the thing and they couldn't get
it started. So, that is still there, and
I think there aren't a lot of people who are very adept at doing exchange
transfusions anymore.
So,
that is an effective therapy all right, but it has with it a little risk.
Now,
the first time I met Dr. Kappas was when he presented his first paper on
hemoxygenase inhibitor and right away I knew the days of phototherapy were
limited, because here was something that you look forward to, a shot that you
could give.
I
have been responsible for the introduction of phototherapy in the United
States, doing a randomized trial in the late 1960s, and, first of all, people
didn't believe it. I started out
thinking light would never work myself, as a matter of fact.
It
was done because I had a Chilean research fellow who they were doing it using
it all over in South America and Italy and France, but I am monolingual and I
never read any of these articles. When
my research fellow came to me, he said why aren't you doing phototherapy, I
said, oh, it doesn't work.
If
you look at the early papers as far as evidence is concerned, that first paper
didn't convince very many people. It
came out in '58 and nobody in the United States started using it until after we
at least did a randomized trial in '68.
Then,
there was 10 years, you know, phototherapy would never pass the FDA
regulations, I think, at this point, or take years to do it. In those days, all you had to do was prove
that the therapy was effective, and people started using it because it was a
device, and obviously, the device was safe, nobody ever got too hurt by a light
bulb unless they touched it or something.
So,
there was a therapy that came in and then there was just an academic debate
that went on for a decade because actually there wasn't a way of telling where
did the bilirubin go, where did the yellow go.
That took about 11 years to be worked out, and there is still people who
worry about phototherapy.
You
will be presented tomorrow, I gather, when you are making your deliberations on
tin mesoporphyrin about what are the long-term effects. Well, to get long-term effects, it takes a
long time. Bill Oh summarized all the
limitations of phototherapy. There is
certainly several of them. They can be
handled, but if you wanted to be a purist, you could say, well, nobody has ever
followed those people for 30 or 40 years.
Well,
please remember that very few, I don't know of any drugs that have been
followed where somebody who introduced and then followed the people for 30
years. That is just not possible. So, I think you are going to have to take a
chance.
When
I got interested in light and realized it worked, my idea was that we give it
to everybody, because I had the idea that if you walked around on the outside
and didn't get hurt, and that was 10,000 times more radiant energy than you got
from the light therapy, then, this is probably going to turn out to be safe.
So,
if you read the little paper carefully, you will see it was proposed as a way
of preventing jaundice in newborn infants.
It hasn't been used that way anymore because people got worried about
separation from mothers and the effect of blinders, and everything, and we
backed off, and that may be one of the reasons why you are seeing more--I mean
as phototherapy went down, maybe the incidence of kernicterus went up, but we
started seeing more anyway.
Then,
I got really disenchanted with the field because I didn't see any way out how
you could ever do a study in which you would allow a level to go up to
something that was toxic and then have a control group, so there aren't any
real possibilities for much of a control study with a high risk group out
there.
I
wrote a thing called, The Bilirubin Mess.
There never was a level, there never will be a level, which I still
believe. Judging the toxicity of a
certain level versus the baby in the situation, I just don't think is a
practical approach.
Other
people have held onto the idea that maybe you should do unbound bilirubin,
scientifically, quite sound, practically, not apt to be very practical.
So,
I would urge you to look at new proposal before you as far as the treatment is
concerned and that we proceed on two levels.
One is use the new treatment, approve the new treatment, use it and then
start doing some other studies with it, and try to selectively treat as few
babies as you can by using some variation of Dr. Bhutani's graph for picking
out babies.
Thank
you very much.
DR.
CHESNEY: We have two more speakers, Dr.
Timos Valaes, a clinical instructor in the Pediatric Program at Boston
University.
DR.
VALAES: It is an advantage and a
disadvantage to be one of the last speakers.
The advantage is that you know, you have heard what everybody else has
said. The disadvantage is that you
cannot have prepared slides of anything because then you will repeat what some
of more eloquent people have already said.
First
of all, I guess I have to do my disclosure part, and I am Professor Emeritus at
the Tufts University School of Medicine in Boston, and I have been involves
with the tin mesoporphyrin studies in Greece from 1988 to the year 2000.
During
this 12-year period, I spent 50 percent of my professional time doing the
studies. The studies were, as you heard,
supported by National Institute of Child Health and Human Development and when
the contract was over, the WellSpring Pharmaceutical Corporation became the
custodian of the computerized database and also paid for the last months the
nurse practitioners that was involved with the five-year follow-up. So, that is my contact with the company.
When
they asked me while I was traveling if I am interested in attending this
meeting, they volunteered to pay my travel expenses from Boston to here.
Having
said that, I must say that I have not yet recovered from the emotional impacts
on me from the speech, the presentation rather than the speech, of Mrs.
Sheridan. The reason I am so involved and impacted by her presentation, that in
my earlier professional life, I had the bad luck of having seen more than 300
cases of kernicterus.
This
was after my training in England where I was part of the revolution there in
taking care of the Rh disease babies and see the marvelous disappearance of
kernicterus from this cause by the timely use of exchange transfusion.
Then,
in '59, I went to Greece, established an exchange transfusion service at the
State and University Maternity Hospital in Athens, and we eliminated
kernicterus in that institution, but this left the rest of Greece without the
help of phototherapy, sending us very late, as I said, hundreds of babies and
where we could do nothing to save them or alleviate their condition.
Then,
phototherapy came and the problem was no longer there, and then I decided to
come to Boston, not because I was looking for the problem, no, I was looking to
get away from it.
Having
said that, I think I need to iterate a few things. Neonatal jaundice is a self-resolving
condition and all we do with whatever measure we take is to buy time for the small
minority of babies that are going to develop kernicterus.
Kernicterus
can be prevented, but cannot be treated, and every epidemiologist knows that if
it is prevention, you have to treat many more patients that will eventually
develop the condition, if not for the preventive measure.
It
is also very well established that if a preventive measure succeeds in
eliminating the disease, then, the medical profession and the public start
questioning whether really the preventive measure is necessary. This is exactly what happened with
kernicterus. We have been trapped by our own success in eliminating
kernicterus.
What
happened, we allowed, or as pediatricians, for a drastic reduction of the
in-hospital observation of babies, and we are now experiencing another thing
again. The safety margins for exchange
transfusion or for phototherapy or for tin mesoporphyrin for intervening have
been compressed, and this compression means that it is not only the levels of
bilirubin between these different things that are reduced, but is also the time
available for us to make the intervention, particularly if the baby is already
home and there is no beeper in the baby's system to tell the physician when the
target call for action has been reached,
and there is a lot of delay, and that is really what is happening
everywhere.
I
have produced a mathematical model to show how really bilirubin level, a time
key anytime during the first week of life has been reached. As you see there, there is a cumulative rate
of bilirubin production involved. It is
not one rate, it is a cumulative, because this rate changes, it decreases
throughout this period of time.
The
cumulative intrahepatic circulation of bilirubin is one side and then the
cumulative rate of bilirubin elimination, and that again is not one rate, it is
a continuously changing, fortunately increasing rate of elimination.
Phototherapy
intervenes in this process by increasing elimination. Tin mesoporphyrin is acting on the other side
by decreasing production, and it does it very efficiently and for enough time,
at least 7 to 10 days, so that you only have to give it once.
There
is an historical paradigm available to us, how you react to a situation like
this. There is a condition known to all
the pediatricians known as hemorrhagic disease of the newborn. It is a developmental situation. The baby is born with a low level of vitamin
K dependent clotting factors. They go further down, particularly in
breast-fed babies, and this tendency can be reversed by a single dose of
vitamin K.
In
the '40s, there was a lot of discussion, the commonality is, first of all, that
there is not one level of clotting--low level of clotting factors that will be
for certainly related with clinical manifestations, and there is a continuous
change of these factors different from one baby to another, similar to what is
happening with bilirubin, and there was a lot of discussion in the '40s and
'50s whether you should be giving vitamin K, which corrected the abnormality
definitely well proven, to the mother, so that the baby is protected during a
traumatic delivery, to the baby orally, and the problem there was that there
was not an oral preparation, but who cares, you open the ampule of the
intramuscular preparation and you pour it into the baby's mouth.
But
then in 1961, the American Academy of Pediatrics stepped in and pushed aside
all this controversy, and without any single sort of new study that was
reported as pushing them in this decision, decided that every baby should get
an intramuscular injection of vitamin K, and this was enough and sufficient to
make the complete disappearance and make early and classical analytic [?]
decision of the newborn eliminated, and it is a historical sort of condition
for most of the pediatricians.
Now,
what I said had happened, with the British and some other people first,
questioning why should every baby get an injection. They started saying it is not necessary and
they stopped giving it, but to cut the story short, the American Academy of
Pediatrics again intervened, I think it was two or three years ago, and said
no, let's forget about all this discussion and go back to the intramuscular
injection and continue the practice that was there.
Now,
of course, this is a different situation we are talking about because now we
have to introduce a new practice, and not really stick with the old one.
Thank
you. I didn't see any light, sorry.
DR.
CHESNEY: We don't have a light. That would be an excellent suggestion. I don't think they anticipated quite so many
people for the open session. I thought
you made some very excellent points.
Our
last speaker is Dr. Murray Goldstein, who is the Medical Director of the United
Cerebral Palsy Research and Education Foundation and former Director of the
National Institutes of Neurological Disorders and Stroke, and a former
Assistant Surgeon General.
DR.
GOLDSTEIN: Madam Chairman, I apologize
for being late. I apparently
misunderstood the time frame of your agenda.
You have already introduced me, so I shan't introduce myself.
I
guess I need to say I have no personal social, working, or other relationships
with any industrial organization relevant to this discussion.
First,
I would like to take a moment to congratulate the staff of the
subcommittee. The thoroughness of its
concise staff paper of May 14, summarizing the state of present knowledge on
hyperbilirubinemia of the newborn, and, two, the significance and specificity
of Dr. Cummins' charge to the subcommittee.
Having
been in government for a number of years, I appreciate both the technical
excellence of these documents and the sensitivity with which they were
written. Great staff work.
I
have already submitted a brief document on kernicterus for this committee's
consideration and on the role of hyperbilirubinemia of the newborn as an
important etiologic factor in athetoid cerebral palsy. This information is in your folder, and so I
won't spend time repeating it. However,
I do need to point out that athetoid cerebral palsy is one of the severest
forms of cerebral palsy and is characterized by a serious lifelong interference
with activities of daily living.
Also,
in the past, it was one of the more common manifestations of cerebral
palsy. The important findings of a
generation ago in early diagnosis and therapy essentially removed kernicterus
from the screen of medical attention.
I
daresay there are very few medical house officers today who have ever seen a
case of kernicterus. Also, I would guess they probably will have difficulty
recognizing it if it was presented. In
essence, as a medical research and public health community, we have assigned
kernicterus and its consequences to the category of benign neglect.
As
presented here by previous speakers, the reasons for this benign neglect may no
longer be appropriate. Although
kernicterus is still a rare disorder, it appears to threaten to re-emerge.
As
my paper indicates, there are a number of clinical care, medical research, and
public health measures that now demand additional attention from both government
and nongovernment sources.
To
be specific about the role of the FDA in this new agenda, first, I urge the
subcommittee to advise the FDA to give targeted and priority attention to the
use of its authority to meet its agency-designated responsibilities under the
Orphan Drug Act.
This
Act was passed to stimulate and support needed research development on (a)
improvement in the diagnostic criteria and methodologies for early
identification of hyperbilirubinemia in the newborn; and (b) the development of
more definitive clinical interventions for the treatment of this disorder.
I
had the privilege of being one of the people who helped design the Orphan Drug
Act and was a member of the Assistant Secretary of Health's subcommittee that
designed the specifics of it. Unless
that Act has been changed, and I don't think it has been, I believe the need
for its use as an instrument of the FDA is imperative, and it was designed to
do such.
I
also suggest that the subcommittee recommend that the FDA use its administrative
procedures for expedited review to evaluate the results of this research and
development activities.
These
actions on the part of the FDA would meet its unique responsibilities for
addressing this potentially serious problem of infancy. Although kernicterus is not a public health
problem of the size of SARS or AIDS, to the parents of infants and children
with athetoid cerebral palsy, one case of kernicterus is one case too many.
Madam
Chairman, thank you for your attention and I would be pleased to attempt to
respond to any questions the subcommittee may have.
Thank
you.
DR.
CHESNEY: Thank you very much.
We
need to move on to Dr. Nelson's presentation next and then we will be
addressing Questions 2, 3, and 4. As a personal favor, in order to reinstate my
credibility as somebody who sticks to the time, which I have lost already, I am
going to ask Skip if he could shorten his presentation by some amount of time.
Thank
you.
Ethical Issues
DR.
NELSON: What I would like to present
today is four sets of reflections on four different issues. It is not meant to be a complete presentation
of the ethical issues in drug development in this area, but to stimulate our
conversation. I think they have been
touched on at different points in time.
You
have the complete slides, so I will sort of, in the interests of time, move
through them rather quickly.
[Slide.]
The
first point I want to make is on surrogate endpoints, but for those of you in
the audience, I don't have a biochemical pathway, but this is a regulatory
pathway which, in your handout, is presented as a full page document as the
last page of the handout, and it shows you how you move through 21 CFR 50 and
56 in the case of the FDA, or 45 CFR 46, and to orient my remarks according to
this regulatory pathway, the first question being sound research design.
[Slide.]
The
first point we need to ask, as we are looking at drug development is sound
research design, and the issue I want to raise if the choice of endpoint,
surrogate endpoint.
[Slide.]
The
primary goal for the treatment or in fact prevention, since I will have some
reflections on prevention, of hyperbilirubinemia is to prevent kernicterus and
other irreversible neurodevelopmental impairment in case some of the concerns
about other impairments at lower levels of total bilirubin are confirmed.
The
association with total bilirubin level suggests that the control of this level
may be an appropriate surrogate endpoint, but even within that, we still have
other possible surrogate endpoints - bilirubin above 20, bilirubin above 25,
bilirubin above 30, maybe something lower, peak or maximum bilirubin comparing
two interventions or an intervention against a non-intervention control, or
decrease in the use of other treatments, such as exchange transfusion and/or
phototherapy. All of those are surrogate
endpoints.
[Slide.]
A
set of quotations from an article by Fleming and DeMets in the 1996 Journal of
Annals of Internal Medicine where they looked at surrogate endpoints, and these
are several points they made about the use of surrogates:
"The
surrogate must be a correlate of the true clinical outcome and fully capture
the net effect of treatment on the clinical outcome;
"To
be a valid replacement endpoint, a surrogate must provide a high level of
accuracy in predicting the intervention's effect on the true clinical endpoint;
"The
primary goal (in these definitive phase 3 trials that they were discussing)
should be to obtain direct evidence about the intervention's effect on safety
measures and true clinical outcomes."
So,
I am not going to answer the question, but the question is what is the
appropriate endpoint to use in some of these studies. I think it is fairly clear it is not
kernicterus. The question then is what
is it.
[Slide.]
So,
now some reflections about the justice of healthcare distribution, and I am
going to actually present some data from California. I think it might even be Southern California,
but I am not sure.
[Slide.]
But
the point is raised by this notion of equitable selection. Now, usually, equitable selection means if
you have a research trial, that you equitably select those who go into the
trial, so I am using this, though, to raise some more general questions about
equitability.
[Slide.]
What
struck me in looking at the AAP's document on neonatal hyperbilirubinemia,
which looks like it was also reflected in the same list that Dr. Bhutani put
up, is that the root causes of kernicterus, if you look at them all, early discharge with no early follow-up,
failure to check, failure to recognize, underestimating, lack of concern,
delay, failure to respond, all of these are behavioral aspects, all of these
are systems issues that appear to be totally unrelated to phototherapy,
unrelated to the giving of a medication.
Now,
I am not presuming to say what the answer is to correct the deficiencies, and I
also agree with the comments that you don't look for a behavioral
solution. Practicing in an intensive
care unit, we need systems to correct this, but question is what is the best
system for correcting these root causes - is it drug development, is it
universal screening, is it some other process.
[Slide.]
Now,
the issue of equitability was raised for me in looking at an article that came
out in Pediatrics just recently, again based on data from the 1999 California
Maternal and Infant Health Assessment.
In
looking at the adjusted odds ratios for either early discharge or for
inadequate follow-up with early discharge described as less than two days after
vaginal delivery or less than four days after cesarean section, and the
particular question was, in spite of the fact that we had a federal law
stipulating that they had to be provided, who didn't get it.
[Slide.]
At
least for early discharge, the only variables that fell out as important was
maternal income, and that was the adjusted odds that you see there in terms of
predicting who got discharged early, odds ratios for untimely follow, and I see
the formatting here didn't work quite perfectly, but basically, maternal race
or ethnicity, Latina, maternal income again, Medicaid insurance, or the primary
home language being non-English, those were the predictors of untimely
follow-up. So, those infants who were
born to mothers that had these criteria were those that were at risk for not
having appropriate follow-up.
Now,
that may reflect a number of different factors that were outlined by our
speaker from Southern California, but this is the population that, in fact, is
at risk. So, it would also be the
population that is at risk for whatever intervention we decide to design.
[Slide.]
The
authors point out that this is an inequitable pattern.
[Slide.]
Now,
what is interesting to me is if you rely on the IRB system to help with these
kind of public policy decisions, you will be sorely disappointed because
actually in the regulations, the IRBs are told that they shouldn't pay
attention to the impact of research on public policy, and this is a direct
quote from both FDA and it also is mirrored in the HHS regulations:
"The
IRB should not consider possible long-range effects of applying knowledge
gained in the research (for example, the possible effects of the research on
public policy) as among those research risks that fall within the purview of
its responsibility."
But
the question before us is, does that fall under the FDA's mandate in terms of
promote and protect the public health.
[Slide.]
Let's
talk a little bit about treatment versus prevention. In reflecting on this, it struck me that the
paradigm has always been one of prevention.
It was mentioned by a number of speakers. There is no treatment for kernicterus.
So,
the choice of total bilirubin of 20, I was taught, and it was, of course, in
Boston in the early '80s that part of the reason for this number of 20 was the
balance between the risks of kernicterus and the risks of exchange transfusion. Now, whether or not that was ever carried out
in a systematic way, who knows, but that at least was the argument for picking
20, that if you did it at a lower level, you are exposing an inappropriate
number of infants to the risk of mortality and morbidity from the exchange
transfusion.
Now, the choice of the lower level for
phototherapy reflects a judgment of the greater safety of phototherapy versus
exchange transfusion, and it had the particular therapeutic goal of preventing
the need for exchange transfusion, again, a surrogate outcome.
The
intervention then, in reflecting on this, is designed to prevent the need for
phototherapy, if you chose that as a surrogate outcome, should prove at least
as safe as phototherapy, assuming equal efficacy in limiting peak bilirubin
level.
[Slide.]
So,
the risk-benefit that we need to look at depends very much on the endpoint that
we select, whether we pick preventing kernicterus, preventing the need for
exchange transfusion, some maximum bilirubin level whether it is 20, 19, 18,
17, 16, 15, whatever number we pick is going to mandate then a different
balancing of the risks and benefits for each endpoint.
The
safe and efficacy tradeoff, nothing is ever perfectly safe and 100 percent
effective. There is going to be a
balancing.
The
risks of developing kernicterus and/or other irreversible neurodevelopmental
impairment should be at least equal to the risks of an intervention at any
given bilirubin level, again assuming that it's 100 percent effective. If it's less effective, then, of course,
perhaps the risks of the intervention need to be even less.
[Slide.]
Now,
this reflects to some extent the notion of equipoise, the position within which
we are truly uncertain whether we are uncertain as an individual or at least
uncertain as a community of experts about the comparative merits of the two
different interventions.
[Slide.]
In
trying to take this notion of equipoise into this setting, I tried to ask
myself what does it mean to say I am in equipoise or we are in equipoise in
this setting. It is that level of
bilirubin at which the risks of the intervention are comparable to the risks of
irreversible neurodevelopmental impairment, what are the risks of that
bilirubin level again assuming effective intervention.
Other
ways of stating this is that the risks of whatever intervention we are
considering using, whether phototherapy, exchange transfusions, or medication,
to stop the rise in bilirubin needs to be comparable, balanced with the risks
of the impairment of that bilirubin level, below bilirubin at that point, the
risks of the intervention exceed the risks of the actual condition itself.
[Slide.]
Now,
the treatment paradigm is perhaps applicable for a subpopulation of newborn
infants at known risk. It struck me as
interesting that most of the early studies were done in infants with increased
production, so I asked myself whether going forward we should begin to make
distinctions between, if you will, a condition of production versus slow
elimination and begin to parse out the population of infants that are at risk
for elevated bilirubin in that manner and begin to wonder should there be
differential interventions based on that.
This,
of course, if went that direction, would have a big impact on the kinds of
target populations that we would select for our interventions, whether it is
newborn infants with increased production or so-called healthy infants who may
have an elevated bilirubin due to slow elimination.
[Slide.]
This
has been touched on a bit. One of the
major issues that we need to talk about is at what risk for what, and, of
course, the numbers needed to treat for any given intervention at any given
bilirubin level will impact then on the risk-benefit assessment of that
particular intervention, and these are just numbers that were taken from the
reports that were part of today's documents.
So,
there are really two questions: what is
the acceptable false positive rate for selecting infants at risk for an
elevated bilirubin, say, above 10 at any given bilirubin level? Another way of asking that, which was an
earlier question by Norm Fost is what is the acceptable false negative rate, if
you will, upon discharge if you are trying to exclude infants for coming back
for follow-up for bilirubin. All of
these are questions that we will need to struggle with, the answers of which
are not, from hearing the discussion, obvious to me.
[Slide.]
Finally,
what about the ethical and regulatory issues in study design. Now, briefly, when we look at pediatric
research, if that child is not going to have the possibility of direct benefit,
there is limits about what we can do as far as risk, and even if the child is
going to benefit, there is limits about the justification for that risk
exposure.
[Slide.]
I
am not going to spend a lot of time on the non-therapeutic risk in the
interests of efficiency, but basically, this notion of minimal risk, which is
debated about how it should be interpreted, but basically, tries to get a
handle around the risks that if there is no benefit to that infant, we should
restrict those risks to no greater than minimal risk, of if we consider that
infant to have a condition, maybe a minor increase over minimal risk.
So,
when you look at some of the components of a study, certainly blood sampling
and PK data, you know, regardless of whether or not a parent wants their infant
to be stuck with a needle, that's a separate question, or would consent to
that.
I
think most IRBs would consider that if the sampling follows closely sort of the
routine sampling you would have for the following of a child with
hyperbilirubinemia, that they would consider that sampling either no more than
minimal risk or even a minor increase over minimal risk, but either one would
likely be approvable by an IRB if it followed kind of what our standard
practice is, and generally, blood sampling is considered minimal risk even if
it went above that to a reasonable number and volume and frequency. So, I don't think that is the issue.
[Slide.]
The
issue is going to be then judging the intervention itself. The regulations, although they predate this
notion of equipoise in the literature, I think roughly try to capture this notion
of equipoise or balancing, and this is taken from the regulations themselves
and it particularly is 21 CFR 50.52, which is the FDA version of the pediatric
regulations.
The
IRB is supposed to allow a trial to go forward if there is two things that that
trial satisfies under the assumption that that infant has the prospect of
direct benefit.
The
first is that the risks must be justified by anticipated benefits. That is within each arm of the trial, so that
the risk of the intervention and the anticipated benefit of that intervention
is relatively matched for that particular arm.
So,
for example, if there is a placebo intervention, you are going to assume then
that the risks of the placebo and the benefits to that infant are roughly
balanced, and that is what I call internal equipoise. Each arm of the study has to have that kind
of balance.
But
then there is another relationship that I call external equipoise or even
equipoise between the arms, which is this risk-benefit relationship needs to be
at least as favorable as available alternatives, and it is sometimes lost in
the discussion of this, that it is not only the two arms of the trial itself,
but it is also what that infant may or may not be getting that they would
otherwise receive, so that you need to have a sense that there is balance
between the interventions and the arms.
That needs to be the balance within this case. I could give examples, but I would probably
come up with ones that are not pertinent to bilirubin.
So,
the question is are the risks of the intervention justified by the anticipated
benefit. This relates as much on the
selection of outcome - the risk of a medication to avoid phototherapy, the risk
of phototherapy to avoid a bilirubin above 20, the risk of a medication to
avoid kernicterus. Each one of these has
a different risk-benefit balance, and each one of these, depending on how you
designed a trial, to put one arm against the other, would have a different
sense of whether we would be more or less certain about the balancing between
those interventions.
Then,
again, the risk of medication versus the risk of phototherapy at any bilirubin
level, for example, if you decide to treat at 17 or 16 or 15, what would you
say to a mother who is asking what is the risks of phototherapy at this level
versus the risks of a medication, and could you say that medication in the
trial or at least in the trial where you are randomized perhaps to phototherapy
or medication, is, in fact, in equipoise.
That
is a question that we would need to ask and answer in the affirmative for a
trial to be able to go forward.
[Slide.]
So,
to justify a risky or less safe intervention requires a greater anticipated
benefit, and not simply the ability to achieve the benefit whether achieving
that benefit is worthwhile. So, that is
a question we have to ask.
I
think I am leaving you with my final question, which is sort of a whirlwind
tour through my remarks, which is I think the important question that we need
to ask and answer, and I suspect we will not be able to answer it today, but
whether we end up in the same position both looking at the issue of sound
research design with respect to surrogate endpoints, but also looking at the
sort of ethical analysis of equipoise, is that really the key issue here is
appropriate outcome selection to reflect genuine benefit for the selected
target population, so we need to define in the course of answering that
question, not only are outcomes that we think are appropriately selected for
the design of a trial, but what benefit we anticipate achieving by having
selected that outcome and then what population we think that is appropriate to
then target out interventions towards in order to make a change in that
outcome.
Thank
you.
DR.
CHESNEY: Thank you very much.
I
think this is such an important issue, are there any questions? We could probably entertain a small number of
questions for Dr. Nelson before we go on with the official questions.
DR.
FREEMAN: May I ask a question of Dr.
Nelson? If the FDA is not to be involved
in policy, in social policy questions, and the IRBs are not to consider social
policy questions, then, if you are going to use a medical intervention to avoid
phototherapy and the consequences of hyperbilirubinemia, and since as the
problem has been presented to us with phototherapy, it's the women getting
discharged early and the difficulties coming back, how do you factor that into
the equipoise?
DR.
NELSON: Maybe I stated it too
quickly. I think the IRBs are directed
not to look at issues of public policy, but personally, I think that although
FDA may or may not agree, I think is within the purview of this notion of
promoting the public health, and where that comes in is trying to decide what's
the appropriate safety and efficacy profile since, you know, what does safe
enough and what does effective enough mean in the context.
As
I recall that first slide that went up, that Dianne Murphy showed where the
different balancing is, where do you balance that relative to the volume of
individuals that a certain drug would be targeted for and the indications. So, I do think that is within the purview of
trying to decide from a public policy perspective what is the appropriate
intervention.
The
only question I am raising is when a lot of the root causes for this are
systems issues that are unrelated to the drug.
Maybe a drug development program would answer that, maybe it wouldn't,
maybe universal screening would answer that, which is what I heard a number of
our speakers argue for, maybe some other systems approach within the healthcare
setting would begin to address that.
I
was simply raising that question for our consideration.
Discussion of Questions 2, 3, and 4
DR.
CUMMINS: First, I want to thank everyone
for sitting through quite a complex series of presentations and also comments
during our public hearing.
We
don't have our questions available to you as PowerPoint files, but you do have
a handout in front of you in the packet that was set out in front of you today,
that have all the questions on them in the second page following the
agenda. Tom is trying to load them now,
but we can also start to walk through them.
We
actually decided to skip Question 1 and go straight to Question 2, and we
reordered the agenda today because we felt it was important that Dr. Nelson's
talk go before Question 2, and I will read that to you now. It's a multi-part question and we would like
you to really discuss the various issues that are raised in this question.
Question
2. In the context of current medical practice,
including phototherapy, should drugs be developed for an earlier intervention
to prevent hyperbilirubinemia in newborn infants?
In
answering this question, we would like you to please discuss the following:
Your
understanding of the relationship between bilirubin toxicity and
neurodevelopmental outcome;
How
you define the population at risk for complications of hyperbilirubinemia;
The
intervention sequence and what that might be, should it be more screening--and
these are just examples, there might be other interventions that we have not
mentioned--but examples might include more screening, additional monitoring and
assessments, phototherapy, hydration, pharmacotherapy, cessation of breast
feeding, changes in infant nutrition, home nursing visits, and why would you
propose that intervention sequence.
Let
me just also say for those of you that are new to this process, what we will do
is we will discuss each of these questions for about 15 to 20 minutes, and then
we will move on to the next one. That is
how the question process works.
With
that, I will turn to Dr. Chesney and open the committee up for discussion.
DR.
CHESNEY: So, we are being asked the
question of should drugs be developed for an earlier intervention and to take
into consideration our understanding of bilirubin toxicity and
neurodevelopmental outcome, who are the high risk populations, and with respect
to the intervention sequence.
Comments?
I
should also tell you that it has been suggested to me that we do a round robin
after Questions 3 or 4, so that we hear from everybody, so everyone will have
to come to grips with this issue at some point.
Dr.
Mattison.
DR.
MATTISON: I guess there is no reason to
think that therapeutic strategies including medications should be excluded from
consideration in dealing with strategies to prevent hyperbilirubinemia, but it
seems to me that the question has behind it a set of qualifiers or steps that
may need clearer explication, for example, and it has been brought up
repeatedly in the presentations, one of the areas that appears to be missing in
terms of thinking through the issue of hyperbilirubinemia is the actual
strategy for identifying those kids.
So,
while drugs might be a good strategy, it seems like the basic public health
surveillance that we often use to identify our problem hasn't yet been put in
place.
So,
I am not answering the question, I am backing away from it perhaps.
DR.
MURPHY: I think you are giving us the
level we are trying to lay out of all the issues that you have been presented
today - what would be the role of drug development in this environment and how
do we deal with these issues of definitions of occurrences, definitions of when
we intervene, outcomes, you know, those all are things that you have heard
about in various forms today, that you would try to synthesize that into some
thoughts about how one would go about considering developing a product in this
arena when you have to address some of these issues of what is the relationship
because we have to be able to know what the endpoints are, and to be able to
get to the endpoints, you have got to know where you are going to intervene.
Again,
it is trying to bring back all those issues you heard today to an approach
developing products in this present environment. So, you were right, it is trying to
synthesize all that into a few bullets.
DR.
CHESNEY: Dr. O'Fallon and then Dr.
Danford and Dr. Hudak.
DR.
O'FALLON: The question here is really a
mixture of a whole lot of stuff and I think we have to sort out what the major
themes really are. I think the very
first theme is a matter of, as you said, identifying the patients, the babes,
the children that are truly at risk.
So,
there is a whole diagnostic issue that needs to be dealt with, and it has
nothing to do with treatment, it has to do with diagnosing and characterizing
that.
The
second part is okay, if we are going to treat, it sounds like there are only
two treatments right now, the treatment quiver has only two arrows in it, and a
third one sounds like it would be very appropriate to have a third one, so,
yeah, go ahead and develop it for something, but how to do that and how to test
it brings up all the issues that Dr. Nelson was bringing up, all of the design
issues, choosing an endpoint, you know, and what you are going to buy by it,
and another thing that was brought up earlier this morning and has just been
sitting there, but the negative predictive value of these treatments.
It
is very important, it seems to me, when you have a rare disease, a rare
condition, that the testing be capable, it is very important to prevent a lot
of kids that don't need it from getting something.
The
other part of it is, that has to be dealt with, are the long-term effects. I think those of us with more gray hair in
this room, the problem is that we have been around and we have seen, I can name
you several treatments that I was told at the beginning, oh, this is wonderful,
there are no long bad effects at all to it.
Yeah, sure. They do show up and
so there are issues here that have to be dealt with.
So,
it seems to me there are basically four things going on here, and we have got
to sort them out and get answers for each one of them.
DR.
CHESNEY: Dr. Danford.
DR.
DANFORD: I would like to address the
first bullet point under Question 2, my understanding of the relationship
between bilirubin toxicity and neurodevelopmental outcome.
Despite
the wonderful presentations of a large volume of information today, I would
characterize my understanding of that relationship as poor. I would point to the large numbers of
children in Northern California presented to us with bilirubin levels in the
classically scary ranges who seem to be neurodevelopmentally fine.
I
would also point to the allusions that our speakers made to perhaps some
neurodevelopmental issues of more minor importance occurring in children whose
bilirubin levels were well within the ranges we would accept as safe.
I
don't know what the relationship of that is, and the implication of that, as I
looked at Dr. Nelson's slide, bilirubin levels are not necessarily a very good
surrogate for kernicterus as he laid out what makes a good surrogate. That is a
very difficult point for me right now.
DR.
CHESNEY: Dr. Hudak.
DR.
HUDAK: I guess I will make some
relatively simplistic answers here. I
think the first question about the relationship between toxicity and bilirubin
and outcome is there is apparently a lot of biological variability. Some babies can sustain a higher bilirubin
level than others without damage, others wind up apparently having some toxic
effects at lower levels, and there is no way of knowing ahead of time how a
baby is going to behave in that setting.
I
think the evidence is persuasive and undeniable that babies don't get
kernicterus without having bilirubin levels that are higher than we like to see
in most cases with the exception of certain babies with comorbid conditions
like sepsis where they might get effects that lower levels or the blood-brain
barrier perhaps is impaired.
So,
I think that we have to grant from all the evidence we are not going to get any
better knowledge about this issue at any time in the future, that, yes, there
is a relationship between high bilirubins and the risk of kernicterus, and it
is very variable and it is very unpredictable.
The
issue of should there be drug development, I think the answer to that is
yes. I think we are all struggling with
how to sort of phase that into testing and what are the study designs, but the
basic answer is yes. If we had a drug that
had no side effects whatsoever, I think that would be--and we knew that for a
fact--that would be a no-brainer. I
think every baby in the country would get a drug to prevent hyperbilirubinemia
at birth, just like they get vitamin K and erythromycin ointment for the eyes,
and things like that.
The
question is understanding what the level of acceptability of risk is with that
sort of intervention, and that's a big question. If you consider we don't know how many cases
of kernicterus there are in this country out of 4 million babies every year,
but if it is 1 in 200,000, that is 20, if it is 1 in 100,000, it is 40, if it
is 1 in 50,000, it is 80, so even if you say that it is 100 babies a year, and
think of that, that is a very, very small percentage.
So,
if you say all right, what happens if there is a complication from your
treatment, that is on the order of 100 out of 4 million, you will never find
that in a randomized placebo-controlled study.
You will have to wait and hope and pray that you do not experience that
once you go to the route of having prophylaxis in every baby. There will be no way of knowing until you do
that.
But
we do need a treatment. Exchange
transfusions are not nice, they are complex, the expertise is deluded, there
are neonatologists out there practicing who have never done an exchange
transfusion, I daresay.
There
is a mortality, there are other morbidities, and exchange transfusions do not
necessarily prevent kernicterus either.
I just reviewed a legal case from a very well respected busy tertiary
nursery where a baby came back at two or three years of age with sort of what
you would call I guess, not the full-blown kernicterus, but a little bit of
choreoathetoid CP and hearing deficit, and this baby was sitting in an intensive
care nursery getting bilirubins monitored every 4 to 6 hours, and because
people were reluctant to do exchange transfusions, the bilirubin went up to 32,
and this kid had an exchange transfusion, but then did have the clinical
sequelae.
So,
I think that certainly if there had been a drug available to prevent
kernicterus in that baby, it might have been used at an earlier point in time,
that baby might have done much better, and that would be a relatively limited
population.
But
I think yes, we do need a drug, we do need some development. The real hard questions are who do we treat,
when do we treat them, and what are the ways that we can develop to sort of
improve the system, so a lot of these babies don't slip through the cracks.
DR.
CHESNEY: Yes, Dr. Oh.
DR.
OH: I am willing to stick my neck out
and say that the answer to the question should be yes, and I tell you the
following reasons. One is that although
we don't know the exact incidence of kernicterus, the fact that we do see them,
particularly with the data, in the population-based data from New Jersey,
suggests that we do have a problem, and we also don't know what the threshold
number is for the bilirubin that will cause kernicterus.
On
the other hand, understanding the pathophysiology of kernicterus, we know that
although there is no threshold number that we are worried about in terms of
producing kernicterus, we do know that the higher it is, that might exceed the
so-called binding capacity of albumin for bilirubin, the more risk you are
taking.
So,
anything that we can do--and we also know that phototherapy itself has some
problem in terms of keeping the levels at a certain range on the basis of
perhaps, not so much the effect of the therapy itself, but the behavior and
system involved that might cause problems in terms of allowing the bilirubin to
a certain level--and that anything that we can do to try and keep the bilirubin
level down as low as we can will be I think a benefit.
I
think it will be a good surrogate, not so much a surrogate for the outcome, but
in terms of keeping it low enough, so that we are in the comfort zone, so to
speak. But I hasten to add that any kind
of drug trial, any development of the drug should be very well designed to not
only look at the acute, but also the long-term potential side effects of a drug
that may have some problem that we don't know about.
Right
now we don't know what the potential complication is for this particular drug
we are talking about, and any drug trial should have the safety aspect looked
at very carefully before, you know, so that we will come out with data will
show that, not only that it has some benefit, but the side effect is minimal,
going to the point about balancing the risks versus benefits.
So,
that is my comment on the issue. I think
the important thing is that despite the guideline and maybe because the
guideline being too gentle in terms of managing the bilirubin, in spite of the
phototherapy that we use, we are seeing kernicterus in our population, and I
think that we need to develop another intervention to try and improve our
ability to handle the bilirubin in the newborn period.
DR.
CHESNEY: Thank you.
Dr.
Lau.
DR.
LAU: I think there is still quite a bit
of debate as to whether bilirubin is a neurotoxin, but I think in terms of
causality, but I think the evidence for association is fairly strong.
Then,
there is also strong evidence to suggest that by lowering bilirubin with the
treatment of phototherapy, we would reduce the incidence of kernicterus.
For
the other question about defining the population, my perspective is often from
the evidence-based approach of reviewing the literature is backward, that
is, I often end up with studies rather
than prospectively designing trials, so the approach that we often take in
looking at the validity of trials would be what is known as the peephole
process or looking at a patient population, what intervention were examined,
and what are the comparators, and then what are the outcomes.
I
think we have discussed a lot of those issues today, and those are not easy
things to tackle in a population, I think obviously we are not thinking of
treating millions of babies, and defining the population is going to be difficult, but I think we may
have some tools from some of the work done by various investigators to try to
define a population.
The
intervention, I think that is more well defined and there is only one drug
being considered. The comparators, that
also would be somewhat difficult to define exactly what it is being compared
with.
The
outcomes, this condition is not a disease.
I think there is also going to be quite a bit of uncertainty, how best
to define that.
DR.
CHESNEY: Thank you.
Dr.
Wilfond, I think was next, and then Dr. Stevenson.
DR.
WILFOND: With regard to the question of
kernicterus, it is unclear to me what is going on with that, however, I am not
sure, I feel comfortable without even knowing that making some other
reflections.
I
think that the slides that were presented, that suggest that the causes of
kernicterus are behavioral make sense, and in that regard, it would seem like
having a drug wouldn't necessarily address that problem.
However,
I am still in favor of the idea of drug development conceptually because if we
look at the choices that Skip gave us for what we might want to make as a
comparison, if we believe at some point it is a reasonable thing to do
phototherapy on some people, if we had a drug that was sufficiently safe and
sufficiently expensive to reduce the number of individuals who had
phototherapy, that would be a good thing.
So,
I think it is going to depend upon, in the end, its safety and its ultimate
cost, but I think the objective would be to decrease phototherapy.
DR.
CHESNEY: Thank you.
I
have Dr. Stevenson, Dr. Glodé, and Dr. Fost next.
DR.
STEVENSON: I just want to weigh in on
the issue of bilirubin toxicity although I think that in the human
circumstance, it is hard to do an experiment that would do prove that causative
link definitively.
For
those of us that work in the animal model, there is no question that bilirubin
is toxic, and you can create conditions of a variety that mimic what we would
see clinically and see the impacts of those factors like infection, and so
forth. There are biological ways in
which that can be understood.
We
haven't spent a lot of time talking about those models today, but there is a
whole area of biology that is focused on that, so I don't want people to think
that there is any doubt about bilirubin as a toxin from a biological standpoint
under certain conditions and at certain levels.
The
comment that I would like to make besides that, though, is to sort of remind
people that there is an undeniable biology here, and part of that has been
addressed by a drug like phototherapy light, and that part of the biology is
the limited elimination that the newborn has.
We
don't use that medicine very well, but we can probably use it better and more
efficiently. But the other part of the
biology is really the production of the pigment, and I told you that all
newborn babies have a higher production compared to adults, about two or three
times higher, and for many of the individuals who find themselves on these
unfortunate lists, being near term or individuals that develop other
conditions, like G6PD, they have very high production rates of the pigment.
So,
there is an undeniable logic that an additional arrow in the quiver is
required, which addresses that part of the biology, so as a scientist, the
logic for that is undeniable.
The
issue then becomes one of putting that in the context of your other arrows and
when do you shoot them, and I think that some of you are touching upon those
more difficult questions about how best to identify the individuals that would
be the target of that kind of intervention.
I
think that the kinds of drugs that are represented by this new class of heme
analogues, that are competitive inhibitors, suggests that there is a way to use
them that can target them very precisely.
They may even work in more precise ways than phototherapy works, and
could be very, very useful in the circumstance.
So,
the last thing I would say, to make this thing come full around for you, is
that because of the unpredictable nature of the onset of this condition, and
the fact that when you see it, you are deep into it, and unlikely to be able to
prevent it, because it is happening. There may be some debate about if you get
it early enough, you may have some reversibility.
Then,
you are faced with there being the best quiver solution, the best arrow in your
quiver, because by that point in time, you are already dealing with something
that is upon you. It is hard to use as a
preventive tool because the bilirubin is not there to actually undergo the
photo isomerizations.
So,
the chemical approach is actually a more logical approach if you are interested
in prevention and avoiding something that is, as you have heard, very hard to
predict.
So,
I would just like to leave you with those thoughts.
DR.
CHESNEY: Dr. Glodé.
DR.
GLODE: I sort of have two lines of
thinking I wanted to bring up. The first
one would be that at least from my sense of top priority, the question would be
that the priority is prevention of kernicterus and perhaps other subtle forms
of neurologic impairment, and the question would be do we currently have
effective therapies that we believe can at least prevent the tip of the
iceberg, the kernicterus that we recognize.
It
seems to me from the discussions today that the phototherapy and exchange
transfusion are effective therapies. If
there were another effective therapy that was proven to be more effective or
equally safe to those two, then, I would certainly favor its development, but I
would favor that it be studied in selected populations of children with
hemolytic anemias predominantly.
The
second issue has to do with the paradigm that was brought up today. The one we heard most often was the vitamin K
deficiency paradigm, and all babies get an injection of vitamin K. But I would like to bring up the other
paradigm of the newborn screening, which deals with rare conditions, but really
does not, except from a public health point of view that we can't effectively
identify and track patients, so we have systems set up.
We
don't say we can't prevent cretinism because it is impossible to do a newborn
screen and follow it up. We say we can
do that, and so we have systems in place, at least in Colorado, through out
state health department and through our section of Pediatric Endocrinology,
that we follow up everybody with an abnormal thyroid screen. We just don't give all babies thyroid
hormone, and we follow up all babies with abnormal PKU, et cetera, where we are
able to do that effectively and prevent those rare but devastating conditions.
So,
I just think we should be able, even though again maybe it is not within the
purview of the FDA, but somehow we should be able to develop public health
policies that identify high risk children based on the nomogram, and they get a
letter sent home with them, they are reported to the state health department,
they are followed up on, they get another bilirubin, they get interventions,
and we prevent kernicterus.
Now,
I am again not against developing another drug, but I am really worried about
giving it to 4 million children and the safety profile issue, but I am all in
favor of preventing kernicterus by identifying babies and treating them early.
DR.
CHESNEY: Thank you.
Dr.
Fost.
DR.
FOST: We are all concerned about
studying history so we don't repeat it, but the question is which historical
examples are relevant. There are several
examples of newborn screening and treatment that I worry about, that I am
concerned we don't repeat.
The
first would be PKU screening, the granddaddy of all newborn screening and
intervention programs, and there are several echoes with this story that
concern me.
In
1960, we had a rare disease, its biochemistry was very well worked out. It was very clear by 1960 that if you reduced
exposure to phenylalanine, you could ameliorate and even prevent retardation,
and there was great passion by advocacy groups, including affected families and
Dr. Guthrie himself, and the president John Kennedy.
So,
we mandated PKU screening in every state, and it was 10 years before we
realized that the screening test was too sensitive, that is, that 95 percent of
the children with high blood phenylalanines, not just Guthrie's, but confirmed
by whole blood assays, did not have PKU, but had a benign form of
hyperphenylalaninemia that were destined to be normal.
Second,
that restriction of diet could be just as
harmful as excess, that is, the toxicity of the diet was not
appropriately anticipated, so many of these normal children were not only made
retarded by the diet, but were killed by severe protein malnutrition.
We
don't know how many. We know that it
took a decade, and it wasn't until 1972, '71, '72, that the Institute of
Medicine formed a panel, and we now understand it perfectly, and we now know
how to identify the subset of children with elevated blood phenylalanines who
are really destined to become retarded, and we now know exactly the right dose
of the diet.
All
this sounds very worrisomely similar to what we have now, that is, we have a
cohort of children who have an abnormal screen, whether it's visual or biochemical. We don't know exactly what subset of them is
destined to have anything very bad happen.
We know that kernicterus is very bad, but I agree with Dr. Danford, it's
a little unclear whether the vast majority of these children are going to have
anything very bad happening to them.
We
have an intervention that looks very promising,
whose biochemistry is well understood, but we just don't have a lot of
data on the safety of it and maybe not as much as we would like on the efficacy
either, although that seems a little bit more clear.
There
are five other examples. I mean
bicarbonate for respiratory acidosis, hyaline membrane disease, the
biochemistry was well understood, the kids were all dying of severe acidosis,
just give them bicarbonate, the Aschner
[ph] regimen, it will be fine, and it was 10, 15 years before Mike Simmons did
a randomized, controlled trial, and said
it was killing kids, it was causing intracranial hemorrhage in some, and now
nobody gives it, but there was no prospective, careful trial for a decade.
Oxygen. For a century we inspected the kids, these
obviously need oxygen, then, we got more fancy, we measured it, give them
oxygen, it can't possibly hurt, and look how devastating the consequences of
hypoxemia are.
Then,
finally, we learned that it had a dose-response curve, you could give too much,
and so on.
Antibiotics. I mean sulfonamides, there are half a dozen
examples, and the number of normal children who have been killed by these
things is probably in the tens of thousands.
So,
it is not that we don't care about the small number of cases of kernicterus or
PKU, or whatever, the question is how to capture those and reduce them even
further or eliminate them, and not harm a lot of other people in the process.
So,
it seems to me doing studies that, as Skip put it, that would maximize the
benefit-risk ratio for each child in a study, so a child who has a discharge
bilirubin of 5, I assume has nothing to gain from being in a study of a new
drug that might prevent kernicterus. One
that has a discharge bilirubin of whatever the number is, a much higher number,
15, obviously has a lot to gain by being in this trial, and it might avert
something that maybe is more risky, I don't know if phototherapy is more risky
than this drug or not.
It
seems to me the first challenge, is drug development good, of course, it is
good. I mean it is self-evident that if
we have a drug that is equally effective as phototherapy or exchange
transfusion, and it is cheaper and safer, of course, it should be preferred,
but that is what we are trying to find out.
So,
in trying to find out, it seems to me we should be as narrow as possible in the
beginning, so that the children who are entered into these studies have the
most to gain and the least to lose, we have the least number of kids in these
studies who are at almost no risk of developing a problem.
Those
are just some of thoughts about that. I
want to say a second thing, which is the elephant in the room that we are sort
of not allowed to talk, which is cost, not an FDA concern, not an IRB concern,
it is nobody's concern in this country, so we have these expansive
technologies, we have these innumerable examples of drugs that are developed
for very narrow purposes, in this case, to prevent a disorder that affects a
mere several hundred children a year, terrible for each one obviously, but we
know that that is not how it is going to be used once it's approved, and that
the FDA is virtually powerless to stop the expansive use of it.
We
know how the pharmaceutical companies manage to influence that even though they
are legally not supposed to be marketing off-label uses, but it has happened so
over and over and over again that, as the background materials suggest, the
concern always is that even if we were able to reduce the number of children
with kernicterus, what will the cost be, that is, how many millions of children
will get this drug who have nothing to gain from it, and what will the toxicity
be.
Now,
if it's like vitamin C, we prevent lots of scurvy with vitamin C or like
vitamin K, if it's virtually riskless, then it won't matter. If it's free, it won't matter, like vitamin C
or virtually free, but if it costs a lot, either in terms of toxicity or in money,
then, we have a problem.
The
cost in terms of toxicity, FDA is authorized to pay attention to and will. The cost in terms of money, they are not, so
we might have another, what, I don't know, billion dollar drug on the market
that does nothing for 99 percent of the people who get it? And we continue to have a healthcare system
in which 40 million people are insured,
one-third of them children, and we say we can't afford to do anything
about that, but we can afford to give everybody 10 protoporphyrin.
So,
those are the two things that worry me, the one that we can't do much
about. The first one, we can do
something about, which is to make sure that studies that are designed are done
in a way to maximize the benefit to the children who are in the study, so that
eventually, hopefully, the use of the drug could be limited to those children
who have something to gain from it.
DR.
CHESNEY: Thank you.
Dr.
Newman and Dr. Freeman.
DR.
NEWMAN: I want to comment on these two
examples that have been used, the vitamin K and the newborn screening. I appreciate Dr. Fost's PKU example, which I
hadn't heard before.
It
is a little bit misleading to compare, oh, all we need to do is do a bilirubin
level that costs a dollar or two dollars and ten dollars, it could be like
newborn screening. If you picture, if
your screen for hyperthyroidism had a specificity of 40 percent, because the
recommendations for the systems approach to hyperbilirubinemia screening are
that the top 60 percent, it is only the bottom 40 percent we are reassured they
don't need another bilirubin level, the top 60 percent, they all are labeled as
having a bilirubin problem and need to come back and all need a mandatory
second bilirubin test.
So,
that is sort of the problem for me, which is that it would be wonderful if we
could do a test before they left the hospital, that said yes, you have a
problem, you don't need to worry, and it had anywhere near the sensitivity and
specificity of our newborn screens, but they don't.
One
of the speakers said prevalence should not be an issue. Prevalence is an issue when you have
diagnostic tests that aren't very good, and you have high false positive rates,
and the lower the prevalence, the higher the number of people you are going to
need to treat and the more false positives.
The
trouble here, the AAP, in their new guidelines, are not recommending universal
bilirubin screening, and it's for this reason, the test just does not seem to
be that good, it is not clear what to do with the result.
DR.
FOST: Can I just ask you one
question? That is why asked Dr. Ip this
morning what the negative predictive--I understood one of his graphs to show a
negative predictive value of 99.5 percent.
That is pretty darn good.
DR.
NEWMAN: Again, if you are in the 40
percent who have, you know, the bottom 40 percent. The trouble is the positive predictive value,
if you have a bilirubin level that is in the top 60 percent, and therefore you
are labeled, but, of course, most of those will be the false positives.
I
think the vitamin K is a really good example because, you know, several years
ago, many of you know there was an alarm about whether vitamin K caused
cancer. There were a couple of studies
in Bristol, in England, that really suggested that intramuscular vitamin K in
newborns doubled the risk of childhood cancer, and the first one, people didn't
pay that much attention to, it was a data dredging thing, and it was
appropriately believed that it should be
confirmed by another study, and the drug company, in fact, funded
another study, which found the same thing, a more than doubling of the risk of
childhood cancer after intramuscular vitamin K in Bristol.
Subsequent
studies mostly have not confirmed that, but I think that is the kind of
example, that is the sort of thing that worries me is, you know, how are you
going to find stuff like that and how many years later might it be, and how big a study for how long do you need
in order to say, oh, yes, this is a drug that we can give to hundreds of
thousands or millions of children to prevent something which is very rare.
DR.
CHESNEY: Dr. Freeman.
DR.
FREEMAN: Dr. Norm Fost made many of my
comments, and I agree with him. As a
neurologist, I fail to believe that kernicterus is an all or none thing. There must be toxicities of bilirubin at
lower levels even though we do not detect them.
So, I don't know what level is toxic or what level we should treat.
I
am also concerned about costs and the cost to society. I am very persuaded by Dr. Moosa's talking
about the number of poor women who leave his place with no ability to follow
them up and how do we deal with that.
Yes,
it would be very nice to have a medical treatment that avoided
phototherapy. I think we can, by and
large, we have avoided exchange transfusion, but we need something to avoid
phototherapy in this population.
On
the other hand, I am very concerned about the unknown toxicities of whatever
medication we do, and would like to see any trial, carefully monitored, in a
high-risk population, so that we can pick up these rare toxicities of whatever
drug we develop.
DR.
CHESNEY: Dr. Fuchs.
DR.
FUCHS: I am glad somebody finally
mentioned bullet point 3. I think that
is the hardest thing because as a medical community, we don't control a lot of
that, things you mentioned already, that people are not coming back as it is
for when you asked them to come back for bilirubins, or the other thing about
going to Home Nursing visits, home nurses will not go into the inner cities to
follow up these children either.
So,
there is a lot of issues that we, as the medical community, can't control
because of the whole system, whether it's HMOs or other things, that I think it
is going to be very hard to answer the intervention sequence when we don't have
a lot of control over that until, like you mentioned, the more screening, until
there is a better test, the same thing.
You can ask for additional monitoring, but if you can't get them back,
then, the system has failed.
DR.
CHESNEY: Dr. Smith, and then Dr. Ip.
DR.
SMITH: I am a chemist, so I believe that
chemicals are saving the world and will continue to save the world, so, of
course, we need as many arrows in our quiver as we can possibly get, but two
things I heard today have me thinking.
One
was Ms. Sheridan told us that really the difference between her two children
was a bilirubin test, and I think it is shocking that regular monitoring of Cal
didn't happen.
Then,
Dr. Valaes told us that in Greece, that as soon as they discovered
phototherapy--I wrote the words down--the problem was no longer there. I, as a chemist, of course, as many drugs as
we can have available, the better, but I am kind of wondering if there is a
problem.
DR.
CHESNEY: Dr. Ip, and then Dr. Aschner.
DR.
IP: The way I think about the issue is,
as a practicing pediatrician, without even thinking about your qualifiers to
your question, if I am presented with a drug that is as safe, as good as
phototherapy, would I use it over phototherapy, the answer is clearly yes.
So,
to answer that question, yes, we should develop this drug. Now, I don't know if you folks, some of you
have the FDA background document, a thick, thick book, if you turn to page 28,
there is a graph. It's at Tab 6. It is basically an analysis of all the
newborns who have idiopathic jaundice who develop kernicterus. It's the case reports, the reviews that we
did for the AAP report.
If
you look at the distribution, actually, 91 percent of these cases had bilirubin
25 or greater. There were three cases
between 20 and 25. I am just doing some
rough calculation. So, if you are going
to try to capture that particular population, if you are looking at 25 as the
cutoff, you would be treating about 6,000 kids, but if you are using 20 as the
cutoff, you would be treating 80,000 kids.
That is something that we need to decide how many kids are we willing to
treat and experiment with it.
DR.
CHESNEY: Thank you.
Dr.
Aschner.
DR.
ASCHNER: I am coming from a little bit
of a different background. I guess my
first comment would be that I am almost not sure that I have seen enough data
to make a good correlation between the level of bilirubin and kernicterus. In trying to think more about it, I would say
that there may be other issues in addition to bilirubin levels that might be
important in terms of determining whether a neonate would go on and develop
kernicterus at the molecular levels, cellular level, in terms of extrusion of
bilirubin from the brain and other parameters.
Now,
looking at a drug, I think obviously, I would be in favor of developing a drug,
but thinking again about toxicity and the potential that millions of children
will be exposed to it, I would like to know much more about the safety of the
drug, and I am just going to posit a simple question for everybody to think.
Let's
just consider, for example, that a drug has a 5-point IQ reduction in the
general population, what would that do to our society in terms of exposure to a
drug in 4 million children over 10, 20 years, and I am not exactly sure
actually how you would go about doing a randomized study to pick up the effect.
DR.
CHESNEY: Dr. Gorman, Dr. Nelson, Dr.
Stevenson, and then maybe we will stop at that point and ask the FDA folks if
they have enough information on this issue, that we can move on.
DR.
GORMAN: I am another one who learns well from analogies or at least I am
impressed by analogies, and the analogy that moved me the most today was the
lead analogy.
Bilirubin
in the blood doesn't hurt anybody, bilirubin in the brain hurts people. In the procedures of any clinical testing, if
there is any way to measure the bilirubin in the target organ rather than the
surrogate marker that we use so poorly, and therefore are troubled with our
results, would be a big advantage to ongoing studies short of brain biopsies or
autopsies on clinical subjects or human subjects.
I
am convinced that bilirubin is a toxin once it gets in gets in the brain.
I
will also agree as a practicing pediatrician that if it was shown to be as
effective and as safe as phototherapy, it would replace phototherapy as a
terrible, you know, with a great rapidity.
The practitioners in clinical practice would vote with their feet very
rapidly and phototherapy would disappear if you could replace that with a
single shot of any agent, be it this one or another agent.
Having
said that, I will address the 600-pound gorilla or the 800-pound gorilla, or
however big it was, in Dr. Fost's opinion, there will be therapeutic
creep. We will start this with a very
small group of people. In the clinical
trials, it will get tested with children with hemolytic disease and then
perhaps children as they enter phototherapy as an alternative to phototherapy,
and then it will be used to see if it can prevent phototherapy, and then it
will be generalized to the population.
That
is the therapeutic creep as I predict it if no untoward safety data come out
shortly, and I would say that this is one of those times which is exactly why
we need clinical research. I would
rather know if this drug is unsafe early rather than later, because I see this
drug potentially being used on 4 million children a year, 4 million infants.
The
other thing that I think as pediatricians, we all see intuitively, there is a
therapeutic window which makes this very difficult for this drug. It has to be used early, it can't be used
later. It is again like lead, if I
ingested lead, there will be those accusing me of that around the table, but if
I ingest lead now, I will be at less risk than if I ingested lead at six months
of age, so there is a therapeutic window for this drug that is also very
important.
Is
there an adult equivalent to kernicterus with high bilirubins? I think the answer is no.
So,
there is another issue about and will that same therapeutic window allow us to
see toxicities of this drug that we would not otherwise see.
DR.
CHESNEY: Thank you. Actually, it was an elephant, Dr. Gorman.
Dr.
Nelson.
DR.
NELSON: I agree, I think it's a
toxin. I am trying to play with some
numbers and I am not necessarily facile with them, but I am struck by the
difference between the numbers that were presented out of California and then
the numbers, although preliminary, from the New Jersey surveillance, having
lived in New Jersey. I was born in New
York, so maybe I am protected from that.
But 8 per 100,000 compared to a lower number, and the question is if you
assume that the bilirubin was greater than 20 in all of those that were at
risk, I was trying to calculate what would be the incidence per 100,000 of
those greater than 20 for kernicterus, and then add to that the question of
subclinical or irreversible neurodevelopmental changes that could be related to
bilirubin.
That
would give you a number and then the question is would you consider that an
appropriate safety profile for any intervention that would prevent anyone from
getting into that range of 20. You end
up with a number, such as using New Jersey statistics, 320 per 100,000 if you
assume all their cases of kernicterus occurred in those who had a bilirubin
greater than 20.
Then,
the question is what kind of trial would you need to see that incidence of
neurodevelopmental impact, and it would (a) be big, but I suspect if we had a
drug that we gave to 100,000 newborns and we got 320 cases of what looked like
kernicterus, we would consider that highly unacceptable.
I
don't really have a conclusion of these reflections, but the debilities sort of
trade off the interventions. You may end
up just in a simple situation where you are talking with the parents about the
relative risks of each intervention, which is what happens now with exchange
transfusion, phototherapy, and if the trust you, they will let it go up into
the 25 range, and if they are risk-averse on that, they may say exchange at 22
or 23, or 28 these days, so there is some variability in practice based on that
conversation.
DR.
CHESNEY: Skip, I am sorry, maybe it was
because I was writing, I didn't quite get the 300--I understand the first part
of how you were approaching this, but--
DR.
NEWMAN: I may have the math wrong. Part of it is coming up with assumptions
here. If you take the New Jersey
statistics, 71/2 per 100,000, round it up to 8, then, the question is if you
assume that all of their cases occurred in infants with bilirubins greater than
20, consistent with the report, then, what is the incidence in infants greater
than 20 of kernicterus based on their statistics, and I get 320--400, so it is
reasonably large in that population depending upon what you pick.
Then,
you go down to 15 or down lower, then, you get obviously lower numbers, but the
safety profile of any intervention, if the risk is 400 per 100,000, I mean I
suspect there is a lot of drugs on the market that are not considered that safe
that might not have that high an incidence of serious adverse effects, similar
to neurodevelopmental changes you see in kernicterus.
So,
if the New Jersey numbers are correct as opposed to the California numbers--and
that will be a debate I am sure once that comes out--that has a big impact on
how you would evaluate the safety of any given intervention.
DR.
CHESNEY: Dr. Stevenson, then Dr. Newman
and Dr. Hudak.
DR.
STEVENSON: This is a brief comment again
about production. I have heard people
talk about targeting, and people use categories of infants, ABO incompatible,
ABO incompatible with a positive Coombs' test,
and so forth, and so on.
Those
are actually surrogates for actually accurate measurements can be made to
understand what a production rate is in an individual, so if narrowness of
targeting is what is going to allow something to be introduced, then, you can
get that kind of narrowness by actually looking at the population from the
perspective of the part of the biology you want to control with the drug, and
that, in fact, improves the likelihood of benefit where productions are
increased as opposed to any risks that might be understood to exist or possibly
exist with the drug.
The
difficulty I have with even I guess making that statement--coming back to what
Dr. Fost said--and that is that if all drugs have to be subject to this issue
of the creep, which I think is important to understand, it makes it very
difficult to introduce anything because that means that as soon as something is
introduced, it will be used if it's easy to use, and there is not an obvious
complication rate or it's not too expensive.
So,
I think you have to be careful not to exclude things that might be of
considerable value, just to say with appropriate instruction and maybe
guidelines with respect to use, knowing that there are limitations on how you
can control behavior.
DR.
CHESNEY: Just two more. Dr. Newman and Dr. Hudak. Then, we will return to our FDA colleagues.
DR.
NEWMAN: Just a quick comment on the data
from New Jersey. Those are based on
discharge abstracts, so it is based on a code, and ICD-9 code and a discharge
abstract, and we use those at Kaiser as sort of a screen to see were there any
cases of kernicterus, found I think 8 or 9 of them, and all of them were false
positives.
If
you think about if the true frequency of kernicterus as something less than 1
in 100,000, even if the specificity of the coding is 99.99 percent, occasional
digits being transposed, and the 773 instead of a 776, anything like that will
give you a very, very low rate of false positive diagnoses.
So,
the ICD-9 code discharge abstracts, I think you really can't use for something
as rare as kernicterus. I think that
actually the case for what the toxicity of bilirubin is, is at least I think
clearer than has been suggested so far, and that is that really, it looks like
kernicterus mostly occurs with bilirubin levels over 30, maybe very, very
rarely over 25, and between 20 and 25, if it occurs at all, it would be
extraordinarily rare, so I want to correct what one person said.
We
recommend phototherapy for bilirubins in the 20, 25 range. That is not because those bilirubins are
dangerous. The whole reason for
phototherapy in that range is to keep the bilirubin from rising to a level where
it would be dangerous, where someone would contemplate exchange transfusion.
So,
if you are thinking about this question, you know, should drugs be developed to
prevent hyperbilirubinemia, it seems like there are sort of three levels at
which one might use the drug. One would
be actually to prevent kernicterus in people who have hyperbilirubinemia, and
that would be as an alternative to an exchange transfusion, as illustrated in
the Jehovah's Witness child, which I thought looked very promising, and I would
have no trouble saying this either should be used or a randomized trial be done
instead of exchange.
The
next step would be instead of phototherapy, and still the goal here I think is
to keep the bilirubin from rising higher, to keep it from rising to a dangerous
level while the baby's liver matures and it comes back down.
The
number of babies in whom it would be indicated for that would be presumably a
few percent, the number who get phototherapy.
The
last indication would be to prevent the need for phototherapy, that is, to give
it ahead of time, and, of course, that is so attractive because it deals with
all the follow-up issues that are such a headache for everybody, but then, of
course, the potential number of people being treated would be way higher, and
the number who would be treated who otherwise wouldn't need any phototherapy
would be very high.
DR.
CHESNEY: Dr. Hudak.
DR.
HUDAK: Just a few comments. One is I think that although we haven't
really looked at the evidence, we have been told that there have been no
complications that have been seen in babies who have received this treatment,
and there have been several hundred, I gather, in a variety of different
studies.
I
would say right now that given that the risk of exchange transfusion is a 1
percent mortality, that the issue of whether or not to do the exchange or give
this drug if it were available is not an issue, I would give the drug based on
the available evidence.
The
other issue, coming back to Dr. Fost's point about screening tests, I think
maybe just once again to put out something about advocacy here, we have in this
country a very chaotic system of infant screening. Every state goes its own path. There are some states that do a lot of
screening and do it very well, and other states, such as Florida, where we are
still back in the prehistoric age, and do about five different screens.
There
are lots of different metabolic conditions that are amenable to treatment in
infants that have frequencies on the order of 1 to 2,000, to 1 to 10,000, and
we do not screen as a society for these conditions even though it would require
a relatively minimal extra expense in the scheme of things, and these are
things where babies have long-term deficits because they aren't identified.
Even
if you were to grant that kernicterus has an incidence of 10 per 100,000, I mean
we have lots of things that are very morbid to children that are possibly
preventable that we don't pay any attention to.
The
issue of complications, I think clearly I agree with everybody who suggests
that we need to target a population, but I also agree with the issue of
creep. If the supposition is that one
case of kernicterus is too much, by definition, any high-risk group you target
to treat, even if it's only 50 percent in the population, you are going to wind
up reducing the incidence of kernicterus from whatever it is by 70 percent, 75
percent, and you are still going to have that registry grow every year.
So,
for those reasons, I think you would have some creep going on.
DR.
CHESNEY: Dr. Cummins and Dr. Murphy,
shall we move on to the next question, or would you like more input?
DR.
MURPHY: I would like to just take that
entire conversation and pull a few points out that maybe I have selective
hearing, but I want to make sure that these are some of the main themes that we
heard here.
People
are interested in a therapy, drug therapy, that that therapy clearly needs
studies, these studies would have to maximize--the word was maximize the study
to those who can benefit, and to maximize the studies to define the harm, in
other words, define the safety profile as a theme.
I
heard also that surrogate endpoints--I am just going to say it because that is
really what it is--we cannot do a randomized, controlled trial for an endpoint
for kernicterus, that we have to do a randomized, controlled trial with a
surrogate; that the committee is I think trying to tell us, and this is why I
am repeating this, that they think that the surrogate is preventing an increase
in bilirubin; and that the randomized trials would be possibilities, again, I
am trying to synthesize all this, would be prevention of exchange transfusion
as an endpoint, or randomization between phototherapy and a drug treatment.
The
definition of phototherapy intervention somewhere around--knowing all the other
things--around 20, but knowing there is a whole nomogram, all that sort of
stuff, but that's what I think I have heard so far. I have heard a concern about defining the
trial design as a prevention for hyperbilirubinemia.
I
mean we need the bilirubin there to work basically, too, in other words, not a
trial that would be randomized to children who received a dose when they left
the nursery and those who did not. I
didn't hear a lot of support for that kind of a trial, because I am not sure
what the endpoints on that would be.
Bob,
were there any other points that you thought were coming out of this
discussion? The definitions of
predictability clearly underlie the problem here.
DR.
JUSTICE: No, I think you summarized it
well.
DR.
MURPHY: Any comments that I got that
wrong, incorrectly? Yes, sir.
DR.
OH: I think several of us indicated that
a safety feature should be incorporated in any drug development. I don't think I heard you say that.
DR.
MURPHY: Oh, absolutely, yes. I was stumbling on it because I wrote in
shorthand here, but basically, that any trial clearly needs to have safety as a
major assessment. We do that
anyway. I guess what we don't have
enough time to discuss is what is the definition of what long-term safety is
and how in the world you would do but I think that that is a real issue that
you all brought up, and I was trying to say that, that that is something that
we will have to struggle with because, in general, long-term safety studies are
not usually asked for as part of an FDA approval.
You
know, there are some exceptions, but it is a very big issue, and there is a
national study, as you know, ongoing to try to look at how to do long-term
safety studies.
DR.
CHESNEY: Dr. Nelson.
DR.
NELSON: A think it is a question for Dr.
Stevenson, because I heard him say one thing that follows on that slide you
showed where you show the three black lines going up from the nomogram as to
whether or not there would be any use for trying to distinguish within
stratifications of bilirubin at different levels, whether 20, 25, 30, or 15, those who are at that level
because they have above a certain percentile in production versus just above a
certain percentile on bilirubin as a way of trying to make an additional
distinction within the nomogram itself using carbon monoxide or some other
testing.
DR.
STEVENSON: That is a good question. I don't know the definitive answer yet. Dr. Bhutani is analyzing some of the data
from the large multiethnic, multinational trial that we did.
As
I mentioned briefly in passing, the nomogram seems to be informed in part, as
would be expected, by production rate, so the higher you are up in those
percentiles, the higher the average production for the individuals in those
percentiles.
There
are also individuals who seem to be producing bilirubin excessively, and what
Dr. Bhutani is exploring is whether that information is sufficient for
identifying or targeting these individuals as the individuals that will also
jump tracks and proceed to leave the nomogram all together.
So,
I think the issue you bring up is an important one, that is, that it's a
balance, it's a matter of impaired conjugation and production, but if you have
excessive production and you are already behaving in a certain way in terms of
your ability to handle the pigment, then, you may be self-identifying as a very
narrow group of individuals who are uniquely disposed to being helped by
something to control their abnormal production rates.
DR.
NELSON: Do you think that when that data
is analyzed, that it would reduce the false positives and that number needed to
treat, that is of concern, in other words, those infants who, in retrospect,
would not have needed an intervention, that if you combined bilirubin plus some
measure of production, that you might treat three to get one instead of five to
get one, for example?
DR.
STEVENSON: I don't know, but my guess is
that it would likely decrease that number, but I don't know for sure.
DR.
CHESNEY: Dr. Justice.
DR.
JUSTICE: Yes, just one thing to add to
what I heard the committee say, at least a couple of members of the committee
suggested that the population be narrowed to a higher risk population, such as
hemolytic anemias.
DR.
CHESNEY: We have a plan for the last two
questions, which have to do with safety and efficacy. As you know, the FDA has a legal
responsibility to assure both safety and efficacy, and that is what these two
questions are about. So, I will read
these briefly and then we will have 10 to 15 minutes to discuss them.
Then,
at the end, we will go all around the table, so everybody can have a last
comment relative to whatever they feel they need to comment about.
Question
No. 3. Assuming that hyperbilirubinemia
only requires therapeutic intervention with phototherapy 3 to 5 percent of the
time, what safety information would you require from a sponsor for a new
molecular entity before it could it introduced into the newborn population?
Question
No. 4. In today's healthcare setting,
does the benefit of drug therapy to prevent hyperbilirubinemia in the newborn
population as a whole outweigh the risk to individual newborns, the majority
of whom require no intervention?
Comments? Dr. Freeman.
DR.
FREEMAN: I am very concerned about these
two questions and about any study that you design particularly if it's limited
to a defined population being able to pick up low-risk side effects of your
medication, and I would urge the FDA to build in long-term studies after
whatever drug gets marketed presuming that it will get marketed.
DR.
WILFOND: I think that these two
questions bring us back to the comment before about trying to maximize benefit
to minimizing risks, and the problem with the questions, they are framing it as
preventing hyperbilirubinemia, whereas, if instead these questions are framed
as either preventing exchange transfusions, for example, I think the questions
would be very different, so unless we decide what our goals are, and what our
population is, these are hard questions to answer. The answers are different, I guess.
DR.
CHESNEY: Thank you.
Dr.
Nelson.
DR.
NELSON: I guess a question for those
more knowledgeable and perhaps Dr. Stevenson, whether you think there would be
any possible surrogates that could be used to measure risk of certain adverse
events, such as impact on neurodevelopmental outcome, whether tagged drug
distribution studies that show none get to the CNS. As I recall, there was some of your slides
that you went through rather quickly showed differential distribution of
different drugs and different targets.
In other words, if it doesn't get to the CNS, it would be less
concerning to me, or maybe that's just being naive. So, that's a question.
DR.
STEVENSON: It's a good question and
obviously a concern. I think most of the
information is probably known about tin mesoporphyrin, and that work has been
done by Rockefeller. I don't remember
the exact nature of the experiments that looked for traces of the compound in
the brain, but my recollection of the report was that none was found.
Our
work has been primarily looking for biological effects. We have not done labeling studies. So, coming back to your general question, I
am not sure if that would be possible to do in humans, and in trying to get to
the issue, understanding what the risk might be or what surrogate you might
have for looking for that risk, that is very difficult. We are learning now something that I think is
very frustrating to most of us, and that is, when we look at long-term
neurodevelopmental outcome as a primary outcome for a lot of our large trials,
in ACC network, oftentimes things which we think are appropriate surrogates for
long-term neurodevelopmental outcome, turn out not to be so.
The
most recent example is in the TIP trial, the
indomethacin prophylaxis trial, where as the smaller studies had
suggested, there was a marked decrease in Grade 3 and Grade 4 hemorrhages in
response to that prophylactic treatment, but there was no difference in the
long-term neurodevelopmental outcome between the two groups.
So,
when you try and pick even fairly gross surrogates for neurodevelopmental
outcome, you may miss the mark, and part of that is related to the plasticity
of the newborn brain, and there are many other things that will impact that
brain over the course of the first couple of years of life, and that is not
just in terms of function, that's in terms of its anatomy, as well.
DR.
CHESNEY: Dr. Mattison.
DR.
MATTISON: In terms of the safety
information, I guess thinking about it from sort of several different levels, I
would be interested in really very well conducted traditional segment one,
segment two, segment three FDA animal tox studied.
These
are studies that are done to look critically at effects on reproductive
performance and developmental function, pregnancy outcome, and so on.
The
problem with the current designs, though, I think for the most multi-gen and
the three segment tox studies, don't get at functional endpoints, so I think,
you know, careful discussion with any proposed sponsor of a molecular entity
like this, given that there are a range of developmental activities that have
to go on in the newborn, I think would be really very important.
Having
spent a lot of time thinking about developmental toxicity, I am also troubled a
little bit by the fact that there is kind of the other side of the question
that we haven't addressed, and I am reminded of the vitamin A story, which is
that no question at high levels, vitamin A produces adverse effects, but we
also understand that vitamin A deficiencies are also associated with adverse
neurodevelopmental outcomes.
Dr.
Stevenson alluded to the fact that he seems a little perplexed by is there a
level of bilirubin below which we wouldn't want to go, and from that
perspective, then, it is not simply designing a dose that lowers the level of
circulating bilirubin, it is understanding what happens at these lower levels
in terms of neurodevelopmental outcome, they may not be related to the drug at
all, but altered biochemistry in the individual, which I think also suggests a
different way of thinking about the traditional three-segment and
multigeneration tox studies in animals and might actually suggest the need to
look at perhaps several different species in the developmental tox studies.
DR.
CHESNEY: Thank you.
I
wanted to ask a question and then I see Dr. Luban. Dr. Stevenson, I was struck in your slides by
the contrast between the one naturally occurring mesoporphyrin, zinc
mesoporphyrin--I hope I have this correct--in almost every instance had the
lowest of the effects that you were describing as something that we see as
maybe good.
Teleologically,
that gives me a little anxiety.
DR.
STEVENSON: Zinc protoporphyrin is the
naturally occurring protoporphyrin. Its
role is still being investigated. Of
course, it's an indicator of lead toxicity and probably reflects availability
of iron for incorporation into hemoglobin, and so forth, but I think what I
describe is simply a compound that has moderate effects and then has many of
the other desirable features that, in fact, the other compounds do have, either
at the dose they are being used or by their unique synthetic nature.
Those
would be besides the efficacy, which can be established at a much higher dose,
it has the lack of photoreactivity in vivo and other things of that sort. But it is a hard compound to work with, and
is probably at the bottom of the list in terms of one you might pick from a
drug development perspective because of that property alone.
I
am not sure if I answered your question exactly, but I think when you engineer
the other compounds, you can end up using them at doses where you achieve the
other desirable features that you see with that compound.
DR.
CHESNEY: I probably didn't express it
very well, but it just seemed a contrast between a naturally occurring compound
and a contrived one. In some of the
areas, it was so striking that you just worry about toxicity issues.
Dr.
Luban.
DR.
LUBAN: In my review of the two books,
there were a few things that I was struck with, that I think we need to spend
some time talking about apropos of Question 3, and the two systems that I think
we need to send some time looking at in any kind of a long-term safety trial
are the hematopoietic systems, since this is a hemoxygenase inhibitor, and iron
metabolism particularly at the nadir of iron absorption could be affected.
The
second, from a long-term adverse potential, is the RES system. Some of the data indicated lymphocytopenia,
for example, in some of the children that were studied with this class of
compound.
So,
I am being very specific rather than general, but I think those are two areas
that we need to concentrate on.
DR.
CHESNEY: Thank you. I think those are issues that we probably
will address tomorrow.
Any
other? Dr. O'Fallon.
DR.
O'FALLON: I think somebody should say at
this point the fact that we haven't--I mean we have been told that no bad
things have been found in certain areas--I think it is very important to point
out that not finding things in the number of people studied, it doesn't tell us
anything, that in order to find relatively rare events, which we would
certainly hope most of these long-term toxicities would be, or any kind of
toxicity, we would have to study a lot in order to be finding them.
So,
the fact that there is nothing out there yet is somewhat comforting, but not
completely comforting.
The
other thing is we have been listening, we have been told in two or three
different ways that there are parents who simply are not able to even come back
for a follow-up bilirubin test within a week after the baby was born. If we are going to be putting kids into
long-term studies where they are going to have to be coming back at year 1,
year 2, year 5, that type of thing, in order to see what is happening to their
intelligence levels and their blood counts, and that sort of thing, this is
going to be difficult.
I
think the drug companies have to be prepared to deal with this type of thing or
we are going to have a problem. Well, I
think that our results that we have already been told are already biased
because there was so much missing data on some of the long term, and the
question is who was missing, who didn't get tested, and we can't have that
happen for a good study of these new therapies, because if by the treatment
creep, we are going to end up treating a whole lot more kids that don't need
it, we have to have a darn good idea of what kind of adverse events that are
likely to be occurring five year hence.
DR.
CHESNEY: Dr. Newman.
DR.
NEWMAN: I think to answer the question
about how much we need to know about safety or how big the trials have to be is
partly informed by biochemistry and understanding these drugs and the biologic
plausibility that they would have effects on various tissues, and I don't know
that much about that.
My
kind of simple-minded thought would be, well, if we are going to use it instead
of exchange transfusion, we should know that it's as least as safe as exchange
transfusion. If we are going to use it
instead of phototherapy, we should try to have somewhere around as much data
that it is as safe as we have for phototherapy.
For phototherapy, we at least do
have the Collaborative Phototherapy Study, which was a long-term study
following kids up to I think age six or seven to look at their
neurodevelopmental outcome.
If
we were going to try and use it to prevent phototherapy and be treating, you
know, 5 or 6 or some number of kids for each one who otherwise would have
gotten phototherapy, then, it seems like we kind of need to know that it is at
least five times as safe as phototherapy, so that would be even a bigger study
just to be able to reassure ourselves that we are not doing more harm than
good.
DR.
CHESNEY: Dr. Hudak.
DR.
HUDAK: I think in terms of the specific
answer to that Question 3, I think it is pretty clear that whatever study is
done, we need to have a minimum of a two-year careful follow-up including the
full neurodevelopmental exam and assessment.
I think that is what is standard for the NIH studies where we looked at
entities like nitric oxide and other things.
I think that would be expected.
The
difficulty there is, of course, that even in the small networks where there is
a lot of effort to getting these kids back, we take all babies regardless of
likelihood that they are going to be coming back for follow-up, so we take the
poor and the not so poor, and so forth.
We get about an 80 percent follow-up.
If
you wind up spreading this among many centers, we are going to have fewer
babies at each center, and you don't have that sort of network to encourage
patient capture. It is going to be very
hard to get a very good follow-up rate, but nonetheless, one has to do the best
one can do.
The
other issue is in terms of the actual study design, we have talked about
exchange transfusion. I think I would be
very worried about limiting entry to those babies who are at high risk for
getting exchange transfusion because if in the control arm you had a lot of
babies who had exchange transfusion, and if there is some consequence to an
exchange transfusion in terms of neurodevelopmental outcome, you may falsely
reassure yourself your drug intervention is reasonable. It may even look better than the group that
got high incidences of exchange, so I think there are caveats there.
DR.
CHESNEY: I don't think any of us ever
want to do an exchange transfusion again.
How
about if we start going around the table and letting everybody address the most
compelling issue for them at this point.
Dr. Luban, you have the good luck of being the first person.
Committee Final Comments
DR.
LUBAN: Do you want me to go over
Questions 2, 3, and 4 or just make a general comment?
DR.
CHESNEY: I think the idea is more that
you maybe address the one or two points that are most important to you, most
compelling to you, that may have to do with any one or all three of the
questions.
DR.
LUBAN: Well, I think it would be
wonderful if we had an absolutely safe drug that could stop the need for doing
exchange transfusions. Since as the
director of a blood bank, I can tell you that I don't sleep at night when those
are being done at my institution.
On
the other hand, I can also tell you that the number of times that we perform
exchange transfusions now is lingeringly small.
So,
from my perspective, much of the treatment of Rh hemolytic disease has taken
away exchange and what we are left with are the severe G6PDs, the tiny preemies
with sepsis and multiple complications, metabolic diseases, and then the other
class, which nobody has mentioned, which are the kids neither with ABO nor Rh,
but with other antibodies, and those are actually growing in number rather than
decreasing in number, particularly Kell, so that is a group of hemolytic
disease of the newborn that no one has mentioned that we need to keep in mind.
There
is something intrinsically gut-wrenching to consider treating a very large
number of babies with a treatment modality without a known safety record for
the prevention of a very limited number of severe adverse outcomes.
I
will stop there.
DR.
CHESNEY: Dr. Stevenson.
DR.
STEVENSON: I can be very brief. I think exchange transfusions are dangerous,
and that is something that needs to be avoided.
It may be avoided through a whole variety of different ways, some of
which don't have to include novel therapies.
I
guess from my perspective, the rationality of the approach that lies behind
this kind of targeted therapy is best complemented by a targeting of the group
that might benefit the most.
So,
I guess I would weigh in with respect to identifying individuals who are at
greatest risk and who might benefit from altering this part of the biology
which is contributing to the problem in their particular case, understanding
that not everybody who has high production has high levels of bilirubin, they
would not self-identify as being individuals that would require treatment.
A
final thing is just that I think that it is important to understand that some
increased production is a normal part of the transitional period after birth,
the up-regulation occurs normally, and so it becomes a powerful lever if you
want to control something that you otherwise can't control.
So,
I understand the interest in getting one's hand on that handle, but I think it
should be done with appropriate respect for the complexity of that
biochemistry, which I think people have, and try to maximize safety with that
in mind.
DR.
CHESNEY: Dr. Lau.
DR.
LAU: My comment will be brief. I think that we need to be very precise about
our language that is mentioned earlier, that hyperbilirubinemia is not a
disease, it is a condition, and even in Question 4, it is stated as to prevent
hyperbilirubinemia treatment, so we are not really trying to prevent
hyperbilirubinemia, because we are already doing intervention on kids with
hyperbilirubinemia, so what we are trying to do, we are trying to keep them
from rising. I think we just need to be
precise about our language.
DR.
CHESNEY: Dr. Newman.
DR.
NEWMAN: I have mostly said what I want
to say. I just had one other thought,
which is this whole issue of difficulty with follow-up and therefore, you know,
patients getting their high bilirubin levels, and I totally sympathize with
that because we struggle with that, too, but I guess it bothers me a little bit
that the direction where this might head is that if you are caring for a family
that is poor and has bad access, then, you give them the drug, whereas, the
families who are better connected with the medical system, you can just follow
them and have a Home Health nurse go out to their house.
So,
I guess there is some sort of troubling ethical issues there about who would be
the people in the studies and then who would the drug actually be given
to, and maybe as a society, we really
should commit that we can do better than just sort of throw up our hands and
say we can't do follow-up a day or two postpartum.
DR.
CHESNEY: You articulate that so well.
Dr.
Oh.
DR.
OH: One final thought I have is issue of
powering any of my control trial. Very
often what happens is particularly using this surrogate as an endpoint. The sample size is not powered enough to look
at long-term outcome, and that needs to be addressed in any kind of design in a
study.
The
other thing that I need to point out is that since we are concerned about
potential side effect, any trial--I am probably saying something
obvious--should have a data safety monitoring committee, independent DSMC
monitoring the study to make sure that the patients being enrolled are
protected during the study period.
DR.
CHESNEY: Dr. Smith.
DR.
SMITH: I am in favor of development of a
new drug. I am more concerned about what
we are targeting as the endpoints for it.
I have heard several people say--and I know nothing about these
things--but several people have said exchange transfusion is dangerous. I don't think that anyone has said that
phototherapy is dangerous. It is
inconvenient, but nobody said it's dangerous.
So,
I think we should pay particular attention to what we are addressing to replace
rather than injecting 4 million kids with this.
DR.
CHESNEY: Dr. Wilfond.
DR.
WILFOND: My comment actually follows on
the prior comment. If we were to have as
an objective trying to prevent exchange transfusions using a drug rather than
phototherapy, we would not be subjecting 4 million kids, we would be subjecting
that very small number who currently gets phototherapy.
I
think that really would be the way to go in terms of designing a trial that
randomized children either to phototherapy or to a drug based upon clear
criteria when we otherwise think phototherapy is appropriate with the objective
of trying to avoid exchange transfusions and to establish efficacy and safety
in that subpopulation.
DR.
O'BRIEN: I guess my first comment is I
am also struck by the fact that our safety systems issues, although not a part
of this deliberation here, just as a comment, that I would hope that we could
do a lot better than we are doing, and certainly was very struck by Mrs.
Sheridan's presentation of what happened with her son.
I
also would agree that starting certainly with the most at-risk infants and any
way that we could sort of identify those that may have increased production
where we know that the drug would be most effective presumably would be the way
to start.
DR.
CHESNEY: Dr. Aschner.
DR.
ASCHNER: I like the idea of developing a
new drug especially I think I have been convinced for those who need it
most. What I would like to see is much
more studies on the distribution of the drug in different tissues.
I
would like to see proper screening studies done in terms of various
toxicological endpoints, and to echo what Dr. Mattison said before, I think I
would like to know much more about what the consequences are of reducing
bilirubin levels to levels that might be below optimal in the newborn.
DR.
CHESNEY: Dr. Freeman.
DR.
FREEMAN: I think Dr. Newman expressed my
opinions. I have concerns on two
sides. One, I think a drug should be
developed, but I am concerned about even low incidence of toxicity and the need
for these long-term studies in large numbers of patients, but I also am
concerned about the way we treat the poor, the difficulties in follow-up, and
the need for something to prevent phototherapy or the need for phototherapy in
this population that is so at high risk.
I
am concerned that as we design these studies, that we will be targeting a poor
indigent population and how do we deal with the equities involved in that.
DR.
CHESNEY: Dr. Ip.
DR.
IP: Am I allowed to comment on the
confidential stuff I have been reading?
I will reserve my comment until tomorrow.
DR.
CHESNEY: Dr. Mattison.
DR.
MATTISON: I guess I would just reiterate
my concerns about functional developmental consequences and echo some of the
comments that others have made with respect to frustration with the current
system for screening and identification of these infants.
That
is not a drug development question, it's an entirely different kind of system
question, but my biggest concern is sort of long-term functional developmental
impact.
DR.
CHESNEY: Dr. Gorman.
DR.
GORMAN: A couple of random
thoughts. The pursuit of convenience is
pretty obvious in our healthcare system.
We want things that are convenient, but sometimes they also simplify,
those same pursuits simplify the systems for both us and our parents to provide
care for their children, so I am not sure they are always mutually exclusive.
It
is clear to me that healthcare is not the number one priority of a large number
of our populations, so that systems we set in place, that seem logical to us,
don't always seem logical to our patients.
I
have a comment to follow up on Dr. Luban's.
I think that I would be even more specific in my long-term safety
profiling than you were. Who knew there
were so many ways to make carbon monoxide in the body? Certainly not I. But I think that at 18 and
24 months, carbon monoxide production, since we are specifically targeting it
and changing it, should be monitored, and the hemoxygenase system, in whatever
way you measure it, in 18- and 24-month- olds should also be tested.
I
would also like to echo something that Dr. Freeman said, which was that he
thinks that there is a distribution that does not include only kernicterus with
bilirubin's effect, and I would hope that a gross developmental screen, such as
the one we do, would pick up a halo effect if, by reducing bilirubins, we look
at confounding or contributing variables to other neurological diseases that we
see and we can only poorly explain.
DR.
CHESNEY: Dr. Ebert.
DR.
EBERT: I am in support of the
development of drugs for the management of hyperbilirubinemia, and I would see
the role in therapy here being somewhat before exchange transfusion. Where exactly that fits, I think certainly
that discussion has led us to believe that we are not sure exactly where that
would be at this point.
I
think probably first and foremost, we need to do a better job of characterizing
patients who are high risk for progression to high bilirubin levels and/or
kernicterus, whether that be through more intensive history taking and sampling
of individual or ideally by developing a test that can be administered prior to
discharge because of the concerns about follow-up of patients after they have
been discharged.
I
don't think that we can really determine at this point what the safety would be
of this compound without first testing it in a group that is at higher risk for
complications, try to at least at that point get a risk versus benefit
assessment, and perhaps then with post-marketing assessments, Phase IV trials,
as lower risk populations are tested, we can continue to follow up with safety
at that point.
DR.
CHESNEY: Mine is more reflection. I think it is ironic that the healthcare
system has put us in this situation because pediatricians, I think almost
uniformly, decried the move to discharge at 24 or less than 48 hours, and it is
because of that that we seem to be having a problem now, and it is also because
our processes are imperfect that we don't seem to be able to get children back
and to monitor what, on the face of it, should be a fairly simple thing to
monitor, but we don't have the processes in face, so it is just a reflection.
Dr.
Fost.
DR.
FOST: I hate to wake anybody up at 10
after 6:00 with a new idea, and I also regret disagreeing I think with John
Freeman, my teacher, and Tom Newman, whose work I admire so much in this area,
but it seems to me there is something close to consensus developing around the
table on a general principle that, first of all, that a new drug, there seems
to be wide agreement that a new drug, if it were safe, effective, and
reasonably cheap, would be a great help, and that, second, it should be tested
on children who have the most to gain from it.
If
that is true, it seems to me that the ideal target population is those who are
most underserved at the moment, that is, children in a developing country, who
presently have no access to anything and for whom being in a trial of a
reasonably promising drug against phototherapy would be a boon for the children
in the trial, it would almost certainly have a benefit if we take high-risk
children, that is, children with hemolytic disease or at high risk for
hemolytic disease, that the benefit-risk ratio for that population would exceed
anything we could do in the United States.
it
might also, if the drug were cheap enough, lead to a treatment or a
preventative for underserved populations since phototherapy is extremely
unlikely. I am guessing, maybe I am
wrong about that, certainly, home phototherapy.
So,
it seems to me the ideal place to develop, to study this drug is in a
population that presently has no access to any treatment for hyperbilirubinemia
and that is at high risk.
DR.
CHESNEY: Dr. Hudak.
DR.
HUDAK: That's a great idea, I just wish
it were possible to get follow-up on those kids. That is the key. I think everyone is in consensus that we need
the drug development study. It is just
the details that are the devil, and the power issues are critical and depending
upon what you are looking at, the power calculation will be different.
I
think we do need to look at the high risk group. I have no idea how you define
that. Anything you do, by definition, is
going to be somewhat arbitrary because we don't know at any given point what
the exact risk is for getting from bilirubin level X to bilirubin level 30
without intervention, we just don't know.
So,
it would be reasonable to pick by the nomogram, for instance, if you wanted to
get a good number of patients in, you can either pick the hemolytic disease
patients, who have a high incidence of having high levels, or you can sort of
by the nomogram pick those who are at the 98th percentile anytime within the
first 48 hours and assume they are the ones who are going to be most at risk
for getting the very, very high levels, although we don't know that. So, there is something about the natural
history we don't know.
In
terms of the follow-up, I think the point that was made about is there a
5-point difference in IQ that might result from this treatment, well, you can
put a number on how many babies you need to study to reassure yourselves that
there in no more than, you know, a 1-point difference or whatever. I think that sort of study design needs to be
done because a 5-point difference in IQ, I think is a significant societal
issue and needs to be carefully examined what the impact on that is.
You
know, other outcomes, for instance, like what happens if this drug were to
double the underlying incidence of aplastic anemia, how many patients are you
going to need to determine that. I go
back to the studies that were done on the rotazyme vaccine, and very well done
studies showed it to be very safe and effective, and within nine months of it
getting on the market, being used in a lot of patients, the issue of
intussusception came up, and the drug was withdrawn.
So,
I think there are clearly instances where something gets into widespread use
despite the best study efforts at determining safety and efficacy and there are
problems that are detected, and I think it is just critical as we go along whatever
path this goes down, that the FDA hopefully has the authority to make sure that
there are the appropriate large registries once this drug gets outside into
open clinical use.
DR.
CHESNEY: Dr. O'Fallon.
DR.
O'FALLON: My comments, I keep
remembering my dad saying that it took a dentist to invent the railroad
couple. You know, I am outside the
medical community, I work with physicians, but I am listening to you, and it
just seems to me in listening today that it isn't that hard.
You
guys are all talking about eligibility criteria. As a statistician, I think that defining the
eligibility criteria very precisely is an extremely important thing to do in
each of these studies, and you guys are all talking about levels of
hyper--well, I can't say it, but the level of bilirubin, you are talking about
rates of bilirubin rise. There are ways
to measure that. You talked about that.
So,
I think you already know and could define a group that you could agree would be
at real risk and should be studied first.
So, I think that can be done, listening to you. Then, the comment about the population, about
going to Africa and some places like that, come on, guys, we have all these
Americans sitting in our inner cities that have no medical care either, and I
think that we should make an effort to include those guys in any studies, too,
that the companies should make sure that they are spreading around the benefits
and the liabilities.
The
endpoint definition is absolutely crucial and again, what I am hearing you say,
you say, well, should we give exchange transfusion when it hits 30 or 28. I think you have got to just define your
endpoint as being some extreme value, and if the bilirubin hits that level in
either group, they have failed, that treatment has failed. I think you can do
that, define it some way like that, but it would not be to avoid either of
these therapies because the physicians, you know, you are kind of a rebellious
group, and you tend to say nobody is going to make me do anything, and you
aren't always following the guidelines.
But
if it comes down to the level itself, understanding the variability and the
laboratory measurements, and all that, I mean there are going to be problems,
but that would seem to me as close to an objective endpoint as you could have.
The
careful follow-up is so important and it has go to be long term, and it has to
be very vigorous to make sure that everybody comes back, that we are not losing
a large percentage of the patients out on the long-term follow-up, and that is
going to be hard.
Then,
oh, yeah, the modeling. We keep talking
about the modeling, and I do a lot of that, I am a statistician. Folks, a model is only as good as the items
that are in the--I call them the shopping lists, the independent variables, and
we are finding out it is very humiliating to recognize that we are missing a
lot of very important variables that nobody ever knew were important, and we
all know that there are genes that are important, that we don't know anything
about.
So,
the modeling we take with a block of salt on each shoulder.
DR.
CHESNEY: Dr. Fuchs.
DR.
FUCHS: I think I echo a lot of people's
opinion that this is going to be a long-term, several step process. I think the idea about comparing drug versus
phototherapy to prevent exchange transfusion is probably step number one with
long-term follow-up, and that group, it could be the ABO group, the G6PD group,
that is your target population as one option.
Then,
when that is proven as safe or as effective as phototherapy, then, you jump
back down and then you can get into your healthy newborns with whether you want
to use with risk factors or without risk factors, it is going to take a long
time no matter what you do.
DR.
CHESNEY: Dr. Danford.
DR.
DANFORD: I think everybody probably
agrees that ignoring extreme hyperbilirubinemia is dangerous and there are two
ways to approach that problem to make it go away. One is to make the extreme hyperbilirubinemia
go away, the other is to tune the system, so that we no longer are permitted to
ignore it.
I
wonder a little bit about the risks of developing a drug that could come into
common practice that could be perceived as the magic bullet that prevents
extreme hyperbilirubinemia, you have had your shot, you go home, nobody ever
worries about hyperbilirubinemia and kernicterus anymore, and yet there will be
system failures in either the administration of the drug or the effectiveness
of the drug in certain small populations yet to be identified where that drug
will be a failure and the next generation of patients entering the kernicterus
registry will be those who have received the magic bullet and the medical
community has given themselves permission to forget about them.
That
having been said, I really do think that we need to investigate the development
of a drug like this. I agree with the
remarks that the safety data that we need to accumulate will require a large,
long-term expensive and difficult to interpret studies.
I
would like to be assured that the drug that we unleash on society is safe as
phototherapy.
DR.
CHESNEY: Dr. Glodé.
DR.
GLODE: Just on a historical note. As you noted, Dr. Chesney, about the change
in medical practice with early discharge, I do now recall that the most common
conversations I ever had with mothers during my training was the conversation
about how your baby could not go home because of the yellow jaundice, and, in
fact, had that same statement made to me with the birth of my first child,
staying in the hospital because my baby's bilirubin was 12 and we need to check it tomorrow. So, it is a remarkable effect.
Back
to again the priority, prevention of kernicterus, do we currently have
effective therapies, I would say yes, we just have an inability right now to
correctly identify and capture who needs those therapies.
I
am happy to have a new therapy developed.
I think the bar for that therapy is very high because it has to be as
safe as phototherapy and either equally effective because more convenient or
more effective than phototherapy. So, the bar is very high. I am happy to have it be developed.
The
last comment I would make is that I think if you had an opportunity to read the
two statements at the back from people who didn't present at the open hearings,
but the Joint Commission and the March of Dimes both had an interesting letter
there. Perhaps again this is outside the
realm of the FDA, but on my desert island, if I were advising the FDA on the
issue of prevention of kernicterus, I would recommend that they send--I don't
know if they can do this--a formal letter that would go to NICHD, to the CDC,
to the American Academy of Pediatrics urging funding of pilot studies
concerning the efficacy of newborn bilirubin screening to prevent bilirubins
of--and then you name it, 22, 25, 27, I don't know, I would like to see those
pilot studies funded, and that would be my recommendation.
DR.
CHESNEY: Dr. Nelson.
DR.
NELSON: I am still thinking about Norm's
suggestion. I think an active control
superiority trial with phototherapy head to head with a medication to try and
prevent not so much exchange transfusion, but perhaps a bilirubin where most
people might contemplate an exchange transfusion, say, 25, so you could get it
at 20 and then you hopefully prevent 25, and then you would have to have, if
the phototherapy fails, some crossover to the drug, but all those kinds of
details could be worked out.
But
then I am not sure what the control group would be in an area of underserved,
because I would be tempted to want to build up the infrastructure to provide
phototherapy, and I am not sure that would, in fact, be doable, and it would
worry me if we then take a drug that hasn't been used a lot, but we have
efficacy here, and then decide, well, let's just hand it out to a million kids
elsewhere and see what happens in terms of safety.
I
will follow you a ways down that road. I
am not sure, though, on the details. We
would have to work that out.
DR.
CHESNEY: Dr. Cummins and Dr. Murphy and
Dr. Justice.
DR.
JUSTICE: I think I hear a consistent
message that the drug should be studied in a population that is at higher risk,
and there should be long-term safety, follow-up particularly neurological,
hematopoietic, and that the trial design I have heard is a randomized trial of
phototherapy versus the drug with perhaps an endpoint of a bilirubin of a
certain value or perhaps an exchange transfusion.
That
is what I have heard the committee suggest.
DR.
CUMMINS: I would add to that, that there
needs to be and I have heard very detailed preclinical safety testing because
the bar for any new intervention is high because of the safety, known safety of
phototherapy.
DR.
MURPHY: I would just like to say thank
you and I think we ought to let you go because we have got another long day for
you tomorrow.
DR.
CUMMINS: I could add to that thank you
very much. This has been a really
productive day and we appreciate your time and input.
DR.
CHESNEY: Tomorrow morning we start at 8
o'clock is my understanding. Let me also
thank everybody for letting us go so far over, but I think it has been
extremely interesting.
[Whereupon,
the meeting was recessed at 6:30 p.m., to reconvene the following day,
Thursday, June 12, 2003, at 8:00 a.m.]
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