Short title: Digoxin for respiratory distress syndrome
Reviewer(s): Soll RF
Date of most recent amendment: 18/02/1998
Date of most recent substantive amendment: 29/01/1998
Date next stage expected: / /
Contact
Dr Roger F. Soll
Associate Professor of Pediatrics
Department of Pediatrics
University of Vermont College of Medicine
A-121 Medical Alumni Building
Burlington
VT USA
05405-0068
Telephone1: +1-802-656-2392
Telephone2:
Facsimile: +1-802-656-2077
E-mail: rsoll@salus.med.uvm.edu
Sources of support for the review
Neonatal Collaborative Review Group, NIH Contract #N01-MD-6-3253,
USA
Acknowledgements
I would like to thank Nancy Moreland for preparation of the
manuscript.
Conflict of interest
None
To assess the effect of digoxin on clinical outcome in infants at risk of, or with, respiratory distress syndrome (RDS).
Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: digoxin; limits: age groups, newborn infants; publication type, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language.
Randomized controlled trials of digoxin in either the prevention or treatment of respiratory distress syndrome are included in this overview.
Data regarding clinical outcomes were excerpted from the trial reports by the reviewer. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.
Two randomized controlled trials have studied the effects of digoxin in the prevention and treatment of respiratory distress syndrome. No improvement in respiratory status or mortality was noted. Meta-analysis of the effect of digoxin given to infants at risk of or with RDS on mortality does not suggest any benefit of digoxin treatment (typical relative risk 1.27 95% CI 0.78, 2.07; typical risk difference 0.06, 95% CI -0.06, 0.17).
Although hemodynamic disturbances play a role in the overall pathogenesis of respiratory distress syndrome, the specific contribution of early congestive heart failure (unrelated to hemodynamically significant patent ductus arteriosus) does not appear to be a significant factor in RDS. Treatment with digoxin has no proven value in infants solely affected with respiratory distress syndrome.
In 1955, Lendrum (1955) suggested that pulmonary edema secondary to congestive heart failure may contribute to neonatal Respiratory Distress Syndrome. Based on this hypothesis, investigators began to use digitalis glycosides to improve myocardial contractility and decrease congestive heart failure. The first use of digitalis glycosides in infants with respiratory distress syndrome was reported by Stahlman (1959). Stahlman reported a reduction in mortality in an uncontrolled trial of digitalis in infants with RDS. This experience led to two randomized controlled trials of digoxin in the prevention and treatment of RDS.
The following analysis is a systematic review of the two randomized controlled trials which compared digoxin administration to placebo treatment in infants at risk of, or with, established respiratory distress syndrome.
To assess the effect of digoxin on mortality in the prevention or treatment of respiratory distress syndrome.
Types of studies
Randomized controlled trials comparing digoxin to placebo
treatment.
Types of participants
Infants at risk of developing respiratory distress syndrome
(infants delivered by cesarean section, infants of diabetic mothers,
and low birthweight infants) or infants with a clinical diagnosis
of respiratory distress syndrome are included in these studies.
Types of intervention
Infants were randomized to receive digoxin (initial digitalizing
dose followed by 72 hours of maintenance therapy) or placebo treatment.
Treatments were given intramuscularly.
Types of outcome measures
Investigators evaluated infants for respiratory distress (illness
severity scores), electrocardiographic abnormalities, and mortality.
Only mortality is discussed in the meta-analysis.
Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: digoxin; limits: age groups, newborn infants; publication type, clinical trials), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.
For each included study, information was collected regarding the method of randomization, blinding, drug intervention, stratification, and whether the trial was single or multi-center. Information regarding trial participants (specific inclusion criteria including diagnosis and birthweight criteria) was noted. Information on clinical outcome included only mortality.
Studies included in this review: Martin (1963) and Braudo (1969). Details of each study are given in the "Characteristics of Included Studies" table and references.
Martin (1963) studied the effect of digoxin in preventing respiratory distress syndrome in a diverse group of newborns. Infants delivered by cesarean section, infants born to diabetic mothers, or infants with low birthweight (less than or equal to 5 1/2 lbs) were given digoxin during the first three days of life. No improvement in respiratory status or mortality was noted. Bradycardia, EKG abnormalities, and vomiting were more frequent in the digoxin treated infants.
Braudo (1969) studied the effects of digoxin in 77 infants with respiratory distress syndrome. Infants were randomized to either a 72 hour course of digoxin or placebo treatment. No difference in mortality between treatment groups was noted. No adverse effects of digoxin were reported.
Randomized controlled trials which compared the effect of digoxin to placebo treatment in infants either at risk of developing respiratory distress syndrome or with clinical respiratory distress syndrome are included in the analysis. Specific methodologic issues regarding the two studies included are discussed below:
Randomization: Both included studies allocated assigned treatment by randomization. In both studies, randomization was accomplished using sealed envelopes at the participating center.
Blinding of treatment: Treatment was blinded by the use of placebo injections. Neither the physicians nor the nurses caring for the infants knew which treatment the infants received.
Blinding of outcome assessment: Investigators were blinded regarding treatment assignment and, therefore, blinded regarding outcome assessment.
Exclusion after randomization: Minimal exclusions were noted after randomization.
Neither the study of Martin (1963) or Braudo (1969) noted an improvement with the administration of digoxin. Martin (1963) noted an increase in bradycardia, EKG abnormalities, and vomiting associated with digoxin administration.
The meta-analysis of the effect of digoxin in the prevention or treatment of respiratory distress syndrome suggests no benefit of digoxin treatment regarding mortality (typical relative risk 1.27, 95% CI 0.78, 2.07; typical risk difference 0.06, 95% CI -0.06, 0.17).
In the 1950s, investigators believed that pulmonary edema secondary to congestive heart failure may contribute to neonatal respiratory distress syndrome. Based on this hypothesis, investigators began to use digitalis glycosides to improve myocardial contractility and decrease congestive heart failure. Two randomized controlled trials which studied the effects of digoxin in the prevention of treatment of respiratory distress syndrome are detailed in this analysis. Neither the study of Martin (1963) or Braudo (1969) were able to note any improvement associated with digoxin administration. Martin (1963) noted bradycardia and EKG abnormalities in infants who received digoxin.
Although these studies had very different criteria regarding entry and timing of treatment, neither study demonstrates any effect of digoxin in the treatment or prevention of respiratory distress syndrome.
Although hemodynamic disturbances play a role in the overall pathogenesis of respiratory distress syndrome, the specific contribution of early congestive heart failure (unrelated to hemodynamically significant patent ductus arteriosus) does not appear to be a significant factor in RDS. Treatment with digoxin has no proven value in infants solely affected with RDS.
There is little reason to believe that further research on digoxin in the prevention or treatment of RDS is warranted.
Study: Braudo 1969
Method: Single center
Blinding of Randomization: Yes (sealed envelopes)
Blinding of Intervention: Yes (placebo IM injections)
Complete Follow-up: Yes (87/88 enrolled)
Blinding of Outcome measurement: Yes
Stratification: None
Participants: Infants with clinical diagnosis of respiratory
distress syndrome
Silverman retraction score >3
Interventions: Digoxin vs. placebo treatment
Digitalizing dose: 0.065 mg/kg
Maintenance dose: 1/10 digitalizing dose 24 hours after start
of treatment
1/10 digitalizing dose every 12 hours for 72 hours
Outcomes: Electrocardiographic abnormalities
Mortality
Study: Martin 1963
Method: Single center
Blinding of Randomization: Yes (sealed envelopes)
Blinding of Intervention: Yes (placebo IM injections)
Complete Follow-up: Can't tell
Blinding of Outcome measurement: Yes
Stratification: None
Participants: Phase 1:
Infants delivered by Cesarean section
Infants of diabetic mothers
Low birthweight infants (less than or equal to 5 1/2 lbs)
Phase 2: Low birthweight infants (less than or equal to 5 1/2
lbs)
Interventions: Digoxin vs. glucose placebo
Digitalizing dose: 0.03 mg/lb in two divided doses over 24 hours
Maintenance dose: 0.01 mg/lb/day x 3 days
Outcomes: Respiratory and retraction score
Electrocardiographic abnormalities
Mortality
Braudo M, Keith JD. The value of digitalis in the respiratory distress syndrome: a controlled study. J Pediatr 1969;74:310-314.
Martin JK. A controlled trial of digoxin in the prevention of the respiratory distress syndrome. Can Med Assoc J 1963;89:995-997.
Lendrum FC: The 'pulmonary hyaline membrane' as a manifestation of heart failure in the newborn infant. J Pediatr 1955;47:149-156.
Stahlman MT: In: Adaptation to Extra-uterine life. Report of 31st Ross Conference on Pediatric Research. Columbus, OH: Ross Laboratories, 1959.
01.00.00 Digoxin vs placebo
01.01.00 Mortality