Furosemide for transient tachypnea of the newborn
Lewis V, Whitelaw A
Background - Methods
- Results - Characteristics
of Included Studies - References - Data
Tables & Graphs
Cover sheet
Title
Furosemide for transient tachypnea of the newborn
Reviewers
Lewis V, Whitelaw A
Dates
Date edited: 28/11/2001
Date of last substantive update: 15/11/2001
Date of last minor update: 25/10/2001
Date next stage expected / /
Protocol first published: Issue 2, 2001
Review first published: Issue 1, 2002
Contact reviewer
Dr Vaughan E Lewis
Specialist Registrar
Neonatology
Neonatal Unit
Southwell Street
Bristol
UK
BS2 8EG
Telephone 1: +44 0117 9215411 extension: 2700
Telephone 2: +44 0117 9285275
E-mail: vaughan_lewis@hotmail.com
Secondary address (home):
14 Melrose Place
Bristol
UK
BS8 2NG
Telephone: +44 0117 973 1859
Contribution of reviewers
VL had the idea for the review and carried out the search. AW collaborated
on the structure of the review, repeated the search and advised on the
use of RevMan. Both VL and AW have read the references and wrote sections
of the review.
Intramural sources of support
United Bristol Healthcare Trust, UK
Extramural sources of support
None
What's new
Dates
Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
It is common for full term infants born by elective Caesarean section to
have laboured and rapid breathing (tachypnea) and to require oxygen for
about 48 hours. Although transient and not usually serious, the condition
requires admission to a neonatal intensive care unit and involves separation
of mother and baby and use of expensive resources. Furosemide is a powerful
diuretic which, in other circumstances, can reduce fluid in the lungs.
We found only one trial (involving 50 infants) that had tested furosemide
in this condition. The drug was given orally and made no difference to
either the severity or duration of the illness or to length of hospitalization.
Giving furosemide intravenously, or even to the mother before Caesarean,
might have a more powerful effect and may merit investigation.
Abstract
Background
Transient tachypnea of the newborn results from delayed clearance of lung
liquid and is a common cause of admission of full term infants to neonatal
intensive care units. The condition is particularly common after elective
Caesarean section. Conventional treatment involves appropriate oxygen administration
and continuous positive airway pressure in some cases. Most infants receive
antibiotic therapy. Hastening the clearance of lung liquid should shorten
the duration of the symptoms and reduce complications.
Objectives
To determine whether furosemide reduces the duration of oxygen therapy
and respiratory symptoms and shortens hospital stay in term infants with
transient tachypnea of the newborn.
Search strategy
We searched the Cochrane Controlled Trials Register, PubMed and EMBASE.
The primary author and experts in the field were contacted.
Selection criteria
Randomised or quasi-randomised controlled trials. Infants of less than
7 days of age, born after 37 or more weeks of gestation with the clinical
picture of transient tachypnea of the newborn. Intravenous, oral or nebulized
furosemide compared to placebo or no diuretic in the first 7 days.
Data collection & analysis
Two reviewers assessed trial quality in each potentially eligible manuscript
and two reviewers extracted data.
Main results
Searching revealed only one randomised trial which was methodologically
sound. This recruited 50 infants with transient tachypnea. Infants were
randomised to receive oral furosemide 2 mg/kg followed by 1 mg/kg 12 hours
later, or placebo. Weight loss in the first 24 hours was greater in the
furosemide treated group but there was no evidence of a difference between
the groups in duration of tachypnea or severity of symptoms or length of
hospitalization. The study was methodologically satisfactory.
Reviewers' conclusions
Oral furosemide cannot be recommended as treatment for transient tachypnea
of the newborn and it should not be used unless additional data become
available. The question remains as to whether intravenous furosemide given
to the infant (or even to the mother before Caesarean section) might shorten
the duration of the illness. As elective Caesarean section continues at
a high level, these two interventions might be worthy of trials.
Background
Transient tachypnea of the newborn (TTN) was first described by Avery
1966 in infants born at term who developed rapid respiration (> 80/min),
grunting and retraction at or shortly after birth. Investigations for infection
were negative and the oxygen requirement did not rise above 40%. Chest
X-ray showed streaky interstitial or pleural fluid, prominent interlobar
fissures, perihilar vascular markings and sometimes hyperinflation. The
symptoms usually resolved by 48 hours, occasionally lasting as long as
5 days. The condition is commoner in term infants born by elective caesarean
section (Morrison 1995, Tudehope
1979). It may be difficult to distinguish between congenital pneumonia
and TTN and many infants receive antibiotics until blood cultures are known
to be negative. TTN is regarded as being synonymous with wet lung, benign
unexplained respiratory distress in the newborn, neonatal tachypnea and
type 2 RDS (Rennie 1999). It is attributed to
the delayed clearance of fetal lung fluid with secondary air trapping.
Lung liquid that has been rendered high in protein by either mild asphyxia
or amniotic fluid aspiration may contribute to the problem (Avery
1966). In addition, elective caesarean section deprives the fetus of
the effect of endogenous catecholamines on resorption of lung liquid.
The reported prevalence of TTN varies with some authors attributing
up to 40% of neonatal respiratory distress to TTN (Tudehope
1979) and an overall incidence of around 11 per 1000 births. With a
tendency to delivery by elective caesarean section for an increasing number
of obstetric and fetal indications, the number of infants admitted to neonatal
units with TTN is likely to rise.
There are no specific biochemical or hematological markers and the diagnosis
is essentially clinical with typical radiological features on chest Xray.
The natural history is of gradual improvement of respiratory signs as
fetal lung fluid is reabsorbed. Treatment is supportive with oxygen to
maintain acceptable saturations and occasionally continuous positive airway
pressure (CPAP) and even endotracheal ventilation to obtain adequate oxygenation
and carbon dioxide clearance. TTN usually settles within 24 hours but may
persist for several days and in its more severe forms may be associated
with secondary surfactant deficient lung disease and in extreme cases,
persistent pulmonary hypertension.
Furosemide has been shown to affect fluid dynamics in the lung by both
diuretic and non-diuretic actions (Demling 1978,
Belik
1987, Prabhu 1997). In theory, diuresis
should increase the plasma oncotic pressure and draw water from the lungs
into the pulmonary vascular bed. This has been shown not to be the case
in an adult canine model (Wickerts 1992).
It seems more likely that non-diuretic effects are predominant with several
authors showing improved pulmonary dynamics without demonstrable diuresis
(Demling 1978, Prabhu
1997). Given the effects of furosemide on the fluid overloaded lung
it is reasonable to hypothesize that it might alter the clinical course
of TTN.
Although TTN is generally a benign self-limiting condition there is
much to be gained from shortening its clinical course provided this can
be achieved without side effects. Hastening the clearance of retained fetal
lung fluid should improve oxygenation, shorten the clinical course and
may reduce complication rates. Separation of mothers from their newborn
infants is generally undesirable. Furthermore there are significant economic
implications of reducing duration of hospital admission.
Objectives
The aim of this review was to determine whether treatment with furosemide
reduces the duration of oxygen therapy and respiratory symptoms and shortens
hospital stay in term infants presenting with the clinical syndrome of
transient tachypnea of the newborn.
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials.
Types of participants
Infants of less than 7 days of age, born at 37 or more completed weeks
of gestation with a clinical diagnosis of transient tachypnea of the newborn
(including the synonymous conditions of wet lung, benign unexplained respiratory
distress in the newborn, neonatal tachypnea and type 2 RDS) .
Types of interventions
Intravenous, oral or nebulized furosemide compared to placebo or no diuretic
in the first 7 days of life. Studies looking at single doses as well as
multiple doses were considered.
Types of outcome measures
Duration of oxygen therapy in hours.
Duration of tachypnea (>60 breaths/min) in hours.
Length of hospital stay in days.
Number of infants receiving CPAP
Number of infants receiving positive pressure ventilation.
Patent ductus arteriosus.
Electrolyte disturbances (hyponatremia & hypokalemia).
Search strategy for identification of studies
See: Collaborative Review Group search strategy.
Standard search methods of the Neonatal Collaborative Review Group
were used.
1. Published manuscripts:
Search included MEDLINE (1966-2001), EMBASE (1980-2001) and the Cochrane
Controlled Trials Register (CCTR) from the Cochrane Library (2001, Issue
2). Articles in any language were considered as long as there was an abstract
in English indicating content. The following were considered synonymous
with transient tachypnea of the newborn: 'wet lung', 'benign unexplained
respiratory distress in the newborn', 'neonatal tachypnea' and 'type 2
RDS'. The following keywords were used: 'furosemide', 'frusemide', 'diuretics',
'tachypnea', 'respiratory distress', 'wet lung', 'type 2 RDS' and 'type
II RDS'. Subject heading: 'infant, newborn'
2. Published abstracts:
Search included the abstracts of the Society for Pediatric Research
1987-2001 (published in Pediatric Research). The search was done by hand
or electronically by CD-ROM (2001). For abstract books or CD-ROMs with
keywords, we used the following keywords: 'furosemide', 'respiratory distress',
'transient tachypnea'. For years 1992-3 (volumes 31 and 33 of Pediatric
Research), no keywords are available; therefore, we hand searched the sections
on Neonatal Pulmonology.
3. Database of the Neonatal Review Group of the Cochrane Collaboration:
We screened all publications with the keywords 'furosemide' OR 'frusemide'.
4. If data for review were not included in original articles then authors
were contacted. Expert informants were approached to identify any relevant
unpublished material.
5. Selection process:
Only randomised controlled trials fulfilling the selection criteria
described in the previous sections were selected. Selection was done separately
by two investigators; any disagreement was resolved by discussion.
Methods of the review
Standard methods of the Neonatal Review Group were used. The one eligible
study was independently assessed by each reviewer. Each reviewer assessed
the methodological quality with respect to: i) masking of allocation ii)
masking of intervention iii) complete follow-up iv) blinding of outcome
measure.
Each reviewer extracted data separately and resolved any disparity.
Additional data on randomisation methodology were requested from Wiswell
et al.
The intention was to perform subgroup analysis for route of administration
(oral, intravenous or nebulized). However, since only one study was identified
this was not possible.
Standard methods of the Neonatal Review Group were used for data analysis.
Treatment effects on categorical outcomes were analysed using relative
risk, risk difference and number needed to treat. For treatment effects
measured on a continuous scale, mean difference was used. 95 % confidence
intervals were calculated.
Description of studies
See table of characteristics of included studies
Searching revealed only one randomised controlled trial examining the
use of furosemide in transient tachypnea of the newborn (Wiswell
1985). No unpublished data were identified.
Wiswell investigated 50 consecutive admissions to a single neonatal
unit with transient tachypnea of the newborn as defined by:
• Onset of tachypnea (respiratory rate more than 60/min) within 6 hours
after birth.
• Persistence of tachypnea for at least 12 hours.
• Chest roentgenogram indicating abnormalities characteristic of transient
tachypnea of the newborn (hyperaeration, vascular congestion, and excessive
interstitial and/or pleural fluid).
• Absence of other disorders likely to cause tachypnea (polycythemia,
air dissection syndromes, hypoglycemia, pulmonary hemorrhage, aspiration
syndromes, congenital heart disease, respiratory distress syndrome and
pneumonitis)
After informed consent and within 6 hours of birth, the infants were
randomised to receive either oral furosemide (2mg/kg body weight at time
of diagnosis followed by a 1mg/kg dose 12 hours later if the tachypnea
persisted) or placebo given in the form of an equal volume of coloured
sterile water indistinguishable from the furosemide. They measured response
to treatment in terms of;
• Weight loss as a % of birth weight at 24 hours of age and at discharge.
• Duration of hospitalization.
• Duration of tachypnea (respiratory rate>60 per minute).
Methodological quality of included studies
See table of characteristics of included studies.
Although Wiswell 1985 did not report the
method of concealment of randomisation, Dr Wiswell informed us that he
used randomised opaque envelopes to allocate treatment. Power calculations
were based on a 90% chance of detecting a 24-hour difference in the duration
of tachypnea and estimated that 25 patients would be required. There were
equal numbers of patients allocated to each group with a total of 50. The
placebo preparation (coloured sterile water) was indistinguishable from
the oral preparation of Furosemide. Follow-up was complete and the investigators
remained blinded until the study was complete.
Results
Duration of tachypnea
Wiswell 1985 found no evidence of effect
(mean difference - 5.1 hours (95% CI -14.6 to 4.35 hours).
Length of hospital stay
Wiswell 1985 found no evidence of effect
(mean difference 0.10 days (95% CI -0.60 to 0.80 days).
One intended primary outcome of the review was the duration of oxygen
therapy. This information was not provided by Wiswell
1985. Due to the elapsed time since the study was performed, Dr Wiswell
was unable to provide relevant data.
Wiswell 1985 found that none of the infants
demonstrated pulmonary hypertension, needed CPAP, needed mechanical ventilation
or died. There were no clinically important changes in serum electrolyte
values in either group. None of the furosemide treated infants developed
patent ductus arteriosus. Although weight loss at discharge was similar
in the two groups, the furosemide treated group lost significantly more
weight in the first 24 hours after birth.
Discussion
Only one trial was found to be eligible for this review (Wiswell
1985). This study was well designed. It failed to show a statistically
significant impact of oral furosemide on the duration of oxygen requirement
in transient tachypnea of the newborn. The methodological quality of the
study was satisfactory and the power calculations were reasonably based.
Although no adverse effects were reported in this single study it should
be noted that the study was not powered to look for potential side effects.
The rational for choosing oral furosemide is not clear. Intravenous furosemide
might have been more appropriate in infants with an acute respiratory disturbance
and uncertain enteral absorption.
Reviewers' conclusions
Implications for practice
Based on the available evidence the routine use of furosemide in infants
with transient tachypnea of the newborn cannot be recommended.
Implications for research
It is plausible that with the increasing rates of elective Caesarean section
(Khor 2000) the incidence of transient tachypnea
of the newborn will also increase. Although not usually seriously ill,
infants with transient tachypnea of the newborn may develop secondary surfactant
deficient lung disease and require mechanical ventilation. No group has
to date systematically investigated the role of intravenous furosemide
or any other diuretic in transient tachypnea of the newborn. If shown to
reduce either or both length of stay or requirement for oxygen, then diuretics
could have a significant economic benefit. Such a study would almost certainly
have to be multicentre in design. Furosemide has been shown to pass freely
across the placenta (Beermann 1978). Intravenous
administration of furosemide to the mother before elective Caesarean section
might also be worthy of investigation as a way of assisting clearance of
fetal lung liquid and reducing the duration of transient tachypnea.
Acknowledgements
Potential conflict of interest
None.
Characteristics of included
studies
| Study |
Methods |
Participants |
Interventions |
Outcomes |
Notes |
Allocation concealment |
| Wiswell 1985 |
Design:Randomized double blind placebo controlled trial.
Setting: Single neonatal unit in Tripler Army Medical Center, Honolulu.
Randomization: Method: numbered opaque sealed envelopes. 25 patients
allocated to each group.
Blinding of allocation: yes.
Blinding of intervention:yes.
Complete follow-up: yes.
Blinding of outcome ascertainment: yes. |
Number: 50 consecutive admissions with transient tachypnea of the newborn
to neonatal unit Inclusion criteria: Transient tachypnea of the newborn
as defined by: 1) onset of tachypnea (respiratory rate more than 60/min)
within 6 hours after birth, 2) persistence of tachypnea for at least 12
hours, 3) chest roentgenogram indicating abnormalities characteristic of
transient tachypnea of the newborn (hyperaeration, vascular congestion,
and excessive interstitial and/or pleural fluid), and 4) absence of other
disorders likely to cause tachypnea (polycythemia, air dissection syndromes,
hypoglycemia, pulmonary hemorrhage, aspiration syndromes, congenital heart
disease, respiratory distress syndrome and pneumonitis) |
Oral furosemide 2mg/kg body weight, at time of diagnosis followed by
a 1mg/kg dose 12 hours later if the tachypnea persisted. Placebo given
in the form of an equal volume of sterile water colored with two drops
of MVI solution (USV Pharmaceutical Corp, Tuckahoe, NY) indistinguishable
from the furosemide. |
Outcomes measured: 1) Weight loss as a % of birth weight at 24 hours
of age and at discharge, 2) Duration of hospitalization, and 3) Duration
of tachypnea.
None of the infants demonstrated pulmonary hypertension, needed mechanical
ventilation or died. There were no changes in serum electrolyte values
in either group. None of the furosemide treated infants developed patent
ductus arteriosus. There were no differences between the groups in severity
or persistence of symptoms, duration of oxygen requirement, or length of
hospitalization. Although weight loss at discharge was similar in the two
groups, the furosemide treated group lost significantly more weight in
the first 24 hours after birth. |
Information on randomization obtained from authors. |
A |
Information on concealment of allocation was obtained by contact with
Dr Wiswell.
References to studies
References to included studies
Wiswell 1985 {published data only}
Wiswell TE, Rawlings MC, Smith MC, Goo ED. Effect of furosemide on the
clinical course of transient tachypnea of the newborn. Pediatrics 1985;75:908-10.
* indicates the primary reference for the study
Other references
Additional references
Avery 1966
Avery ME, Gatewood OB, Brumley G. Transient tachypnea of the newborn.
Possible delayed resorption of fluid at birth. Am J Dis Child 1966;111:380-5.
Beermann 1978
Beermann B, Groschinsky-Grind M, Fahraeus L, Lindstrom B. Placental
transfer of furosemide. Clin Pharmacol Ther 1978;24:560-2.
Belik 1987
Belik J, Spitzer AR, Clark BJ, Gewitz MH, Fox WW. Effect of early furosemide
administration in neonates with respiratory distress syndrome. Pediatr
Pulmonol 1987;3:219-25.
Demling 1978
Demling RH, Will JA. The effect of furosemide on the pulmonary transvascular
filtration rate. Crit Care Med 1978;6:317-9.
Khor 2000
Khor LJ, Jeskins G, Cooper GM, Paterson-Brown S. National obstetric
anaesthetic practice in the UK 1997/1998. Anaesthesia 2000;55:1168-72.
Morrison 1995
Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory morbidity and
mode of delivery at term: influence of timing of elective caesarean section.
Br J Obstet Gynaecol 1995;102:101-6.
Prabhu 1997
Prabhu VG, Keszler M, Dhanireddy R. Pulmonary function changes after
nebulised and intravenous frusemide in ventilated premature infants. Arch
Dis Child Fetal Neonatal Ed 1997;77:F32-5.
Rennie 1999
Rennie JM, Roberton NRC. Textbook of Neonatology. 3rd edition. Edinburgh:
Churchill Livingstone, 1999.
Tudehope 1979
Tudehope DI, Smyth MH. Is "transient tachypnoea of the newborn" always
a benign disease? Report of 6 babies requiring mechanical ventilation.
Aust Paediatr J 1979;15:160-5.
Wickerts 1992
Wickerts CJ, Berg B, Frostell C, Schmidt J et al. Influence of hypertonic-hyperoncotic
solution and furosemide on hydrostatic pulmonary oedema resorption. J Physiol
Lond 1992;458:425-38.
Comparisons and data
01 Oral furosemide versus placebo
01.01 Duration of tachypnea in hours
01.02 Duration of hospitalization in days
01.03 Electrolyte disturbance
01.04 Requirement for CPAP
01.05 Requirement for IPPV
01.06 Requirement for CPAP or IPPV
01.07 Persistent ductus arteriosus
Notes
Published notes
Amended sections
None selected
Contact details for co-reviewers
Professor Andrew Whitelaw, MD
Professor of Neonatal Medicine
Division of Child Health
University of Bristol
Division of Child Health, University of Bristol Medical School
Southmead Hospital
Bristol
UK
BS9 1PJ
Telephone 1: +44 117 959 5699
Telephone 2: + 117 959 5325
Facsimile: +44 117 959 5324
E-mail: andrew.whitelaw@bristol.ac.uk