Routine use of diuretics in very-low birth-weight infants in the absence of supporting evidence

Division of Neonatal-Perinatal Medicine, The University of Texas Southwestern Medical School Program, Medical Center at Dallas, Dallas, TX, USA.
Journal of perinatology: official journal of the California Perinatal Association (Impact Factor: 2.07). 10/2011; 31(10):633-4. DOI: 10.1038/jp.2011.44
Source: PubMed
JPER is a multi-disciplinary journal that promotes the health of the preterm infant.


Available from: Luc P Brion, Aug 29, 2014
Routine use of diuretics in very-low birth-weight infants in
the absence of supporting evidence
Journal of Perinatology (2011) 31, 633634; doi:10.1038/jp.2011.44
In this issue of Journal of Perinatology, Hagadorn et al.
confirm the known variability of therapeutic approach among
neonatologists and demonstrate the willingness of some
neonatologists to routinely prescribe diuretics to very-low birth-
weight infants in the first 28 days of life. They also show that
some neonatologists overestimate the benefits (eg, sustained
improvement in pulmonary mechanics, decreased ventilator days
and decreased length of stay) of diuretic administration during the
first 4 weeks of life and underestimate potential risks (eg, patent
ductus arteriosus, hearing loss or renal failure) of diuretic
administration. This study adds to the growing body of literature
suggesting that diuretics may be one of the most commonly abused
drugs in the neonatal intensive care unit.
The 39% response rate in this survey is within the range
(2385%; 52
18% (mean
s.d.)) observed in 13 surveys
involving US neonatologists and preterm infants published in 2005
to 2010 (unpublished data, Stewart and Brion), and similar to that
of academic studies in behavioral sciences (56
However, a
limitation of this study is lack of assessment for possible non-
response bias and lack of any procedures to minimize such bias.
Lung edema occurs in respiratory distress syndrome as a result
of delayed sodium channel (ENaC) expression and may occur in
chronic lung disease because of increased capillary permeability
resulting from lung injury and inflammation, congestive heart
failure due to patent ductus arteriosus, and fluid overload.
Diuretics might improve lung function by improving fluid
absorption, by reducing lung congestion and by reducing lung
However, diuretics have many potential complications:
(A) electrolyte imbalance such as hyponatremia, hypomagnesemia,
hyperuricemia and either hypokalemic alkalosis (thiazides, loop
diuretics) or hyperkalemia and acidosis (potassium-sparing
diuretics); (B) reduction in extracellular volume, dehydration,
hypovolemia, hypotension and pre-renal failure; (C) intrinsic renal
failure potentially increasing toxicity of other medications;
(D) mineral changes including either (most diuretics) osteopenia,
phosphaturia, hypercalciuria, nephrocalcinosis and nephrolithiasis
(associated with reduced glomerular and tubular function in
childhood); or (thiazides, metolazone and potassium-sparing
diuretics other than spironolactone) hypocalciuria and
hypercalcemia; (E) persistent patent ductus arteriosus due to
increased formation of prostaglandin E (furosemide);
(F) metabolic: cholelithiasis (loop diuretics) and glucose
intolerance (thiazides); (G) reduction of alveolar fluid absorption
(amiloride and spironolactone);
(H) binding to androgen
receptors with anti-androgen effects, disturbed gonadal and
adrenal steroidogenesis, estrogen-like side effects, elevated
gonadotrophin levels, interference with newborn screening for
congenital adrenal hyperplasia (spironolactone);
(I) hearing
loss, associated with a potential synergism of loop diuretics and
(J) worse neurodevelopmental outcome
(acetazolamide and furosemide for treating post hemorrhagic
ventricular dilatation).
There is very little evidence to support routine use of
diuretics in very-low birth-weight infants with respiratory distress
syndrome or developing or established chronic lung disease.
The three trials that addressed mostly infants with postnatal
ages of 7 to 28 days
looked at short-term renal and/or
pulmonary outcomes varying from 24 to 96 h post treatment and
not at long-term outcomes. Most trials of diuretics in preterm
infants have only shown short-term effects on lung mechanics or
oxygen requirement; these effects disappear as soon as the
diuretics are stopped and do not shorten the duration of oxygen
administration, long-term lung function or length of stay.
Only one trial showed that chronic diuretic administration
improved important outcomes.
This trial showed that an 8-week
administration of thiazide and spironolactone in intubated
very-low birth-weight infants who were at least 1 month of age and
requiring a minimum of 30% O
improved survival at discharge,
but did not affect the duration of ventilator support and
length of stay. The patients did not receive prenatal steroids or
surfactant. In addition, aminophylline, corticosteroids and
bronchodilators were not allowed.
Another trial showed that
chronic addition of spironolactone to thiazide for 8 weeks did
not affect lung mechanics, serum sodium and potassium
nor FiO
It is surprising that neonatologists are willing to routinely
prescribe diuretics during the first 4 weeks of life
or for a long
duration after extubation,
despite lack evidence for benefit from
randomized controlled trials and for lack of information about
long-term complications. A large randomized trial is needed to
assess important and long-term outcomes including risks and
benefits of diuretic administration to very-low birth-weight infants
using current standard of care including prenatal steroids, caffeine
and vitamin A.
Journal of Perinatology (2011) 31, 633634
2011 Nature America, Inc. All rights reserved. 0743-8346/11
Page 1
Conflict of interest
The authors declare no conflict of interest.
AL Stewart and LP Brion
Division of Neonatal-Perinatal Medicine, The University of Texas
Southwestern Medical School Program, Medical Center at Dallas,
Dallas, TX, USA
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    [Show abstract] [Hide abstract] ABSTRACT: Objectives: To determine (1) between-hospital variation in diuretic use for infants with bronchopulmonary dysplasia (BPD), including hospital-specific treatment frequency, treatment duration, and percentage of infants receiving short (≤5 consecutive days) versus longer (>5 days) courses, and to determine (2) demographic and clinical variables associated with diuretic administration. Methods: A retrospective cohort study was conducted with the use of the Pediatric Health Information System to determine between-hospital variation in diuretic utilization patterns (primary outcome) and variables associated with diuretic use among <29-week-gestation infants with evolving BPD at age 28 days who were discharged between January 2007 and June 2011. Results: During the 54-month study period, 1429 infants within 35 hospitals met the inclusion criteria for BPD at age 28 days, with 1222 (86%) receiving diuretic therapy for a median of 9 days (25th-75th percentile: 2-33 days). Short courses were administered to 1203 (83%) infants, and 570 (40%) infants received treatment for >5 consecutive days. Furosemide was the most widely prescribed diuretic (1218 infants; 85%), although chlorothiazide had the longest median duration of use (21 days; 25th-75th percentile: 8-46 days). The range of infants receiving a diuretic course of >5 days duration varied by hospital from 4% to 86%, with wide between-hospital variation even after adjustment for confounding variables. Conclusions: The frequency of diuretic administration to infants with BPD at US children's hospitals, as well as the specific diuretic regimen used, varies markedly by institution. Safety and effectiveness research of long-term diuretic therapy for BPD patients is needed to develop evidence-based recommendations.
    Full-text · Article · Mar 2013 · PEDIATRICS
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