Routine use of diuretics in very-low birth-weight infants in
the absence of supporting evidence
Journal of Perinatology (2011) 31, 633–634; doi:10.1038/jp.2011.44
In this issue of Journal of Perinatology, Hagadorn et al.1
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.2–4
The 39% response rate in this survey is within the range
(23–85%; 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to 2010 (unpublished data, Stewart and Brion), and similar to that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±20%).5However, 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.6–10
Diuretics might improve lung function by improving fluid
absorption, by reducing lung congestion and by reducing lung
fibrosis.6–12However, 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);13(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);14,15(I) hearing
loss, associated with a potential synergism of loop diuretics and
aminoglycosides;16,17(J) worse neurodevelopmental outcome
(acetazolamide and furosemide for treating post hemorrhagic
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.6–10
The three trials that addressed mostly infants with postnatal
ages of 7 to 28 days19–21looked at short-term renal and/or
pulmonary outcomes varying from 24 to 96h 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.22This 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% O2improved 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.18Another trial showed that
chronic addition of spironolactone to thiazide for 8 weeks did
not affect lung mechanics, serum sodium and potassium
It is surprising that neonatologists are willing to routinely
prescribe diuretics during the first 4 weeks of life1or for a long
duration after extubation,4despite 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.24
Journal of Perinatology (2011) 31, 633–634
r 2011 Nature America, Inc. All rights reserved. 0743-8346/11
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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