Jasim Anabrees1, Khalid AlFaleh2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Neonatal Intensive Care, Dr Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
2Department of Pediatrics (Division of Neonatology), King Saud University, Riyadh, Saudi Arabia
Citation example: Anabrees J, AlFaleh K. Fluid restriction and prophylactic indomethacin versus prophylactic indomethacin alone for prevention of morbidity and mortality in extremely low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD007604. DOI: 10.1002/14651858.CD007604.pub2.
Neonatal Intensive Care
Dr Sulaiman Al Habib Medical Group
Arrayan Hospital
Riyadh 11635
P.O.Box 100266 Riyadh
Saudi Arabia
E-mail: jasim1800@yahoo.com
| Assessed as Up-to-date: | 21 December 2010 |
|---|---|
| Date of Search: | 21 December 2010 |
| Next Stage Expected: | 21 December 2012 |
| Protocol First Published: | Issue 1, 2009 |
| Review First Published: | Issue 7, 2011 |
| Last Citation Issue: | Issue 7, 2011 |
Although survival of extremely low birth weight (ELBW) infants has dramatically improved over the last decades, the rate of bronchopulmonary dysplasia (BPD) has not changed. The use of indomethacin prophylaxis in ELBW infants results in improved short-term outcomes with no effect on long-term outcomes. The addition of fluid restriction to the indomethacin prophylaxis policy could result in a reduction of BPD and improve long-term survival without neurosensory impairment at eighteen months corrected age.
To determine the effect of a policy of fluid restriction compared with a policy of no fluid restriction on morbidity and mortality in ELBW infants receiving indomethacin prophylaxis.
We used the standard search strategy for the Cochrane Neonatal Review Group (CNRG). This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1), MEDLINE (1966 to December 2010), and EMBASE (1980 to December 2010). Additional searches included conference proceedings, references in articles and unpublished data.
We planned to include all randomized or quasi-randomized trials that compared fluid restriction and indomethacin prophylaxis versus indomethacin prophylaxis alone in ELBW infants.
Respiratory and long-term neurosensory outcomes are common morbidities among extremely low birth weight (ELBW),(birth weight less than 1000 g) survivors. Patent ductus arteriosus (PDA), a connection between vessels of the heart, is one of the known causes of respiratory morbidity. Indomethacin (a drug given early to close PDA) prophylaxis studies fail to show an improvement in the incidence of respiratory and long-term outcomes, although there is a 50% reduction in the incidence of PDA. The addition of fluid restriction to indomethacin therapy might prove helpful. However, our review found no studies to answer this question.
Extremely low birth weight (ELBW) infants have a high incidence of significant morbidities and mortality. Bronchopulmonary dysplasia (BPD) is a common morbidity among ELBW survivors (Lemons 2001). The pathogenesis of BPD is multifactorial (Bancalari 2003). Excessive fluid intake in these high-risk neonates during the early postnatal period has been suggested as a risk factor for the development of BPD (Van Marter 1990; Costarino 1992; Hartnoll 2000). High fluid intake with increased extracellular fluid (ECF) is associated with a higher incidence of symptomatic patent ductus arteriosus (PDA) (Bell 1980), which is associated with an increased risk of BPD (Brown 1979). The retention of ECF and the presence of PDA with left-to-right shunt may lead to a higher fluid content in the pulmonary interstitial tissue causing decreased lung compliance and increase the need for greater respiratory support in the form of oxygen administration and mechanical ventilation. These may result further in lung inflammation, lung injury and BPD (Oh 2005).
Body water content is very high in the ELBW infant, with a large proportion of the water in the extracellular fluid compartment (Friis-Hansen 1957; Friis-Hansen 1961). During the first week of life, there is a physiologic contraction of the ECF with negative fluid balance (Stonestreet 1983; Bauer 1989). Negative fluid balance allows for the physiologic contraction of ECF, which is associated with weight loss during the early neonatal period. This is achieved by fluid intake that is less than the amount of water excreted through the kidney and via insensible water loss (Bidiwala 1988; Bauer 1989).
In the published systematic review by Bell and colleagues (Bell 2001), fluid restriction was shown to significantly reduce the risks of PDA, necrotizing enterocolitis (NEC) and death along with a trend towards decreasing BPD that did not reach statistical significance. No significant increase in adverse effects was noted (Bell 2001). Caution should be used in extrapolating these results to extremely premature infants. Most of the included studies in this systematic review were old, enrolled a small number of infants, and included very few ELBW infants.
The efficacy of prophylactic indomethacin for the prevention of important intermediate and long-term outcomes has been tested in more than 19 randomized controlled trials. Although included studies did not report the fluid policy in their methodology, their systematic review Fowlie et al found that in ELBW infants, indomethacin prophylaxis reduces the risk of significant PDA by 56% (typical risk ratio (RR) 0.44; 95% confidence interval (CI) 0.38 to 0.50), surgical ligation of the PDA by 49% (typical RR 0.51; 95% CI 0.37 to 0.71), serious intraventricular hemorrhage (IVH) by 34% (typical RR 0.66; 95% CI 0.53 to 0.82) (Fowlie 2010) and serious pulmonary hemorrhage during the first week of life (Alfaleh 2008). However, these positive effects did not translate to a reduction of BPD or improve long-term survival without neurosensory impairment at 18 months corrected age (Fowlie 2010). These results have led to a controversy among neonatal practitioners that has resulted in a decrease in the use of indomethacin prophylaxis in ELBW infants after the publication of the large Trial of Indomethacin Prophylaxis in Preterm infants (TIPP) in 2001 (Schmidt 2001; Clyman 2007).
In a secondary analysis of the TIPP trial data (Schmidt 2006), it was noted that infants treated with indomethacin had a lower urine output and a slightly higher oxygen requirement during the first week of life. This may indicate that indomethacin-treated infants might have been disadvantaged with fluid overload secondary to an anticipated treatment side-effect (decreased glomerular filtration rate). This disadvantage could have resulted in increased rates of BPD, which might mask a beneficial effect of indomethacin therapy on long-term neurosensory outcomes. Strict fluid management protocols or prophylactic fluid restriction in indomethacin-treated infants could ameliorate the consequences of this anticipated side-effect.
To determine the effect of a policy of fluid restriction compared with a policy of no fluid restriction on morbidity and mortality in ELBW infants receiving indomethacin prophylaxis.
We planned to carry out a subgroup analysis to investigate the effect of prophylactic indomethacin and fluid restriction in high-risk infants with birth weight < 750 g.
We planned to include all randomized or quasi-randomized trials that compared indomethacin prophylaxis (starting within the first 24 hours of life) and fluid restriction (to achieve at least 10% weight loss in the first week of life) versus indomethacin prophylaxis alone in ELBW infants. We planned to exclude cross-over trials.
ELBW < 1000 g at birth who received prophylactic indomethacin in the first 24 hours of life.
Fluid restriction (to achieve at least 10% weight loss in the first week of life) plus indomethacin prophylaxis (starting within the first 24 hours for three doses) versus indomethacin prophylaxis alone.
We planned to accept all strategies for fluid restriction and all indomethacin-dosing regimens and rates of infusion.
Bronchopulmonary dysplasia defined as oxygen requirement at 36 weeks postmenstrual age (Shennan 1988).
We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG). We searched for randomized and quasi-randomized controlled trials that compared indomethacin prophylaxis and fluid restriction with indomethacin prophylaxis alone in ELBW infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 1); MEDLINE (1966 to December 2010) using the following subject headings (MeSH) and text word terms: patent ductus arteriosus or PDA, indomethacin, and publication type 'controlled trial', limited to infants; and EMBASE (1980 to December 2010). We did not apply any language restrictions. Two review authors independently performed the electronic database search. We also performed a manual search of the abstract books published by the Society of Pediatric Research (SPR) and the European Society of Pediatric Research (ESPR) for the period 1995 to 2010.
We planned to seek additional references from the bibliography of any articles retrieved that met the inclusion criteria. We contacted subject experts and searched trials registration sites (clinicaltrials.gov) to identify unpublished and ongoing studies.
Both review authors planned to screen independently all potential articles to check eligibility for inclusion in the review. Unpublished data and abstracts were eligible for inclusion provided we could obtain adequate information regarding primary and/or secondary outcomes. We planned to resolve discrepancies by discussion and consensus.
Both review authors planned to independently extract data from included studies. We planned to resolve discrepancies by discussion and consensus. Where data were incomplete, we planned to contact the primary investigator for further information and clarifications.
We planned to use the standard methods of the CNRG to assess the methodological quality (validity criteria) of the trials. For each trial, we planned to seek information regarding the method of randomization, blinding and reporting of all outcomes of all the infants enrolled in the trial. We planned to assess each criteria as 'yes', 'no', 'unclear'.
For dichotomous outcomes, we planned to calculate the RR and its associated CI. For continuous outcomes, we planned to express treatment effect as mean difference (MD) and its calculated standard deviation (SD).
Heterogeneity was defined as a significant test of heterogeneity (P < 0.1) and differences in the treatment effects across studies. We planned to apply tests for between-study heterogeneity (including the I2 test).
If appropriate, we planned to perform a meta-analysis of pooled data using a fixed-effect model. We planned to use Review Manager 5 software for statistical analysis.
If we had identified relevant studies for inclusion, we planned to perform subgroup analyses to investigate the effect of prophylactic indomethacin and fluid restriction in high-risk infants with birth weight < 750 g. We hypothesized that heterogeneity, if present, might be due to differences in the dose of indomethacin, rate of infusion used, degree of fluid restriction, population under study (< 1000 g versus < 750 g infants) and study quality.
We did not find any randomized controlled trials to investigate the possible interaction between fluid restriction and indomethacin prophylaxis versus indomethacin prophylaxis alone in ELBW infants.
The indomethacin story is indeed a puzzling one to all neonatal practitioners. Although indomethacin prophylaxis has resulted in an excellent reduction of important intermediate outcomes, indomethacin prophylaxis has not demonstrated an effect on long-term neurosensory outcomes. The TIPP trial is by far the largest trial to investigate the efficacy of prophylactic indomethacin in preterm infants (Schmidt 2001). In the published meta-analysis by Fowlie et al (Fowlie 2010), the data of the TIPP trial weighed more than 50% in intermediate outcomes and 80% in long-term outcomes. A few possible methodologic and indomethacin-related factors could possibly explain this:
In the era of evidence-based medicine, neonatal practitioners should always evaluate therapies directed to preterm infants within three main domains; clinical experience, research evidence and patient preferences. In neonatal medicine history, indomethacin prophylaxis is one of the most effective therapies in the reduction of important intermediate neonatal outcomes without proven long-term benefits or harms. Patients' decision aids have been increasingly used in various fields of medicine over the last ten years. Prior to withholding prophylactic indomethacin, clinicians need to explain (utilizing structured instruments) the proven short-term benefits of this therapy along with the doubts of its future effect to parents of ELBW infants. Randomized clinical trials are needed to investigate the targeted approach where prophylactic indomethacin is given to a selected subgroup at the highest risk and the possible interaction between fluid restriction to prophylactic indomethacin.
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Both review authors:
JA wrote the manuscript which then was reviewed by KA.
None noted.
None noted.
Alfaleh K, Smyth JA, Roberts RS, Solimano A, Asztalos EV, Schmidt B. Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. Pediatrics 2008;121(2):e233-8.
Bancalari E, Claure N, Sosenko IR. Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition. Seminars in Neonatology 2003;8(1):63-71.
Bauer K, Versmold H. Postnatal weight loss in preterm neonates less than 1,500 g is due to isotonic dehydration of the extracellular volume. Acta Pediatrica Scandinavica Supplement 1989;Suppl 360:37-42.
Bayley N. Manual for the Bayley Scales of Infant Development. 2nd Edition edition. San Antonio: Psychological Corporation, 1993.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7.
Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration of the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. New England Journal of Medicine 1980;302(11):598-604.
Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 3. Art. No.: CD000503. DOI: 10.1002/14651858.CD000503.
Bidiwala KS, Lorenz JM, Kleinman LI. Renal function correlates of postnatal diuresis in preterm infants. Pediatrics 1988;82(1):50-8.
Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. Journal of Pediatrics 1979;95(5 Pt 2):865-6.
Clyman RI, Saha S, Jobe A, Oh W. Indomethacin prophylaxis for preterm infants: the impact of 2 multicentered randomized controlled trials on clinical practice. Journal of Pediatrics 2007;150(1):46-50.e2.
Costarino AT, Gruskay JA, Corcoran L, Polin RA, Baumgart S. Sodium restriction versus daily maintenance replacement in very low birth weight premature neonates: a randomized, blind therapeutic trial. Journal of Pediatrics 1992;120(1):99-106.
Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD000174. DOI: 10.1002/14651858.CD000174.
Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003;289(19):2554-9.
Friis-Hansen B. Changes in body water compartments during growth. Acta Paediatrica Supplement 1957;46(Suppl 110):1-68.
Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 1961;28:169-81.
Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Wilson-Costello D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005;116(2):333-41.
Hartnoll G, Betremieux P, Modi N. Randomized controlled trial of postnatal sodium supplementation on body composition in 25 to 30 week gestational age infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2000;82(1):F24-8.
ICROP. An international classification of retinopathy of prematurity. Pediatrics 1984;74(1):127-33.
ICROP. The International Classification of Retinopathy of Prematurity revisited. Archives of Ophthalmolmology 2005;123(7):991-9.
Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107(1):E1.
Montori VM, Permanyer-Miralda G, Ferreira-González I. Validity of composite end points in clinical trials. BMJ 2005;330(7491):594-6.
Oh W, Poindexter BB, Perritt R, Lemons JA, Bauer CR, Ehrenkranz RA, et al. Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. Journal of Pediatrics 2005;147(6):786-90.
Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):529-34.
Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344(26):1966-72.
Schmidt B, Roberts RS, Fanaroff A, Davis P, Kirpalani HM, Nwaesei C, Vincer M; TIPP Investigators. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). Journal of Pediatrics 2006;148(6):730-4.
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82(4):527-32.
Stonestreet BS, Bell EF, Warburton D, Oh W. Renal response in low-birth-weight neonates. Results of prolonged intake of two different amounts of fluid and sodium. American Journal of Diseases of Children 1983;137(3):215-9.
This review is published as a Cochrane review in The Cochrane Library, Issue 7, 2011 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.