A Ohlsson
Writing protocol
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Verifying and entering data into RevMan
Revision of final review
O Da Silva
Writing Protocol
Translation of article
In an updated search to April 2006, no new eligible studies were identified.
The conclusion remains unchanged: there is no evidence from randomised trials
for the use of salbutamol for the prevention of chronic lung disease (CLD)
at the present time. We are unable to address the question as to whether
bronchodilators are useful in the treatment of CLD. Future use of salbutamol
and other bronchodilators in preterm infants should occur in the scenario
of a placebo-controlled randomised clinical trial.
Chronic lung disease (CLD) is common in babies who are born before 34 weeks gestation. Bronchodilators are drugs that cause widening of the air passages in the lungs. They have been used for CLD because of their potential effect of dilating small airways in babies born preterm. Bronchodilators can be inhaled, taken by mouth (a puffer) or injection or by a nebulizer with a pressurized aerosol. This review of trials found that there was not enough evidence to show either positive or negative effects of bronchodilators for CLD. More research is needed.
The use of bronchodilators in CLD has been justified by their potential effect of dilating small airways having muscular hypertrophy. Increase in compliance and tidal volume and decrease in pulmonary resistance has been documented with use of bronchodilators in short term studies of pulmonary mechanics in infants with CLD (Sosulski 1982; Cabal 1987; Kirpalani 1990; Brudno 1989, Pfenninger 1993; Gappa 1997; Fok 1998b).
There are numerous available bronchodilators. Inhaled bronchodilators include non-specific beta adrenergic agents such as isoproterenol and isoetharine, and specific beta adrenergic agents such as albuterol, metaproterenol, terbutaline and isoetharine. Side effects of beta agonists include hypokalaemia, tachycardia, cardiac arrhythmias, tremor, hypertension and hyperglycaemia (Davis 1990; Farrell 1997; Sweet 2000). Inhaled anticholinergic agents include atropine and ipratropium. There are more side effects of atropine than of ipratropium as the latter is poorly absorbed. Side effects of inhaled anticholinergic agents include tachycardia, decreased gastrointestinal motility, tremor and drying of respiratory secretions (Davis 1990). Systemic bronchodilators include the methylxanthines, caffeine and theophylline, which act by blockage of adenosine receptors. Reported side effects include vomiting, diarrhoea, tachycardia, hypertension and agitation (Davis 1990; Farrell 1997; Sweet 2000) .
Bronchodilators may be delivered orally, intravenously, by nebuliser or pressurised aerosol with or without a spacer device. With nebulisation or aerosol only 0.22 - 1.3% of the dose will reach the lung (Grigg 1992, Fok 1996). Aerosol tends to be deposited in the central lung region rather than the periphery (Fok 1996). Humidification of the gas reduces lower respiratory tract deposition of aerosol (Diot 1995). Addition of a spacer device between the nebuliser and the endotracheal tube (Harvey 1995) and synchronising nebulisation with inspiratory airflow (Diot 1995) increase deposition. There is also considerable intersubject variability in lung deposition (Fok 1996). All these factors will modify therapeutic effects.
For treatment: primary outcomes were mortality within the study period. Secondary outcomes were number of days on oxygen, number of days on ventilator, patent ductus arteriosus (PDA), pulmonary interstitial emphysema (PIE), pneumothorax, any grade of intraventricular haemorrhage, necrotizing enterocolitis (NEC), sepsis and adverse effects of bronchodilators.
In MEDLINE the following MeSH terms were used: bronchopulmonary dysplasia, chronic disease, lung diseases, bronchodilator agents, adrenergic agents, anticholinergic agents, albuterol, aminophylline, atropine, clenbuterol, cromakalim, ephedrine, epinephrine, fenoterol, hexoprenaline, ipratropium, isoetharine, isoproterenol, orciprenaline, procaterol, terbutaline, theophylline, tretoquinol. The following textwords were used: chronic lung disease, caffeine, salbutamol, terbutaline, albuterol, aminophylline, atropine, ipratopium, isoetharine, theophylline. Limits: newborn infant <birth to 1 month>, human, clinical trial, controlled clinical trial, meta analysis, multicenter study, randomised controlled trial.
In EMBASE the following terms were used: bronchodilating agent, adrenergic receptor stimulating agent, albuterol, clenbuterol, fenoterol, salbutamol, terbutaline, isoetharine, isoproterenol, lung dysplasia, evidence based medicine, clinical trial, multicenter study. The following textwords were used: bronchopulmonary dysplasia, clinical trial, rct, rcts, random, meta-analysis, meta analysis, multicenter, newborn, neonate, neonatal. Limits: infant < to one year >.
In CINAHL the following terms were used: bronchopulmonary dysplasia, chronic disease, lung diseases, adrenergic agents, anticholinergic agents, bronchodilator agents. The following textwords were used: albuterol, aminophylline, atropine, clenbuterol, cromakalim, ephedrine, epinephrine, fenoterol, hexoprenaline, ipratropium, isoetharine, isoproterenol, orciprenaline, procaterol, terbutaline, theophylline, tretoquinol. Limits: newborn infant < birth to 1 month >.
The methodological quality of the trials were independently reviewed by
two review authors (GN, AO) for the following questions:
1. Blinding of randomisation
2. Blinding of intervention
3. Complete follow up
4. Blinding of outcome.
There were three options to answer these questions: yes, no and cannot
tell. Each review author extracted the data separately, then the data were
compared and differences were resolved. The standard methods of the Neonatal
Review Group were used to synthesise data using relative risk (RR), risk
difference (RD) and number needed to treat (NNT) if there was a statistically
significant reduction in RD and number needed to harm (NNH) if there was
a statistically significant increase in the RD. Mean difference (WMD) was
used for continuous variables. A fixed effect model was used for meta-analysis.
We examined heterogeneity using the I2 statistic.
In the study by Denjean 1998, 173 infants needing ventilatory support in a multicentre trial in six NICUs were randomised into four groups: salbutamol + placebo, salbutamol + beclomethasone, placebo + placebo, or placebo + beclomethasone for 28 days. Randomisation was stratified by centre, GA ( < 28 wks vs. 29 - 30 wks) and the type of ventilatory support. The salbutamol + placebo and salbutamol + beclomethasone groups were compared to the placebo + placebo and placebo + beclomethasone groups in this review. This comparison is unconfounded by beclomethasone as half of each group, salbutamol or placebo, will have received beclomethasone also. Salbutamol was given in a dose of 200 mcg every 4 hrs (1200 mcg daily) via metered dose inhaler and spacer device. Beclomethasone was given in a dose of 250 mcg via metered dose inhaler and spacer device. The groups were similar with respect to the age at entry, sex, severity of the initial respiratory failure (as assessed by initial FiO2 and ventilatory index), maternal prenatal steroid therapy and multiple pregnancy. Treatment was begun on the 10th or 11th postnatal day and was given for 28 days with the dose tapering off over a period of eight days. Primary outcomes were mortality and CLD characterised at 28 days of life on the basis of clinical (oxygen dependency) and radiographic criteria. Secondary outcomes were duration of ventilatory support, duration of oxygen supplementation, ventilatory index (the product of oxygen tension and mean airway pressure) measured every week until extubation, pulmonary complications (pneumothorax, interstitial emphysema), sepsis, mandatory iv corticosteroid treatment according to the usual practice in each centre and episodes of bronchospasm treated with iv bronchodilators. Data on drug deposition were not given in this study.
The studies by Kao 1984; Kao 1987; Kao 1988; Kao 1989; Wilkie 1987; Rotschild 1989; Stefano 1991; Pfenninger 1993; Lee 1994; Gappa 1997; Nguyen 1997; Fok 1998a and Sivakumar 1999 were rejected as these studies dealt solely with pulmonary mechanics. Guimaraes 1993 was rejected as it was not a randomised controlled trial and infants were given both beclomethasone and salbutamol together.
Comparison 01: Salbutamol vs placebo in the prophylaxis of CLD
Outcome 01.01: Mortality
No significant effect was found: RR 1.08 (95% CI 0.50, 2.31); RD 0.01 (95%
CI -0.09, 0.11).
Outcome 01.02: CLD at 28 days
For overall (mild, moderate or severe) there was no significant effect:
CLD RR 1.03 (95% CI 0.78, 1.37); RD 0.02 (95% CI -0.13, 0.17).
Outcome 01.03: Duration of assisted ventilation
There was no statistically significant difference in the duration of assisted
ventilation MD -1.63 days (95% CI -5.63, 2.37).
Outcome 01.04: Duration of oxygen supplementation
There was no statistically significant difference in the duration of oxygen
supplementation MD -2.82 days (95% CI -11.91, 6.27).
Outcome 01.05: Mean age of weaning from ventilatory support
There was no statistically significant difference in weaning from respiratory
support (assisted ventilation or oxygen supplementation): MD -2.87 days
(95% CI -11.28, 5.54).
Outcome 01.06: Need for iv dexamethasone
No significant effect was found: RR 0.77 (95% CI 0.49, 1.19); RD -0.08
(95% CI -0.22, 0.05). These results are not statistically significant.
Outcomes 01.07 and 01.08: Infants with one or more episodes of infection
There was no statistically significant effect found on respiratory infections
defined as increasing ventilatory requirements associated with increased
serum C reactive protein and bacteria in tracheal aspirates: RR 0.61 (95%
CI 0.27, 1.39); RD -0.06 (95% CI -0.16, 0.04). There was no significant effect
found on sepsis defined as a positive blood culture: RR 1.06 (95% CI 0.54,
2.06); RD 0.01 (95% CI -0.10, 0.12).
The authors state that there was no difference in the secondary outcomes of pulmonary complications, weekly ventilatory index until extubation, interruptions in randomised treatment for iv salbutamol and episodes of bronchospasm treated with iv bronchodilators. However, the data are not presented in the paper. Adverse effects associated with salbutamol were not commented on in this paper.
The study by Denjean 1998 shows no evidence that salbutamol reduces mortality or chronic lung disease at 28 days in preterm infants at risk of developing CLD. This study does not report outcomes for CLD at 36 weeks postmenstrual age which is generally regarded as the more important outcome with regards to CLD. The study does not demonstrate earlier weaning from respiratory support with salbutamol or the duration of oxygen supplementation. The study demonstrates that salbutamol does not affect need for iv dexamethasone or sepsis compared to placebo. It is possible that the use of dexamethasone varied between the six neonatal intensive care units in the study. Denjean 1998 makes no comments as to adverse effects of salbutamol in this study.
There are several possible reasons as to why salbutamol had no evidence of effect in the study by Denjean 1998. The study does not assess drug deposition which is important as this will change the therapeutic effect of the drug. The amount of drug delivered to the lung also varies with the route of administration. It is possible that the mode of delivery used in this study did not deliver enough drug to the lung. The pathophysiology of CLD is multifactorial. Since there are other mechanisms besides muscle hypertrophy in small airways, this may be another reason why salbutamol showed no evidence of effect for the prevention of CLD in this study.
The review authors were surprised at the paucity of trials which assessed clinical outcomes of bronchodilators in CLD. No randomised controlled trials could be found in an extensive search of the literature of the use of bronchodilators in the treatment of CLD.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Denjean 1998 | Randomised prospective double-blind placebo controlled trial
1. Blinding of Randomisation - yes |
Number of patients entered into the study - 87 in treatment group
and 86 in control group. Mean (SD) Bw - 1028 +/- 220g in the salbutamol arm and 1071 +/- 254g in the placebo arm. Mean (SD) GA - 27.7 +/- 1.5wk in the salbutamol arm and 27.7 +/- 1.6wk in the placebo arm. Age at enrollment into study - Day 10 or Day 11 Other characteristics - All infants had RDS and a gestational age of < 31 wk and needed ventilatory support on the 10th postnatal day. Exclusion criteria - Infants with major malformations, sepsis, current bronchopulmonary infection, treatment with corticosteroids or bronchodilators. |
Metered dose inhalers were used to administer salbutamol 200 mcg every 4 hrs or the corresponding placebo. Treatment was given on the 10th or 11th postnatal day and was given for 28 days with dose tapering over a period of 8 days. | Primary outcomes were mortality and CLD at 28 days on the basis of oxygen dependency and radiographic criteria. Secondary outcomes were duration of ventilatory support, duration of oxygen supplementation, ventilatory index measured every week until extubation, pulmonary complications (pneumothorax, interstitial emphysema), mandatory iv corticosteroid treatment according to the usual practice in each centre, episodes of bronchospasm treated with iv bronchodilators - no significant differences were noted in any of the outcomes. | The incidence of pulmonary complications and episodes of bronchospasm were said to be the same but the data are not presented. Data for the two main groups, salbutamol and placebo, were assembled by Joseph Beyene from subgroup data in the original report for the following outcomes: duration of assisted ventilation, duration of oxygen supplementation and age at weaning from respiratory support. | A |
CLD = chronic lung disease
g = grams
GA = gestational age
Bw = birthweight
wk = weeks
| Study | Reason for exclusion |
| Fok 1998a | Only pulmonary mechanics were reported |
| Gappa 1997 | Only pulmonary mechanics were reported |
| Guimaraes 1993 | Not a randomised controlled trial. Infants were given both beclomethasone and salbutamol but not separately |
| Kao 1984 | Not a randomised controlled trial |
| Kao 1987 | Only pulmonary mechanics were reported |
| Kao 1988 | Only pulmonary mechanics were reported |
| Kao 1989 | A crossover study where each infants received placebo, metaproterenol, atropine, and combined metaproterenol and atropine. Only reported pulmonary mechanics |
| Lee 1994 | Only pulmonary mechanics were reported |
| Nguyen 1997 | Only pulmonary mechanics were reported |
| Pfenninger 1993 | Only pulmonary mechanics were reported |
| Rotschild 1989 | Each patient was their own control subject and was randomly assigned
to a placebo-salbutamol or salbutamol-placebo sequence. Only pulmonary mechanics
were reported |
| Sivakumar 1999 | Only pulmonary mechanics were reported |
| Stefano 1991 | Only pulmonary mechanics were reported |
| Wilkie 1987 | Only pulmonary mechanics were reported |
Denjean A, Paris-Llado J, Zupan V, Debillon T, Kieffer F, Magny J-F, Desfreres L, Llanas B, Guimaraes H, Moriette G, Voyer M, Dehan M, Breart G. Inhaled salbutamol and beclomethasone for preventing bronchopulomonary dysplasia: a randomised double-blind study. European Journal of Pediatrics 1998;157:926-31.
Fok TF, Lam K, Ng PC, So HK, Cheung KL, Wong W, So HK. Randomised crossover trial of salbutamol aerosol delivered by metered dose inhaler, jet nebuliser and ultrasonic nebuliser in chronic lung disease. Archives of Disease in Childhood 1998;79:F100-4.
Gappa 1997 {published data only}
Gappa M, Gartner M, Poets CF, Von der Hardt H. Effects of salbutamol delivery from a metered dose inhaler versus jet nebuliser on dynamic lung mechanics in very preterm infants with chronic lung disease. Pediatric Pulmonology 1997;23:442-8.
Guimaraes 1993 {published data only}
Guimaraes H, Denjean A, Debillon T, Gaultier C, Dehan M, Santos NT. Efeito da associacao dos aerossois de salbutamol e de beclomethasonan, por via inalatoria, na prevencao da displasia bronchopulmonar. Arquivos Brasileiros de Medicina 1993;7:286-93.
Kao 1984 {published data only}
Kao L.C, Warburton D, Platzker ACG, Keens TG. Effect of isoproterenol inhalation on airway resistance in chronic bronchopulmonary dysplasia. Pediatrics 1984;73:509-14.
Kao 1987 {published data only}
Kao LC, Durand DJ, Phillips BL, Nickerson BG. Oral theophylline and diuretics improve pulmonary mechanics in infants with bronchopulmonary dysplasia. Journal of Pediatrics 1987;111:439-44.
Kao 1988 {published data only}
Kao L, Durand DJ, Nickerson BG. Improving pulmonary function does not decrease oxygen consumption in infants with bronchopulmonary dysplasia. Journal of Pediatrics 1988;112:616-21.
Kao 1989 {published data only}
Kao LC, Durand DJ, Nickerson BG. Effects of inhaled metaproterenol on the pulmonary mechanics of infants with bronchopulmonary dysplasia. Pediatric Pulmonology 1989;6:74-80.
Lee 1994 {published data only}
Lee H, Arnon S, Silverman M. Bronchodilator aerosol administered by metered dose inhaler and spacer in subacute neonatal respiratory distress syndrome. Archives of Disease in Childhood 1994;70:218-22.
Nguyen 1997 {published data only}
Nguyen H-NP, Fitzgerald D, Davis MG. Response of very premature infants with bronchopulmonary dysplasia to inhaled salbutamol. McGill Journal of Medicine 1997;3:19-23.
Pfenninger 1993 {published data only}
Pfenninger J, Aebi C. Respiratory response to salbutamol (albuterol) in ventilator-dependent infants with chronic lung disease: pressurised aerosol delivery versus intravenous injection. Intensive Care Medicine 1993;19:251-5.
Rotschild 1989 {published data only}
Rotschild A, Solimano A, Puterman M, Smyth J, Sharma A, Albersheim S. Increased compliance in response to salbutamol in premature infants with developing bronchopulmonary dysplasia. Journal of Pediatrics 1989;115:984-91.
Sivakumar 1999 {published data only}
Sivakumar D, Bosque E, Goldman SL. Bronchodilator delivered by metered dose inhaler and spacer improves respiratory system compliance more than nebulizer-delivered bronchodilator in ventilated premature infants. Pediatric Pulmonology 1999;27:208-12.
Stefano 1991 {published data only}
Stefano JL, Bhutani VK, Fox WW. A randomised placebo controlled study to evaluate the effects of oral albuterol on pulmonary mechanics in ventilator dependent infants at risk of developing BPD. Pediatric Pulmonology 1991;10:183-90.
Wilkie 1987 {published data only}
Wilkie RA, Bryan MH. Effect of bronchodilators on airway resistance in ventilator-dependent neonates with chronic lung disease. Journal of Pediatrics 1987;111:278-83.
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| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Salbutamol vs placebo in the prophylaxis of CLD | ||||
| 01 Mortality | 1 | 173 | RR (fixed), 95% CI | 1.08 [0.50, 2.31] |
| 02 CLD at 28 days | 1 | 173 | RR (fixed), 95% CI | 1.03 [0.78, 1.37] |
| 03 Duration of assisted ventilation (days) | 1 | 173 | WMD (fixed), 95% CI | -1.63 [-5.63, 2.37] |
| 04 Duration of oxygen supplementation (days) | 1 | 173 | WMD (fixed), 95% CI | -2.82 [-11.91, 6.27] |
| 05 Age of weaning from ventilatory support (days) | 1 | 173 | WMD (fixed), 95% CI | -2.87 [-11.28, 5.54] |
| 06 Need for iv dexamethasone | 1 | 173 | RR (fixed), 95% CI | 0.77 [0.49, 1.19] |
| 07 Infants with one or more episodes of respiratory infection | 1 | 173 | RR (fixed), 95% CI | 0.61 [0.27, 1.39] |
| 08 Infants with one or more episodes of sepsis (positive blood cultures) | 1 | 173 | RR (fixed), 95% CI | 1.06 [0.54, 2.06] |
01.03 Duration of assisted ventilation (days)
01.04 Duration of oxygen supplementation (days)
01.05 Age of weaning from ventilatory support (days)
01.06 Need for iv dexamethasone
01.07 Infants with one or more episodes of respiratory infection
01.08 Infants with one or more episodes of sepsis (positive blood cultures)
Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca
| This review is published as a Cochrane review in
The Cochrane Library, Issue 3, 2006 (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. |
