Geraldine Ng1, Arne Ohlsson2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Neonatology, St Mary's Hospital (Imperial College Healthcare NHS Trust), London, UK
2Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
Citation example: Ng G, Ohlsson A. Cromolyn sodium for the prevention of chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD003059. DOI: 10.1002/14651858.CD003059.
Neonatology
St Mary's Hospital (Imperial College Healthcare NHS Trust)
1st Floor, The Bay's Building
Praed Street
London
London
W2 1NY
UK
E-mail: DrGYTNg@aol.com
| Assessed as Up-to-date: | 04 August 2009 |
|---|---|
| Date of Search: | 28 July 2009 |
| Next Stage Expected: | 04 August 2011 |
| Protocol First Published: | Issue 2, 2001 |
| Review First Published: | Issue 2, 2001 |
| Last Citation Issue: | Issue 2, 2001 |
| Date / Event | Description |
|---|---|
| 04 August 2009 Updated |
This review updates the existing review "Cromolyn sodium for the prevention of chronic lung disease in preterm infants" published in the Cochrane Database of Systematic Reviews (Ng 2001). Updated search found no new trials. No changes to conclusions. |
| Date / Event | Description |
|---|---|
| 16 September 2008 Amended |
Converted to new review format. |
| 30 June 2006 Updated |
This review updates the existing review "Cromolyn sodium for the prevention of chronic lung disease in preterm infants)" initially published in The Cochrane Library, Issue 2, 2001. |
| 07 November 2000 New citation: conclusions changed |
Substantive amendment |
Chronic lung disease (CLD) frequently occurs in preterm infants and has a multifactorial etiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis and may, therefore, have a role in the prevention of CLD.
To determine the effect of prophylactic administration of cromolyn sodium on the incidence of CLD, mortality or the combined outcome of mortality or CLD at 28 days of life in preterm infants at risk of CLD.
The search strategy of the Cochrane Neonatal Review Group was used to identify studies. Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2009), MEDLINE, EMBASE, CINAHL up to and including July 2009, personal files and reference lists of identified trials.
Randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebulizer or metered dose inhaler with or without spacer device
versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks postmenstrual age (PMA), or the combined outcome mortality or CLD at 28 days.
The standard method for the Cochrane Collaboration as described in the Cochrane Collaboration handbook was used. Relative risk (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. A fixed effect model was used for meta-analysis. Heterogeneity was examined using the I2 statistic.
Two eligible studies were identified with small numbers of infants enrolled. Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality or CLD at 28 days; CLD at 28 days or at 36 weeks PMA; CLD in survivors at 28 days or at 36 weeks PMA. Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, days mechanical ventilated. No side effects were noted.
Cromolyn sodium administered in the first few days of life has not been shown to prevent chronic lung disease in preterm infants. Preterm babies (babies born before 37 weeks gestation) often need to be given oxygen for lung problems for many weeks because of chronic lung disease. This is due, in part, to inflammation (swelling) within the lungs. Theoretically, cromolyn sodium is a drug that might help prevent this inflammation. It is relatively safe and adverse effects are rare. It can be given by nebuliser or aerosol inhaler in the first few days in an attempt to prevent chronic lung disease. However, this review of trials found no strong evidence that cromolyn sodium can prevent or reduce chronic lung disease and further research does not seem to be justified.
Chronic lung disease (CLD), defined as oxygen dependency at 28 days or at 36 weeks postmenstrual age (PMA) is a pulmonary disorder that frequently occurs in preterm infants (Northway 1967; Shennan 1988). It is the consequence of unresolved or abnormally repaired lung damage and has a multifactorial etiology that has been described extensively by previous authors. These factors include exposure to high oxygen concentration, volume derived trauma, barotrauma, sepsis and inflammation (Avery 1987; Paita 1991; Rojas 1995). In the past decades the survival rate of very low birth weight infants has increased and the prevalence of CLD remains high (Parker 1992). The incidence varies depending on the population studied, the diagnostic criteria used and variation between centres in clinical management (O'Brodovich 1985; Shennan 1988; Hack 1991; Avery 1987; Lee 2000). CLD may be associated with chronic respiratory difficulties, prolonged and recurrent hospitalisation, growth restriction and death (O'Brodovich 1985; Lee 2000). The administration of antenatal corticosteroids to mothers likely to give birth preterm reduces neonatal mortality and the incidence of respiratory distress syndrome (RDS) but not the incidence of CLD (Crowley 2000. Administration of prophylactic natural surfactant extract does not reduce the incidence of CLD but does reduce the combined outcome of death or CLD (Soll 2000).
Neonates who develop CLD have been demonstrated to have elevated levels of endothelin-1, interleukin (IL)-6, IL-8, and high ratios of IL-1B to IL-1 receptor antagonists in tracheobronchial lavage when compared to those with respiratory distress syndrome (RDS) or controls (Bagchi 1994; Tullus 1996; Niu 1998; Rindfleisch 1996). One study showed elevated levels of tumour necrosis factor (TNF) alpha in neonates who subsequently develop CLD (Tullus 1996), but another study did not (Bagchi 1994).
Cromolyn sodium was originally characterised as a mast cell stabiliser (Hoag 1991). However, it also inhibits neutrophil activation (Kay 1987) and neutrophil chemotaxis (Bruijnzeel 1989) and, therefore, may modulate the inflammatory process in the lung. In a small non-randomised cohort comparison study of cromolyn sodium use in infants with CLD, Viscardi 1994 found that there was a decrease in peak inspiratory pressure, a reduction in intermittent mandatory ventilation requirements and an increase in dynamic compliance after two weeks of cromolyn sodium therapy. Total airway resistance did not change significantly. Compared to matched controls there were no differences in duration of need for supplemental oxygen, ventilation or hospitalisation. These results suggested that cromolyn therapy might improve pulmonary function in some infants with established CLD (Viscardi 1994). Initiating cromolyn sodium treatment in the first few days of life in infants at risk of CLD might inhibit the neutrophil influx and the release of inflammatory mediators in the lung and thereby decrease the lung injury leading to CLD.
Cromolyn sodium may be delivered by nebuliser or pressurised aerosol with or without a spacer device. With either method only 0.22 - 1.3% of the dose will reach the lung (Grigg 1992; Fok 1996). Aerosolized products tend to be deposited in the central lung region rather than in the periphery (Fok 1996). Humidification of the gas reduces lower respiratory tract deposition of aerosolized products (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 considerable intersubject variability in lung deposition (Fok 1996). All these factors will modify therapeutic effects.
Cromolyn is thought to be a relatively safe drug. However, there are occasional reports in the literature of adverse effects. These include dermatitis (Sheffer 1975; Settipane 1979), urticaria (Sheffer 1975; Menon 1977), eosinophilic pulmonary infiltrates (Lobel 1972; Sheffer 1975), pulmonary allergic granulomatosis (Burgher 1974; Sheffer 1975) and anaphylaxis (Ahmad 1983; Brown 1981).
This review updates the existing review "Cromolyn sodium for the prevention of chronic lung disease in preterm infants" published in the Cochrane Database of Systematic Reviews (Ng 2001).
To determine the effect of prophylactic administration of cromolyn sodium on the incidence of CLD at 28 days or 36 weeks PMA, mortality, or the combined outcome of mortality or CLD at 28 days or 36 weeks PMA in preterm infants.
The intervention had to include administration of cromolyn sodium by nebulizer or metered dose inhaler with or without spacer device versus placebo or no intervention. Treatment with cromolyn sodium had to be initiated during the first two weeks of life.
Primary outcomes were mortality within the study period, combined outcome of CLD or mortality at 28 days, CLD at 28 days and 36 weeks PMA.
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 (IVH), necrotizing enterocolitis (NEC), sepsis and adverse effects of cromolyn sodium.
The search strategy used to identify studies was performed according to the guidelines of the Cochrane Neonatal Review Group.
We searched MEDLINE 1966 to April 2006, EMBASE 1980 to April 2006, CINAHL 1982 to April 2006, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), personal files and reference lists of identified trials. The search strategies were adjusted to reflect the different controlled vocabularies of the databases.
In MEDLINE the following MeSH terms were used: bronchopulmonary dysplasia, chronic disease, cromolyn sodium. The following textwords were used: chronic lung disease, cromoglycate. Limits: newborn infant < birth to 1 month >, clinical trial, controlled clinical trial, meta analysis, multicenter study, randomised controlled trial.
In EMBASE the following terms were used: cromoglycate disodium, lung dysplasia, chronic lung disease, evidence based medicine, clinical trial, multicenter study. The following textwords were used: cromoglycate, cromoglicate, cromolyn, bronchopulmonary dysplasia, clinical trial, rct, rcts, random, meta-analysis, metaanalysis or multicent:, newborn, neonate, neonatal. Limits: infant < to one year >.
In CINAHL the following terms were used: bronchopulmonary dysplasia, chronic disease, lung diseases, cromolyn sodium. The following textwords were used: cromoglycate, cromoglicate. Limits: newborn infant < birth to 1 month >.
In July 2009, we updated the search as follows:
MEDLINE (search via PubMed), CINHAL, EMBASE and The Cochrane Library were searched from 2006 - 2009.
Search terms: bronchopulmonary dysplasia OR chronic disease OR cromolyn sodium OR chronic lung disease OR cromoglycate.
Limits: human, newborn infant and clinical trial. No language restrictions were applied.
The standard methods of the Cochrane Neonatal Review Group Guidelines were employed.
Reports were first reviewed to determine whether the trial had a concurrent control group. If not the study was excluded. The method of assignment to control and intervention groups was then determined and if not random or quasi random, the trial was discarded.
Each review author (GN, AO) selected studies and extracted and assessed data separately. The data were then compared and differences were resolved by discussion. Information on the trial participants included birth weight, GA at birth, need for mechanical ventilation, and sex. Information on clinical outcomes included CLD at 28 days, CLD at 36 weeks PMA, combined outcome of CLD or mortality at 28 days, mortality at 28 days, IVH, NEC, air leaks, sepsis and adverse effects due to cromolyn sodium. Information on hospital stay and days in oxygen or on mechanical ventilation was also sought.
The standard methods of the Cochrane Neonatal Review Group were employed. Each identified trial was assessed for methodological quality by both review authors (GN, AO) with respect to a) masking of allocation b) masking of intervention c) completeness of follow-up and d) masking of outcome assessment. There were three responses to these questions: yes, no or cannot tell. This information is included in the table 'Characteristics of Included Studies'.
For the update in 2009 the risk of bias table was completed in order to address the following questions:
1. Sequence generation: Was the allocation sequence adequately generated?
2. Allocation concealment: Was allocation adequately concealed?
3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?
Statistical analyses was performed using Review Manager (RevMan) software. For categorical outcomes estimates for relative risk and risk difference were calculated. For outcomes measured on a continuous scale estimates for weighted mean difference were calculated. 95% confidence intervals were used.
Heterogeneity between trials was evaluated by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. A fixed effects model for meta-analysis.
The standard methods of the Neonatal Review Group were used to synthesize 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. Meta-analyses of data from the included trials were performed using a fixed effect model.
Two eligible studies, both single centre, were identified. No eligible studies were excluded from analysis.
In the trial by Watterberg 1993, 38 infants needing ventilatory support at birth were randomised to receiving sodium cromoglycate or saline. The preterm infants had a mean GA [standard deviation (SD)] of 25.9 wks +/- 0.9 and a mean (SD) birth weight of 845 g +/- 81 in the treatment group and a mean GA (SD) of 26 wks +/- 1.5 and a mean (SD) birth weight of 851 g +/- 150 in the control group. Patients were stratified into those below 1000 g and those from 1000 to 2000 g. Watterberg 1993 states that allocation to treatment groups was by sequential numbers, but it is unclear exactly what this involved and, therefore, whether blinding occurred is also unclear. The patients were comparable in severity of illness on entry into the study (defined as FiO2 and respiratory acuity score). Infants were enrolled into the study less than 12 hrs after intubation for RDS. Sodium cromoglycate or placebo (normal saline) was given as 20 mg nebulized every six hours for the duration of intubation. The length of time that the infants were intubated and, therefore, received treatment is lacking. The study was discontinued when 10 babies of birth weight under 1000 g and 28 babies from 1000 to 2000 g had been enrolled. Although we had not specified subgroup analyses by birth weight, data from this study could be obtained only from babies > 1000 g for some outcomes.
In the trial by Viscardi 1997, 26 infants requiring ventilation on day one for RDS with a greater than 75% predicted probability of oxygen dependence at 28 days were randomised to receive either nebulized sodium cromoglycate given as 20 mg every six hours or placebo (normal saline). The 12 hour CLD predictive score was similar in the two groups. There was no difference between groups in FiO2, alveolar-arterial oxygen gradient, or ventilatory settings on the day of study entry. The infants received the drug from day three to day 28 of life. One infant was withdrawn at day seven at parental request but is included in the analyses of outcomes. Seventy-seven percent of treated infants and 100% of infants in the placebo group received exogenous surfactant. The primary outcome was the concentration of cytokines in lung lavage in these infants.
No data were collected regarding the amount and site of drug deposition in the lung in either trial. The numbers of patients receiving postnatal dexamethasone in each group was not documented in either trial.
Both studies were of small size but of good quality overall. A sample size calculation was included in the study by Watterberg 1993 but not in the trial by Viscardi 1997. Viscardi 1997 states that the randomisation process and the allocation to groups was blinded. In the study by Watterberg 1993 blinding of randomisation was unclear. Patients were enrolled by sequential numbers in the study by Watterberg 1993 but it is unclear as to what this actually means. In the study by Viscardi 1997 randomisation was accomplished by a computer generated table of random numbers. The intervention was blinded in both studies although in the study by Viscardi 1997 the pharmacist was aware of treatment assignment. Both Viscardi 1997 and Watterberg 1993 analysed the data on an intention to treat basis and there was complete follow up of all patients. In the study by Viscardi 1997 the clinical outcome was CLD at 28 days of life. Chest X rays were reviewed by a single radiologist who was blinded to the treatment regimens and the outcomes.
SODIUM CROMOGLYCATE VS PLACEBO (Comparison 1):
Mortality or CLD at 28/30 days (Outcome 1.01):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 1.05 (95% CI 0.73, 1.52); typical RD 0.03 (95% CI -0.20, 0.27). These results are based on two trials, 64 babies and 41 events.
Mortality to 28 days (Outcome 1.02):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 1.31 (95% CI 0.52, 3.29); typical RD 0.06 (95% CI -0.13, 0.26). These results are based on two trials, 64 babies and 14 events.
CLD at 28 days (Outcome 1.03):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.93 (0.53, 1.64); typical RD -0.03 (95% CI -0.27, 0.20). These results are based on two trials, 64 babies and 27 events.
CLD at 36 weeks PMA (Outcome 1.04):
The study by Watterberg 1993 did not look at this outcome. The study by Viscardi 1997 found no evidence of effect: RR 1.25 (0.43, 3.63), RD 0.08 (-0.29, 0.44). These results are based on one trial, 26 babies and nine events.
CLD among survivors at 28 days (Outcome 1.05):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.97 (95% CI 0.58, 1.63, typical RD -0.02 (95% CI -0.29, 0.26). These results are based on two trials, 50 surviving babies and 27 events.
CLD among survivors at 36 weeks PMA (Outcome 1.06):
The study by Watterberg 1993 did not look at this outcome. The paper by Viscardi 1997 found no evidence of effect: RR 1.04 (95% CI 0.38, 2.87); RD 0.02 (95% CI -0.40, 0.43). These results are based on one trial, 22 surviving babies and nine events.
IVH (Outcome 1.07):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.89 (95% CI 0.63, 1.27); typical RD -0.06 (95% CI -0.26, 0.13). These results are based on two trials, 64 babies and 36 events.
NEC (Outcome 1.08):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 1.25 (95% CI 0.37, 4.24); typical RD 0.03 (95% CI -0.14, 0.20). These results are based on two trials, 64 babies and nine events.
PDA (Outcome 1.09):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.88 (95% CI 0.65, 1.18); typical RD -0.09 (95% CI -0.31, 0.12). These results are based on two trials, 64 babies and 47 events.
Air leak (PIE, pneumothorax) (Outcome 1.10):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.67 (95% CI 0.32, 1.39); typical RD -0.13 (95% CI -0.34, 0.09). These results are based on two trials, 64 babies and 20 events.
Days on mechanical ventilation (Outcome 1.11):
This is only commented on in the study by Watterberg 1993, who did not report days on mechanical ventilation for babies under 1000 g; therefore, this outcome was analyzed only for babies over 1000 g. There was no evidence of effect: mean difference 1.00 days (95% CI -6.41, 8.41). This result is based on one trial and 28 babies.
Sepsis (Outcome 1.12):
Both Viscardi 1997 and Watterberg 1993 assessed this outcome. Neither found a significant effect. The meta-analysis of the results of both trials found no evidence of effect: typical RR 0.82 (95% CI 0.41, 1.63); typical RD -0.06 (95% CI -0.28, 0.15). These results are based on two trials, 64 babies and 20 events.
Other effects: cytokines in lung lavage
Viscardi 1997 showed that although the pre-study (day three) cytokine concentrations of cromolyn treated and control groups were similar, IL-8 concentration in cromolyn sodium lavage decreased 2.45 fold from day three to seven, whereas IL-8 concentrations increased 1.7 fold in control lavage during the same interval. Interleukin 8 (IL-8) concentrations were 4.9 fold lower on day seven in lavage from cromolyn sodium treated infants (median 2245 pg/ml) compared to levels in controls [median 11009 pg/ml (p = 0.051)]. TNF alpha was 3.6-fold lower on day seven in lavage from the cromolyn sodium treated infants (median 19.95 pg/ml) compared with lung lavage from controls [median 70.9 pg/ml (p = 0.04)]. There was a trend toward lower lavage levels of interleukin 1B (IL-1B) on day seven in cromolyn treated infants compared to control lavage levels [control median 208.2 pg/ml; cromolyn sodium median 46.75 pg/ml (p = 0.13)] but interleukin 1 receptor antagonist (IL-1ra) concentrations were unaffected by cromolyn sodium treatment (day seven cromolyn sodium median 21.5 ng/ml, day seven control median 23 ng/ml). The IL-1B/IL-1ra ratio was lower in day seven lavage from cromolyn sodium treated infants compared to the ratio in control infant lavage [cromolyn sodium median 0.002, control median 0.005 (p = 0.09)]. It is difficult to interpret these results since there were no clinical benefits noted.
Adverse effects
Sodium cromoglycate seemed to be a well tolerated drug without adverse side effects and there were no reported adverse responses to nebulization.
Although the study by Viscardi 1997 showed a reduction in cytokines in lung lavage from infants treated with cromolyn sodium, this did not translate into clinical benefits. Neither of the two eligible studies found a reduction in CLD or mortality. Cromolyn sodium had no statistically significant effect on the outcomes of IVH, NEC, PDA, air leak, days on mechanical ventilation or sepsis. No adverse effects were noted.
Sodium cromoglycate was given for different duration in the two studies. In the Watterberg 1993 study, sodium cromoglycate was given for the duration of intubation. In the Viscardi 1997 study, it was given for 25 days. The age of entry to the studies also differed. In the Watterberg 1993 study, the age of entry was 12 hrs after intubation and in the Viscardi 1997 study it was on day three of life.
Both studies involved very small numbers of infants. The sample sizes are so small that no reliable estimate of treatment effect is provided. The wide CIs show that clinically important effect sizes on major outcomes have not been excluded. Neither of these trials assessed drug deposition and it is possible that the drug wasn't received in effective doses at the correct sites. However, the available evidence does not justify further trials using the protocols for cromolyn sodium administration used to date.
Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants.
Although results are available only from a small number of infants randomised, the available evidence does not appear to justify further trials using the protocols for drug administration reviewed here unless a more efficient type of delivery device than the jet nebulizer is employed.
We would like to acknowledge the help of Elizabeth Uleryk, Director of the Hospital Library at the Hospital for Sick Children for help with search strategies.
The Cochrane Neonatal Review Group has been funded in part 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.
G Y Ng:
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Verifying and entering data into RevMan
Writing text of review
A Ohlsson:
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 the final review
Geraldine Ng (GN) and Arne Ohlsson (AO) wrote the original review and updated the review in 2000 and 2006.
The July 2009 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Roger Soll, Diane Haughton) and reviewed and approved by GN.
| Methods | Randomised prospective double-blind placebo controlled trial. |
|---|---|
| Participants | Number of patients entered into the study - 26 |
| Interventions | Nebulised 20 mg cromolyn sodium (n = 13) or 2mls normal saline placebo (n = 13) every 6 hrs from day 3 until day 28 |
| Outcomes | Primary outcome was CLD at 28 days of life and at 36 wks corrected gestational age. Changes in inflammatory cell populations and the cytokines in lung lavage in response to cromolyn therapy. Secondary outcomes were number of ventilator days, duration of oxygen supplementation, PDA, air leak, sepsis, NEC, IVH |
| Notes | 100% of the control group and 77% of treated infants received exogenous surfactant. No |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Randomisation was accomplished by a computer generated table of random numbers. |
| Allocation concealment? | Yes | Blinding of randomisation: yes. |
| Blinding? | Yes | Blinding of intervention: yes (however, pharmacist aware of treatment assignment). |
| Incomplete outcome data addressed? | Yes | Complete follow-up: yes. |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Methods | Randomised prospective double-blind placebo controlled trial. |
|---|---|
| Participants | Number of patients entered into the study - 38 |
| Interventions | Aerosolised 20 mg cromolyn sodium (n = 19) or 2 mls normal saline placebo (n = 19) every 6 hrs whilst intubated |
| Outcomes | Primary outcome was survival without oxygen dependence (oxygen saturations > 90% in FiO2 < 25% at 30 days of life). Secondary outcomes were the number of days dependent on mechanical ventilation during the first 30 days of life, the intensity of mechanical ventilation, and pulmonary complications. |
| Notes | No adverse effects which could be attributed to the administration of cromolyn sodium were noted. Days on mechanical ventilation were not reported on for babies < 1000 g. Therefore this outcome was analysed in the review only for babies > 1000 g. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Patients were stratified into those below 1000 g and those from 1000 to 2000 g and enrolled by "sequential numbers". |
| Allocation concealment? | Unclear | Blinding of randomisation - can't tell. We have written to Watterberg et al regarding the allocation concealment. This information will be available for a future update. |
| Blinding? | Unclear | Blinding of intervention: yes. |
| Incomplete outcome data addressed? | Unclear | Complete follow-up: yes. |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
Abbreviations:
CLD = chronic lung disease
g = grams
GA = gestational age
BW = birthweight
IVH = intraventricular haemorrhage
NEC = necrotising enterocolitis
PDA = patent ductus arteriosus
wk = weeks
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| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Mortality or CLD at 28/30 days | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 1.05 [0.73, 1.52] |
| 1.2 Mortality to 28 days | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 1.31 [0.52, 3.29] |
| 1.3 CLD at 28 days | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 0.93 [0.53, 1.64] |
| 1.4 CLD at 36 weeks PMA | 1 | 26 | Risk Ratio (M-H, Fixed, 95% CI) | 1.25 [0.43, 3.63] |
| 1.5 CLD among survivors to 28 days | 2 | 50 | Risk Ratio (M-H, Fixed, 95% CI) | 0.97 [0.58, 1.63] |
| 1.6 CLD among survivors to 36 weeks PMA | 1 | 22 | Risk Ratio (M-H, Fixed, 95% CI) | 1.04 [0.38, 2.87] |
| 1.7 IVH | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 0.89 [0.63, 1.27] |
| 1.8 NEC | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 1.25 [0.37, 4.24] |
| 1.9 PDA | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 0.88 [0.65, 1.18] |
| 1.10 Air leak (PIE, pneumothorax) | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 0.67 [0.32, 1.39] |
| 1.11 Days on mechanical ventilation | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 1.00 [-6.41, 8.41] |
| 1.12 Sepsis | 2 | 64 | Risk Ratio (M-H, Fixed, 95% CI) | 0.82 [0.41, 1.63] |
This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2010 (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. |
