Mohamed E Abdel-Latif1, David A Osborn2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Department of Neonatology, Australian National University Medical School, Woden, Australia
2Department of Mothers and Babies NICU, Royal Prince Alfred Hospital, Camperdown, Australia
Citation example: Abdel-Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD008309. DOI: 10.1002/14651858.CD008309.pub2.
Department of Neonatology
Australian National University Medical School
PO Box 11
Woden
ACT
2606
Australia
E-mail: Abdel-Latif.Mohamed@act.gov.au
| Assessed as Up-to-date: | 01 June 2011 |
|---|---|
| Date of Search: | 01 June 2011 |
| Next Stage Expected: | 01 June 2013 |
| Protocol First Published: | Issue 1, 2010 |
| Review First Published: | Issue 7, 2011 |
| Last Citation Issue: | Issue 7, 2011 |
Laryngeal mask airway (LMA) administration is one way of delivering surfactant to the infant lung, with the potential benefit of avoiding endotracheal intubation and ventilation, ventilator induced lung injury and bronchopulmonary dysplasia (BPD).
To determine the effect of LMA surfactant administration either as prophylaxis or treatment compared to placebo, no treatment, or intratracheal surfactant administration on morbidity and mortality in preterm infants with, or at risk of, respiratory distress syndrome (RDS).
We searched CENTRAL (The Cochrane Library, October 2010), MEDLINE and PREMEDLINE (1950 to October 2010), EMBASE (1980 to October 2010) and CINAHL (1982 to October 2010). We also searched proceedings of scientific meetings, clinical trial registries, Google Scholar and reference lists of identified studies, as well as contacting expert informants and surfactant manufacturers.
Randomised, cluster-randomised or quasi-randomised controlled trials of laryngeal mask surfactant administration compared to placebo, no treatment, or other routes of administration (nebulised, pharyngeal instillation of surfactant before the first breath, thin endotracheal catheter surfactant administration or intratracheal surfactant instillation) on morbidity and mortality in preterm infants at risk of RDS. We considered published, unpublished and ongoing trials.
Two review authors independently assessed studies for eligibility and quality, and extracted data.
We found no studies of prophylactic or early LMA surfactant administration. A single small study of late rescue LMA surfactant was identified as eligible for inclusion. The study enrolled 26 preterm infants born ≥ 1200 g with RDS on continuous positive airway pressure (nCPAP). LMA surfactant administration compared to no treatment resulted in a reduction in mean FiO2 required to maintain oxygen saturation between 88% and 92% for 12 hours after the intervention. No significant difference was reported in subsequent mechanical ventilation and endotracheal surfactant, pneumothorax, days on intermittent positive airway pressure (IPPV), and days on IPPV or oxygen.
There is evidence from a single small trial that LMA surfactant administration in preterm infants ≥ 1200 g with established RDS may have a short term effect in reducing oxygen requirements although the study is underpowered to detect important clinical effects. Adequately powered trials are required to determine the effect of LMA surfactant administration for prevention or treatment of RDS in preterm infants. LMA surfactant administration should be limited to clinical trials.
There is insufficient evidence from randomised controlled trials to guide the use of laryngeal mask surfactant administration in preterm infants at risk of respiratory distress syndrome.
Respiratory distress syndrome is caused by a deficiency of the naturally occurring lining chemicals of the lung (surfactant) and occurs mainly in infants born before term (37 weeks' gestation). The usual treatment includes instilling artificial surfactant directly into the newborn infant's trachea followed by mechanical ventilation. However, this process can lead to lung injury, which can affect the infant's long term health. A potential alternative strategy is to use a laryngeal mask as a delivery conduit for surfactant. This procedure has the potential to reduce the need for tracheal intubation after birth and subsequent lung damage caused by mechanical ventilation. This review found one small randomised controlled trial of laryngeal mask surfactant administration in preterm infants with respiratory distress syndrome that reported a short term reduction in oxygen requirements. In view of the encouraging results from this trial and other observational human studies, high quality trials of laryngeal mask surfactant administration in preterm infants with or at risk of respiratory distress syndrome are justified.
Respiratory distress syndrome (RDS) results from pulmonary surfactant deficiency and is an important cause of morbidity and mortality in preterm infants. Randomised controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of surfactant therapy in both prevention and treatment of RDS. A wide variety of surfactant preparations have been studied. These include synthetic surfactants (Soll 1998a; Soll 1998b) and surfactants derived from animal sources (natural surfactants) (Soll 2002; Seger 2009). Although both synthetic and animal derived surfactant preparations are effective (Soll 1998a; Soll 1998b; Soll 2002; Seger 2009), clinical trials suggest that animal-derived surfactant may be more effective (Soll 2001a) than protein-free synthetic surfactant (Tooley 1987). Furthermore, clinical trials have shown prophylactic surfactant (Soll 1998b; Soll 2001b; Soll 2002) and early surfactant (Soll 1999; Stevens 2007) are superior to selective use of surfactant in preventing morbidity and mortality in preterm infants. They also suggest that a multiple-dose strategy is superior to a single-dose strategy (Soll 2009). New protein-containing synthetic surfactants have also been successfully tested (Pfister 2007) although these preparations are not currently available for clinical use.
However, despite the benefits of surfactant, many infants develop bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD). Although the aetiology of CLD in preterm infants is multifactorial (Allen 2003), ventilator-induced lung injury (VILI) remains one of the main implicated risk factors (Coalson 1999; Clark 2000). We know that only a few resuscitative positive pressure ventilation (PPV) breaths may result in VILI (Grossmann 1986; Björklund 1997; Fleckonoe 2008; O'Reilly 2008).
Both surfactant prophylaxis and therapy require endotracheal intubation to facilitate surfactant administration. Although surfactant is an established effective intervention for either prevention or treatment of RDS (Soll 1998a; Soll 1998b; Soll 1999; Soll 2001a; Soll 2001b; Soll 2002; Stevens 2007; Seger 2009; Soll 2009), endotracheal intubation and PPV which follow have side effects.
Endotracheal intubation is a potentially traumatic procedure often performed without optimal pain management (Sarkar 2006). It may be accompanied by significant haemodynamic instability including hypoxia, bradycardia, blood pressure fluctuations and increased intracranial pressure (Marshall 1984; Ghanta 2007). Intubation is inevitably associated with colonisation of the trachea, retained secretions resulting in collapse, differential aeration and high resistance to air flow resulting in increased work in breathing, potentially leading to nosocomial pneumonia and sepsis (Young 2005; Aly 2008). Intubation is associated with an inflammatory process which can lead to lung injury and BPD (Young 2005). Current evidence suggests that PPV of immature, surfactant-deficient lungs is harmful and may increase the likelihood of development of BPD (Björklund 1997; Van Marter 2000). Björklund demonstrated that resuscitation of surfactant-deficient immature lambs with as few as six breaths damages the lungs and blunts the therapeutic effect of subsequent surfactant replacement (Björklund 1997). Grossmann 1986 showed similar results. Fleckonoe 2008 demonstrated that just six hours' ventilation is enough to cause marked airway epithelial injury in very preterm and near-term fetal sheep. O'Reilly 2008 reported that ventilator-induced injury extends to involve the conducting airways.
One approach to surfactant administration is the InSurE (INtubation-SURfactant-Extubation) technique pioneered by Victorin (Victorin 1990) and Verder (Verder 1994). Evidence showed that early surfactant replacement therapy with prompt extubation to nasal continuous positive airway pressure (nCPAP) is associated with less need for mechanical ventilation, lower incidence of BPD and fewer air leak syndromes when compared with later selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support (Stevens 2007). However, the limited data also show the InSurE procedure to be associated with a trend for decreased cerebral oxygenation, higher cerebral oxygen extraction and decreased electrical brain activity (Hellstrom-Westas 1992; Van de Berg 2009). The InSurE procedure may need to be repeated if the first dose of surfactant was not sufficiently effective (Bohlin 2007), leading to additional risk of brain damage.
The main strategy used to avoid endotracheal intubation and PPV in premature infants is application of nCPAP or continuous distending pressure (CDP), immediately following birth (Kamper 1999; Ho 2002a; Ho 2002b). Recent studies have suggested that CDP may lead to less CLD compared to elective intubation, surfactant and PPV (Aly 2001; De Klerk 2001). Similarly, nasal intermittent positive pressure ventilation (NIPPV) has shown a decreased need for intubation and mechanical ventilation. It also reduces frequency of apnoea and the incidence of CLD without an increase in adverse effects (Davis 2001; Lemyre 2002). Although CDP and NIPPV strategies avoid endotracheal intubation and PPV, they preclude surfactant administration which is a standard and proven treatment for RDS. Furthermore, CDP, NIPPV and InSurE may fail in 25% to 50% of preterm infants (Reininger 2005; Kugelman 2007; Morley 2008; Finer 2010) resulting in late surfactant administration, a strategy proven to be inferior (Soll 1998b; Soll 1999).
Non-invasive methods of surfactant administration may potentially reduce the need for intubation and endotracheal surfactant administration. Possible strategies include:
A Cochrane Review (Grein 2005) found that the LMA can achieve effective ventilation during neonatal resuscitation in a time-frame consistent with current guidelines, and a single, small randomised controlled trial found no clinically significant difference between the LMA and endotracheal tube (ETT) when bag and mask ventilation was unsuccessful.
This review focuses on LMA surfactant administration. An example of a protocol for LMA surfactant administration (Trevisanuto 2005) involves positioning the LMA, followed by instilling the surfactant in two to four aliquots via the LMA. Each aliquot is usually followed by brief PPV until the surfactant disappears from the LMA. Once the surfactant aliquots are complete, the LMA is removed and the baby placed on CDP and managed by standard protocol.
The LMA is a supraglottic device consisting of a curved plastic tube with elliptical inflatable mask which is inserted blindly into the posterior pharynx of the patient. The mask may be inflated in the hypopharynx creating an airtight seal around the upper oesophagus. It offers the possibility of rapid establishment of effective ventilation and access to the airway without tracheal intubation, even when performed by relatively inexperienced personnel. There are different types of LMA available (Classic; ProSeal; i-Gel; PAXpress; CobraPLA). Possible adverse effects of LMA surfactant administration include hypoxia and bradycardia during administration, laryngospasm and malposition of the LMA, with potential effects on the newborn.
Surfactant administration by LMA is designed to avoid endotracheal intubation yet potentially offer the benefits of early surfactant administration. Combining this strategy with prenatal steroid administration and CDP may offer synergy to treat RDS, avoiding both endotracheal intubation and PPV associated with lung injury that may lead to BPD. In a small case series, delivering surfactant via LMA was feasible with no complications reported (Brimacombe 2004; Trevisanuto 2005).
Despite important advances in neonatal intensive care, CLD results in a significant health burden to infants born at less than 32 weeks' gestation who receive mechanical ventilation. CLD results in substantial neonatal and infant morbidities and health resource utilization (Allen 2003). CLD is associated with chronic respiratory difficulties (Kilbride 2003; Doyle 2006), prolonged and recurrent hospitalisation (Chye 1995), neurodevelopmental disability including cerebral palsy, neurosensory and motor disability (Skidmore 1990; Hughes 1999; Majnemer 2000) and poor cognitive outcome (Hughes 1999). CLD has a major impact on the daily life of families that persists beyond the neonatal period (Korhonen 1999). LMA surfactant administration has the potential benefit of avoiding VILI and BPD.
To determine the effect of LMA surfactant administration either as prophylaxis or treatment compared to placebo, no treatment, or intratracheal surfactant administration on morbidity and mortality in preterm infants with or at risk of RDS.
We considered trials using randomisation or quasi-randomisation of patients regardless of unit of allocation (individual or cluster) eligible for inclusion in this review. Published or unpublished studies were eligible for inclusion.
Preterm infants (less than 37 weeks' gestation) at risk for or with RDS of any severity and any postnatal age.
We defined prophylactic surfactant therapy as all treatment strategies in which the intent was to treat a preterm infant based on the risk of RDS within the first hour of life. We defined risk of RDS as gestational age of less than 32 weeks or birthweight of less than 1250 g.
We defined treatment of established disease ("rescue therapy") as treatment of a preterm infant of less than 37 weeks' gestational age requiring respiratory support and having signs and symptoms of RDS.
LMA surfactant administration at any dose, using any type of surfactant (synthetic, animal derived or protein-containing) and any type of LMA (Classic; ProSeal; i-Gel; PAXpress; CobraPLA) compared with either placebo, no treatment, or intratracheal instilled surfactant. We planned to perform separate comparisons for the following:
Primary outcome measures reported after enrolment and intervention included:
Secondary outcome measures reported after enrolment and intervention included:
See: Cochrane Neonatal Group methods used in reviews.
We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library. We considered unpublished studies eligible for review. The searches of MEDLINE and PREMEDLINE (via OVID interphase) included the following MeSH terms and text words: “infant, premature, preterm, newborn, neonate”, “surfactant”, “laryngeal", "mask", "airway". We limited searches to “randomized and quasi-randomized clinical trials”. We did not apply language restrictions. The search strategy used for MEDLINE and PREMEDLINE is given in Appendix 1.
We adapted this search strategy to suit other electronic sources such as the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and CINAHL.
We searched the following electronic databases:
We carried out additional searches as follows.
Proceedings of the Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) from 1990 to 2010 from the journal Pediatric Research and Abstracts Online;
Proceedings of the European Academy of Paediatric Societies (EAPS) (The European Society for Paediatric Research (ESPR), the European Academy of Paediatrics (EAP) and the European Society of Paediatric and Neonatal Intensive Care (ESPNIC)) from 2003 to 2010 from Abstracts Online;
Proceedings of the Perinatal Society of Australia and New Zealand (PSANZ) from 1996 to 2010 (handsearch).
We used the standardized review method of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review (http://neonatal.cochrane.org/en/index.html). We entered and cross-checked data using Review Manager 5 (RevMan 5) software (RevMan 2008).
Both review authors independently assessed eligibility for inclusion in this review. We retrieved full-text versions for potentially eligible studies when we found inadequate information in the abstract.
Both reviewers independently extracted data from the full-text articles using a specifically designed spreadsheet to manage the information. We used these forms to decide trial inclusion/exclusion, extract data from eligible trials, and for requesting additional published information from authors of the original report. We entered and cross-checked data using RevMan 5 software (RevMan 2008). We then compared the extracted data for any differences. If noted, we then resolved differences by mutual discussion and consensus.
We used the standardized review methods of the CNRG (http://neonatal.cochrane.org/en/index.html) to assess the methodological quality of included studies. Review authors independently assessed study quality and risk of bias using the following criteria documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).
When necessary, we requested additional information and clarification of published data from the authors of individual trials. We assessed each trial for risk of bias based on the criteria listed above and marked as:
We resolved any discrepancies by mutual discussion and consensus. We planned to provide information on levels of agreement between review authors and/or details of resolution of differences.
We analysed treatment effects in the individual trials using RevMan 5 (RevMan 2008).
We reported dichotomous data using relative risk (RR) and risk difference (RD), each with 95% confidence interval (CI). Where there was a statistically significant reduction in RD then we calculated the number needed to treat (NNT) or number needed to harm (NNH) and associated 95% CI.
We reported continuous data using mean difference (MD) with 95% CI.
The unit of randomisation was the intended unit of analysis and we expected this to be individual infants.
We planned to include cluster randomised trials in the analyses along with individually randomised trials. We intended to analyse them using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) using an estimate of the intra-cluster correlation coefficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources were used, we intended to report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identified both cluster randomised trials and individually randomised trials, we planned to synthesise the relevant information. We planned to combine the results from both if there was little heterogeneity between the study designs. Where this was the case, we considered interaction between the effect of intervention and the choice of randomisation unit to be unlikely.
We planned to obtain missing data from the authors when possible. If this was not possible, then we planned to conduct analyses on available data (i.e. ignoring the missing data). In addition, we planned to conduct another analysis by using the imputation method (both best- and worst-case scenarios using uncertainty method (Gamble 2005) and last observation carried forward to the final assessment (LOCF) method for dichotomous and continuous outcome data, respectively. The authors of the single included study provided all data prior to publication.
We used RevMan 5 (RevMan 2008) to assess the heterogeneity of treatment effects between trials. We used the two formal statistics described below.
Where there was evidence of apparent or statistical heterogeneity, we planned to assess the source of the heterogeneity using sensitivity and subgroup analysis looking for evidence of bias or methodological differences between trials.
We planned to assess reporting and publication bias by examining the degree of asymmetry of a funnel plot in RevMan 5 (RevMan 2008).
We planned to perform statistical analyses according to the recommendations of CNRG (http://neonatal.cochrane.org/en/index.html). We planned to analyse all infants randomised on an ITT basis. We planned to analyse treatment effects in the individual trials. We planned to use a fixed-effect model in the first instance to combine the data. For any meta-analyses, for categorical outcomes we planned to calculate typical estimates of RR and RD, each with 95% CI; for continuous outcomes we planned to calculate the mean difference (MD) if outcomes were measured in the same way between trials, and standardized mean difference (SMD) to combine trials that measured the same outcome, but used different scales. When we judged meta-analysis to be inappropriate, we planned to analyse and interpret individual trials separately.
Providing sufficient data were available, we planned to explore potential sources of clinical heterogeneity through the following a priori subgroup analyses:
Where sufficient data were available, we planned to explore methodological heterogeneity through the use of sensitivity analyses. We planned to perform sensitivity analyses through excluding trials of lower quality, based on a lack of any of the following: allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow up.
One randomised controlled trial (Attridge 2010) met the inclusion criteria (see 'Characteristics of included studies'). No ongoing trials were identified.
Attridge 2010 enrolled 26 preterm infants with RDS, birth weight ≥ 1200 g and ≤ 72 hours old, who had been on nCPAP for at least 30 minutes and required supplemental oxygen between 30 and 60% to maintain oxygen saturations > 88%.
Attridge 2010 compared Calfactant surfactant (3 ml/kg in two to four aliquots via LMA followed by gentle positive pressure assistance from a flow-inflating bag until the surfactant had disappeared from the LMA tube) versus no treatment. Both groups were intubated when they met 'failure criteria' - initially FiO2 0.65 but changed to 15% greater than the FiO2 requirement at time of enrolment during study.
Attridge 2010 reported primary outcome was number of infants reaching failure criteria and requiring intubation for surfactant. Secondary outcomes reported included pneumothorax, days IPPV and days IPPV and oxygen. None of the pre-specified primary outcome measures of the review were reported by Attridge 2010.
No other randomised, cluster-randomised or quasi-randomised controlled trials were identified for exclusion from the review. Two case series were identified and excluded from this review (Brimacombe 2004; Trevisanuto 2005).
The single included study (Attridge 2010) was of moderate-high risk of bias. Alhough the study had adequate enrolment procedures and reported an intention-to-treat analysis, the study was unblinded, reported one interim analysis, was stopped early due to slow enrolment and changed the definition of the primary outcome during the study. Our ratings of methodologic quality are given in the table 'Characteristics of included studies'.
Attridge 2010 randomised infants using a block design stratified by infant’s birth weight (> 2000 g or ≤ 2000 g) generated using SAS statistical package. Investigators were blinded to randomisation group until after enrolment.
Attridge 2010 did not mask investigators, outcome assessors or families to study group.
Attridge 2010 reported all enrolled infants in an intention-to-treat analysis. There were two infants in the LMA surfactant group, and one in the control group who did not complete the protocol for clinical reasons.
Attridge 2010 reported an interim analysis of 13 infants (post enrolment) to a scientific meeting. Attridge 2010 stopped the study early. Although the projected sample size was 183 infants the study was stopped early after enrolling only 26 subjects due to slow enrolment. This was thought to be due to lack of hesitation by clinicians at the study centre to intubate and administer surfactant by the conventional endotracheal route. Attridge 2010 changed the definition for the main outcome measure (failure criteria) during the study - from a FiO2 > 65% to a FiO2 0.15 above the level at which the patient was upon enrolment.
No studies were found that enrolled infants at risk of RDS irrespective of the need for respiratory support or diagnosis of RDS.
One study compared treatment of RDS with LMA surfactant versus no treatment (Attridge 2010).
Attridge 2010 did not report any of the review's prespecified primary outcomes.
Attridge 2010 reported no significant difference in mechanical ventilation and endotracheal surfactant (RR 1.00, 95% CI 0.25 to 4.07) or pneumothorax (RR 1.50, 95% CI 0.30 to 7.55). Attridge 2010 reported no significant difference in days of IPPV (LMA 7 versus control 6 days, P = 0.5) and oxygen (LMA 7 versus control 7 days, P = 0.96). Attridge 2010 reported the LMA surfactant group had a significantly lower oxygen requirement at 1 and 12 hours after surfactant administration. Other secondary outcome measures were not reported.
The following subgroup analyses were prespecified. As only one pilot study reported data, the outcomes are as reported above.
We planned to perform a sensitivity analysis based on the following: inadequate randomisation, allocation concealment or blinding of treatment, or greater than 10% loss to follow up. Attridge 2010 reported adequate randomisation, allocation procedures and no losses for clinical outcomes reported. Attridge 2010 reported no masking of investigators, outcome assessors or families to study group.
Only one small study was identified and found to be eligible for inclusion in our review. This study enrolled preterm infants born ≥ 1200 g with RDS on nCPAP and reported that LMA surfactant administration resulted in a reduction in mean FiO2 required to maintain oxygen saturation between 88% and 92% for 12 hours after the intervention. No significant difference was reported in subsequent mechanical ventilation and endotracheal surfactant, pneumothorax, days on IPPV or days on IPPV and oxygen.
The single small study included in the review enrolled preterm infants ≥ 1200 g with RDS on nCPAP and used LMA administered surfactant as treatment of established RDS in the first 72 hours after birth. The data are largely applicable to late treatment of established RDS in relatively mature preterm infants. The study is underpowered to detect important clinical benefits and harms of LMA surfactant administration for treatment of RDS. No study was found that examined the effect of LMA surfactant administration for prevention of RDS (e.g. at resuscitation) or early treatment of RDS in keeping with the known benefits of prophylactic (Soll 1998b) and early surfactant treatment (Soll 1999) in very preterm infants. The feasibility, effect and safety of LMA surfactant administration to infants < 1200 g has not been reported.
The single included study (Attridge 2010) was of moderate risk of bias. Alhough the study had adequate enrolment procedures and reported an intention-to-treat analysis, the study was unblinded, reported one interim analysis, was stopped early due to slow enrolment and changed the definition of the primary outcome during the study.
An extensive search for published and unpublished literature was performed including searches of trial registries for ongoing studies. Two review authors independently assessed eligibility, study quality and extracted data. Agreement was reached through consensus.
This review is in keeping with a previously published non-systematic review of the literature which stated that intubation for rapid instillation is still the method of choice (Halliday 2008).
There is evidence from a single small trial that LMA surfactant administration in preterm infants ≥ 1200 g with established RDS may have a clinical effect in reducing oxygen requirements although the study is underpowered to detect important clinical effects. While the data suggests LMA surfactant administration is feasible, there are insufficient data to support or refute its use in clinical practice. LMA surfactant administration should be limited to clinical trials.
Adequately powered trials are required to determine the effect of LMA surfactant administration for prevention or treatment of RDS in preterm infants. Studies should measure short and long term outcomes prespecified in this review. Given the evidence for prophylactic and early surfactant administration, trials should enrol infants early in the course of respiratory illness.
Currently there are two ongoing registered trials for LMA surfactant with ClinicalTrials.gov:
The results of these trials are awaited.
As part of the pre-publication editorial process, three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser have commented on the protocol.
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.
The Australian Satellite of the Cochrane Neonatal Review Group is funded by the Australian Government Department of Health and Ageing.
| Methods | Single-centre, prospective, randomised controlled trial. |
|---|---|
| Participants | 26 preterm infants who fulfilled the following enrolment criteria:
Infants were excluded if they had:
|
| Interventions | LMA group (N = 13): received Calfactant surfactant (3 ml/kg) in 2-4 aliquots via LMA followed by gentle positive pressure assistance from a flow-inflating bag until the surfactant had disappeared from the LMA tube. The LMA was then removed and the baby was returned to nCPAP and managed by standard protocol. Standard protocol (N = 13): received nCPAP alone, without surfactant. A failure threshold for supplemental oxygen requirement was set prior to initiating the trial. Infants reaching failure threshold were intubated and given surfactant. |
| Outcomes | Primary outcome:
Secondary outcomes:
|
| Notes | The study was halted after 33 months of enrolment. This decision was taken because of slow enrolment which was thought to be due to lack of hesitation by clinicians at the study centre to intubate and administer surfactant by the conventional endotracheal route. |
| Bias | Authors' judgement | Support for judgement |
|---|---|---|
| Random sequence generation (selection bias) | Low risk | Randomised block design stratified by infant’s birth weight (> 2000 g or ≤ 2000 g) generated using SAS statistical package. |
| Allocation concealment (selection bias) | Low risk | Investigators could not view the randomisation group until after enrolment. |
| Blinding (performance bias and detection bias) Treatment |
High risk | There was no masking of investigators or families to study group. |
| Blinding (performance bias and detection bias) All outcomes |
High risk | There was no masking of outcome assessors or families to study group. |
| Incomplete outcome data (attrition bias) | Low risk | All subjects accounted for. Intention-to-treat analysis performed - two infants in the LMA surfactant group and one in the control group who did not complete the protocol for various reasons included in analysis. |
| Selective reporting (reporting bias) | Low risk | |
| Other bias | High risk | Interim analysis after enrolment 13 infants presented to scientific meeting. Stopped early. Projected sample size 183 infants but study stopped early after enrolling only 26 subjects due to slow enrolment. Slow enrolment thought to be due to lack of hesitation by clinicians at the study centre to intubate and administer surfactant by the conventional endotracheal route. Definition for main outcome measure (failure criteria) changed during study - from a FiO2 > 65% to an FiO2 15% above where the patient was upon enrolment. |
Abbreviations: FiO2 = Fraction of Inspired Oxygen, LMA = laryngeal mask administration, nCPAP = nasal continuous positive airway pressure, RDS = respiratory distress syndrome
Unpublished data only [ClinicalTrials.gov: NCT00599651]
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Kattwinkel J. Randomized controlled trial of surfactant administration by laryngeal mask airway (LMA) [clinical trial registration]. http://clinicaltrials.gov/show/NCT00599651 May 6, 2010.
Stewart C, Attridge J, Kattwinkel J. Randomised controlled trial of surfactant administration by laryngeal mask airway (LMA). In: American Pediatric Society / Society for Pediatric Research Abstract. 2008.
None noted.
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No table.
For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 2.1 Mechanical ventilation | 1 | 26 | Risk Ratio (M-H, Fixed, 95% CI) | 1.00 [0.25, 4.07] |
| 2.2 Pneumothorax | 1 | 26 | Risk Ratio (M-H, Fixed, 95% CI) | 1.50 [0.30, 7.55] |
None noted.
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