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Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome

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Authors

Mohamed E Abdel-Latif1, David A Osborn2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Neonatology, Australian National University Medical School, Woden, Australia [top]
2Department of Mothers and Babies NICU, Royal Prince Alfred Hospital, Camperdown, Australia. [top]

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.

Contact person

Mohamed E Abdel-Latif

Department of Neonatology
Australian National University Medical School
PO Box 11
Woden
ACT
2606
Australia

E-mail: Abdel-Latif.Mohamed@act.gov.au

Dates

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

Abstract

Background

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).

Objectives

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).

Search methods

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.

Selection criteria

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.

Data collection and analysis

Two review authors independently assessed studies for eligibility and quality, and extracted data.

Results

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 greater than/or equal to 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.

Authors' conclusions

There is evidence from a single small trial that LMA surfactant administration in preterm infants greater than/or equal to 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.

Plain language summary

Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome

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.

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Background

Description of the condition

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).

Description of the intervention

Non-invasive methods of surfactant administration may potentially reduce the need for intubation and endotracheal surfactant administration. Possible strategies include:

  1. intra-amniotic instillation (Petrikovsky 1995);
  2. pharyngeal instillation (Kattwinkel 2004);
  3. administration via laryngeal mask airway (LMA) (Trevisanuto 2005);
  4. administration via thin endotracheal catheter (Kribs 2007; Dargaville 2010; Kribs 2010);
  5. nebulised surfactant administration in spontaneously breathing infants (Jorch 1997).

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.

How the intervention might work

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).

Why it is important to do this review

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.

Objectives

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.

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Methods

Criteria for considering studies for this review

Types of studies

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.

Types of participants

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.

Types of interventions

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:

  1. prophylactic treatment of preterm infants with LMA surfactant versus no treatment;
  2. treatment of RDS with LMA surfactant versus no treatment;
  3. treatment of RDS with LMA surfactant versus intratracheal instilled surfactant.

Types of outcome measures

Primary outcomes

Primary outcome measures reported after enrolment and intervention included:

  1. chronic lung disease (CLD) defined as need for oxygen or respiratory support at 36 weeks' postmenstrual age;
  2. mortality prior to hospital discharge;
  3. neurodevelopmental disability at least 18 months postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay more than two standard deviations below population mean on a standardized test of development, blindness (visual acuity less than 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected);
  4. adverse effects of LMA surfactant administration including hypoxia and bradycardia during administration, gastric insufflation, laryngospasm and malposition of LMA.
Secondary outcomes

Secondary outcome measures reported after enrolment and intervention included:

  1. intratracheal surfactant received postintervention;
  2. doses of postintervention surfactant;
  3. need for mechanical ventilation;
  4. number of days on mechanical ventilation;
  5. number of days receiving nCPAP;
  6. number of days requiring high-flow nasal cannula;
  7. number of days requiring low-flow nasal cannula;
  8. number of days of supplemental oxygen administration;
  9. pulmonary interstitial emphysema;
  10. pneumothorax;
  11. use of high frequency oscillatory ventilation (HFOV) as a rescue treatment for respiratory distress;
  12. use of jet ventilation as a rescue treatment for respiratory distress;
  13. use of extracorporeal membrane oxygenation (ECMO) as a rescue treatment for respiratory distress;
  14. use of postnatal corticosteroids as rescue treatment for respiratory distress;
  15. chronic lung disease defined as need for oxygen or respiratory support at 28 days of age;
  16. use of diuretic as a prophylaxis or rescue treatment for CLD;
  17. use of postnatal corticosteroid as a prophylaxis or rescue treatment for CLD;
  18. use of home oxygen;
  19. asthma diagnosed by physician or challenge test;
  20. rehospitalisation for asthma;
  21. rehospitalisation for respiratory disease;
  22. neonatal mortality (mortality at less than 28 days of age);
  23. intraventricular haemorrhage (any and severe - Papile grade 3 or 4);
  24. periventricular leukomalacia (cystic);
  25. patent ductus arteriosus - symptomatic or treated with cyclo-oxygenase inhibitors or surgical ligation;
  26. necrotizing enterocolitis (proven = Bell stage 2 or higher);
  27. retinopathy of prematurity (any and severe = stage 3 or higher);
  28. apnoea treated with methylxanthines or respiratory support;
  29. time to regain birth weight (days);
  30. systemic infection in first 48 hours of life;
  31. postnatal growth failure (weight less than 10th percentile at discharge);
  32. duration of hospitalisation (days);
  33. discontinuation of intervention because of side effects (e.g. bradycardia).

Search methods for identification of studies

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.

Electronic searches

We searched the following electronic databases:

  1. Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, October 2010);
  2. MEDLINE and PREMEDLINE (1950 to October, 2010) via OVID interphase;
  3. EMBASE (1980 to October, 2010) via OVID interphase;
  4. CINAHL (1982 to October, 2010) via EBSCO interphase;
  5. GoogleScholar.

Searching other resources

We carried out additional searches as follows.

  1. Ongoing trials in the following trial registries (searched October 2010):
  2. Abstracts of conferences from:
    • 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).
  3. Reference lists: after reading the identified individual studies that examined the effect of laryngeal surfactant installation on the morbidity and/or mortality in preterm infants at risk of RDS, we screened the reference lists of these papers to further identify other relevant studies.
  4. Personal communications with expert informants and authors of included studies.
  5. Pharmaceutical companies: we also contacted the companies that developed different types of surfactant for possible unpublished studies using their product.

Data collection and analysis

We used the standardized review method of the Cochrane Neonatal Review Group External Web Site Policy for conducting a systematic review). We entered and cross-checked data using Review Manager 5 (RevMan 5) software (RevMan 2008).

Selection of studies

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.

Data extraction and management

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.

Assessment of risk of bias in included studies

We used the standardized review methods of the Cochrane Neonatal Review Group External Web Site Policy 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).

  1. Sequence generation: was the allocation sequence adequately generated?
  2. Allocation concealment: was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors for each main outcome or class of outcomes: was knowledge of the allocated intervention adequately prevented during the study?
  4. Incomplete outcome data for each main outcome or class of outcomes: 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? We gave particular attention to completeness of follow-up of all randomised infants and to the length of follow-up studies to identify whether any benefits claimed are robust.

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:

  1. low risk of bias;
  2. unclear risk of bias;
  3. high risk of bias.

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.

Measures of treatment effect

We analysed treatment effects in the individual trials using RevMan 5 (RevMan 2008).

Dichotomous data

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.

Continuous data

We reported continuous data using mean difference (MD) with 95% CI.

Unit of analysis issues

The unit of randomisation was the intended unit of analysis and we expected this to be individual infants.

Cluster-randomised trials

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.

Dealing with missing data

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.

Assessment of heterogeneity

We used RevMan 5 (RevMan 2008) to assess the heterogeneity of treatment effects between trials. We used the two formal statistics described below.

  1. The Chi2 test, to assess whether observed variability in effect sizes between studies was greater than would be expected by chance. Since this test has low power when the number of studies included in the meta-analysis is small, we planned to set the probability at the 10% level of significance.
  2. The I2 statistic to ensure that pooling of data was valid. We planned to grade the degree of heterogeneity as: 0% to 30%: might not be important; 31% to 50%: moderate heterogeneity; 51% to 75%: substantial heterogeneity; 76% to 100%: considerable heterogeneity.

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.

Assessment of reporting biases

We planned to assess reporting and publication bias by examining the degree of asymmetry of a funnel plot in RevMan 5 (RevMan 2008).

Data synthesis

We planned to perform statistical analyses according to the recommendations of the Cochrane Neonatal Review Group External Web Site Policy. 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.

Subgroup analysis and investigation of heterogeneity

Providing sufficient data were available, we planned to explore potential sources of clinical heterogeneity through the following a priori subgroup analyses:

  1. type of LMA used (Classic; ProSeal; i-Gel; PAXpress; CobraPLA);
  2. timing of LMA surfactant administration (prophylactic, early rescue (within the first two hours after birth), late rescue (within the first week of life), very late rescue (after the first week));
  3. type of surfactant used (synthetic, animal derived or protein-containing);
  4. gestational age at delivery (less than 28, 28 to 31, 32 to 34 and 35 or more completed weeks' gestation).

Sensitivity analysis

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.

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Results

Description of studies

Results of the search

One randomised controlled trial (Attridge 2010) met the inclusion criteria (see ' Characteristics of Included Studies'). No ongoing trials were identified.

Included studies

Types of participants:

Attridge 2010 enrolled 26 preterm infants with RDS, birth weight greater than/or equal to 1200 g and less than/or equal to 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%.

Types of interventions:

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.

Types of outcomes measures:

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.

Excluded studies

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).

Risk of bias in included studies

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'.

Allocation (selection bias)

Attridge 2010 randomised infants using a block design stratified by infant’s birth weight (> 2000 g or less than/or equal to 2000 g) generated using SAS statistical package. Investigators were blinded to randomisation group until after enrolment.

Blinding (performance bias and detection bias)

Attridge 2010 did not mask investigators, outcome assessors or families to study group.

Incomplete outcome data (attrition bias)

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.

Selective reporting (reporting bias)

Attridge 2010 reported prespecified outcomes.

Other potential sources of bias

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.

Effects of interventions

1. Prophylactic treatment of preterm infants with LMA surfactant versus no treatment

No studies were found that enrolled infants at risk of RDS irrespective of the need for respiratory support or diagnosis of RDS.

2. Treatment of RDS with LMA surfactant versus no treatment

One study compared treatment of RDS with LMA surfactant versus no treatment (Attridge 2010).

Primary outcome measures:

Attridge 2010 did not report any of the review's prespecified primary outcomes.

Secondary outcome measures:

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.

Subgroup analyses

The following subgroup analyses were prespecified. As only one pilot study reported data, the outcomes are as reported above.

  1. Type of LMA used (Classic; ProSeal; i-Gel; PAXpress; CobraPLA); Attridge 2010 reported use of 'LMA (LMA North America, San Diego)'.
  2. Timing of LMA surfactant administration (prophylactic, early rescue (within the first two hours after birth), late rescue (within the first week of life), very late rescue (after the first week)); Attridge 2010 reported late rescue treatment (up to 72 hours after birth).
  3. Type of surfactant used (synthetic, animal derived or protein-containing); Attridge 2010 reported use of animal derived surfactant (Calfactant (3 ml/kg) supplied by ONY, Inc.).
  4. Gestational age at delivery (less than 28, 28 to 31, 32 to 34 and 35 or more completed weeks' gestation). Attridge 2010 enrolled infants with birth weight greater than/or equal to 1200 g. The mean gestation was approximately 33 ± 2 weeks.
Sensitivity analysis

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.

Discussion

Summary of main results

Only one small study was identified and found to be eligible for inclusion in our review. This study enrolled preterm infants born greater than/or equal to 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.

Overall completeness and applicability of evidence

The single small study included in the review enrolled preterm infants greater than/or equal to 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.

Quality of the evidence

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.

Potential biases in the review process

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.

Agreements and disagreements with other studies or reviews

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).

Authors' conclusions

Implications for practice

There is evidence from a single small trial that LMA surfactant administration in preterm infants greater than/or equal to 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.

Implications for research

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:

  • NCT01116921 - Laryngeal Mask Airway (LMA) for Surfactant Administration in Neonate - University of Minnesota ( Kari D. Roberts).
  • NCT01042600 - Randomized Controlled Trial of Surfactant Delivery Via Laryngeal Mask Airway (LMA) Versus Endotracheal Intubation - Albany Medical College (Joaquim M Pinheiro).

The results of these trials are awaited.

Acknowledgements

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.

Contributions of authors

  • Both review authors contributed to the protocol and review.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Attridge 2010

Methods

Single-centre, prospective, randomised controlled trial.

Participants

26 preterm infants who fulfilled the following enrolment criteria:

  • radiograph and clinical history consistent with RDS;
  • birth weight greater than/or equal to 1200 g;
  • less than/or equal to 72 hours old at enrolment;
  • had been on nCPAP for at least 30 minutes;
  • a supplemental oxygen requirement between 30 and 60% to maintain oxygen saturations > 88%.

Infants were excluded if they had:

  • pneumothorax at time of enrolment;
  • any previous history of surfactant or intubation (other than transiently in the delivery room as indicated for meconium);
  • any congenital anomaly thought to contribute to respiratory symptoms, and/or
  • any condition thought to restrict adequate spontaneous breathing (e.g. congenital heart disease, obtundation from maternal drugs, airway malformations, diaphragmatic hernia).
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:

  • reaching or not reaching failure criterion (FiO2 = 65% while receiving nCPAP). [Timeframe:96 hours]. However, part way through the trial, this was changed to 15% greater than the FiO2 requirement at time of enrolment).

Secondary outcomes:

  • duration of intubation;
  • nasal CPAP and requirement for supplemental oxygen [birth to discharge];
  • time to reach full enteral feedings;
  • incidence of laryngeal oedema [to96 hours];
  • duration of hospitalisation.
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.

Risk of bias table
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 less than/or equal to 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

Brimacombe 2004

Reason for exclusion

Case series, not RCT.

Trevisanuto 2005

Reason for exclusion

Case series of 8 preterm infants (not RCT).

Characteristics of studies awaiting classification

  • None noted.

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References to studies

Included studies

Attridge 2010

Unpublished data only [ClinicalTrials.gov: NCT00599651]

* Attridge J, Stewart C, Kattwinkel J. A pilot randomized controlled trial evaluating surfactant administration by laryngeal mask airway. Unpublished 2010.

Kattwinkel J. Randomized controlled trial of surfactant administration by laryngeal mask airway (LMA) [clinical trial registration]. http://www.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.

Excluded studies

Brimacombe 2004

Brimacombe J, Gandini D, Keller C. The laryngeal mask airway for administration of surfactant in two neonates with respiratory distress syndrome. Paediatric Anaesthesia 2004;14(2):188-90.

Trevisanuto 2005

Trevisanuto D, Grazzina N, Ferrarese P, Micaglio M, Verghese C, Zanardo V. Laryngeal mask airway as a delivery channel for administration of surfactant in preterm infants with RDS. Biology of the Neonate 2005;87(4):217-20.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

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Aly 2001

Aly HZ. Nasal prongs continuous positive airway pressure: a simple yet powerful tool. Pediatrics 2001;108(3):759-61.

Aly 2008

Aly H, Badawy M, El-Kholy A, Nabil R, Mohamed A. Randomized, controlled trial on tracheal colonization of ventilated infants: can gravity prevent ventilator-associated pneumonia? Pediatrics 2008;122(4):770-4.

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Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

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Data and analyses

1 Prophylactic treatment of preterm infants with LMA surfactant versus no treatment

  • No table data provided.

2 Treatment of RDS with LMA surfactant versus no treatment

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]

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Figures

  • None noted.

Sources of support

Internal sources

  • No sources of support provided.

External sources

  • No sources of support provided.

Feedback

  • None noted.

Appendices

1 Search strategy for MEDLINE and PREMEDLINE

The search strategy for MEDLINE and PREMEDLINE was as follows:

  1. exp pregnancy
  2. exp infant premature
  3. exp infant newborn
  4. exp obstetric labor premature
  5. exp premature birth
  6. pregnan*.mp OR prematur*.mp OR preterm.mp OR neonat*.mp OR infant*.mp OR newborn.mp
  7. #1 OR #2 OR #3 OR #4 OR #5 OR #6
  8. laryngeal.mp
  9. mask.mp
  10. airway.mp
  11. #8 OR #9 OR #10
  12. exp pulmonary surfactants
  13. surfactant*.mp OR Beractant.mp OR Poractant.mp OR Curosurf.mp OR Survanta.mp OR Exosurf.mp OR Lucinactant.mp
  14. #12 OR #13
  15. #7 AND #11 AND #14

This review is published as a Cochrane review in The Cochrane Library, Issue 7, 2011 (see http://www.thecochranelibrary.com External Web Site Policy 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 recent version of the review.