Should critically ill children with acute respiratory failure be treated with surfactant?
- 1Department of Paediatric Medicine, KK Women's and Children's Hospital, Singapore, Singapore
- 2Children's Intensive Care Unit, Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore
- Correspondence to Dr Zhi Min Ng, Department of Paediatric Medicine, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore;
- Received 7 January 2013
- Revised 10 February 2013
- Accepted 15 April 2013
- Published Online First 16 May 2013
A 9-year-old child with relapsed acute lymphoblastic leukaemia postbone marrow transplant was admitted to the children's intensive care unit (ICU) for non-neutropenic fever with worsening respiratory distress that required mechanical ventilation. Despite broad-spectrum antimicrobials, serial chest radiographs showed worsening bilateral infiltrates and increasing mechanical ventilatory requirements. As the registrar in the unit, you wondered if intratracheal surfactant would be beneficial in treating this child with acute respiratory failure.
Structured clinical question
In critically ill children with acute respiratory failure (patient), does treatment with surfactant (intervention) improve gaseous exchange and shorten duration of mechanical ventilation and length of ICU stay (outcomes)?
Search strategy and outcome
Secondary source—Cochrane Database of Systematic Review, BestBETs
Primary source—PubMed, CINAHL, Web of Science
Search terms were (‘children’) AND (‘surfactant’) AND (‘acute respiratory distress syndrome’ OR ‘adult respiratory distress syndrome’ OR ‘acute lung injury’ OR ‘acute respiratory failure’).
The Cochrane database yielded one relevant review. BestBETs yielded one relevant review. Pubmed, CINAHL and Web of Science yielded 209, 55 and 324 hits, respectively, from which seven relevant randomised controlled studies were identified. Three of these studies were included in the Cochrane review.
Qualitative and quantitative deficiency of surfactant play a role in the development of acute respiratory failure in infants, children and adults.1 ,2 An Archimedes review published in 2003 looking at the use of surfactant in mechanically ventilated infants with severe bronchiolitis suggested that surfactant was associated with improved oxygenation and ventilatory parameters.3 ,4 However, there was only limited evidence to support clear clinical benefit, and thus, the authors proposed that more studies examining pertinent clinical outcomes were necessary.3 ,4 A recent Cochrane systematic review on surfactant therapy for bronchiolitis in critically ill infants showed improvement in gas exchange and shorter duration of ICU stay, but concluded that there was a need for larger studies with adequate power and cost-effectiveness analysis to evaluate the efficacy of surfactant therapy in this group of patients.5 In the last 10 years, clinical studies studying the use of surfactant in critically ill children enrolled larger numbers of patients, placed more emphasis on clinically important outcomes (eg, duration of mechanical ventilation, length of ICU stay and mortality), and had moved away from surrogate outcome measures, such as oxygenation index and ventilation index. Additionally, more emphasis was placed in assessing safety outcomes in the use of surfactant in critically ill children.
Interestingly, while earlier studies6–9 showed that the duration of mechanical ventilation and the length of ICU stay were significantly shorter with the use of surfactant, more recent studies10–12 concluded that there was no significant difference in these outcomes between children who were treated with surfactant compared with placebo. These differences in findings may be due to publication bias leading to only positive studies in favour of surfactant being published in the earlier period. Another reason for differences in study findings is the different types of patients that were recruited for these studies. Three out of four earlier studies6–8 examined mainly patients with respiratory syncytial virus (RSV) positive infection while the three most recent studies10–12 recruited patients with various aetiologies, such as pneumonia, bronchiolitis and sepsis. These three studies did not analyse their results according to the aetiology of the respiratory distress. Current evidence seems to suggest that surfactant use may be associated with reduction in duration of mechanical ventilation and length of ICU stay in children with RSV infection.
Mortality outcomes from available studies are variable. Six out of seven randomised controlled studies examined mortality as their outcome measures. There were no deaths in two studies.6 ,7 Three studies9 ,10 ,12 reported that there was no significant difference in mortality between surfactant and placebo groups. The study by Willson et al11 in 2005 concluded that mortality was significantly higher in the placebo group compared with the surfactant group. The increased overall mortality in the placebo group in this study was most likely contributed by unbalanced randomisation resulting in a difference in proportion of immunocompromised patients in the control group as compared with the surfactant group.
With regard to safety outcomes, earlier studies6 ,8 reported no adverse haemodynamic events. Willson et al9 reported isolated events of air leaks and pulmonary interstitial emphysema that happened in both groups. In a subsequent study,11 investigators reported that fluid-responsive hypotension and transient hypoxia occurred more frequently in the surfactant group as compared with the placebo group. Similarly, Thomas et al12 also showed that the incidence of desaturation and bradycardia were significantly higher in the surfactant group than in the placebo group. Other reported adverse events associated with the use of surfactant include hypertension and pallor.12 Data on the safety of surfactant is severely limited by the small number of subjects in included studies. Furthermore, analysis for safety outcomes is limited by the fact that randomised controlled trials are often underpowered for safety outcomes.
The randomised controlled studies included in our review have certain limitations. Three did not state the method of randomisation clearly.7 ,8 ,12 Concealment allocation was also not mentioned in several studies.7 ,8 ,12 Earlier studies were often small; more recent studies were much larger (>100 patients). However, despite this increase in number, investigators of these studies were still limited by insufficient power. One study ended prematurely due to falling recruitment numbers.10 There was also no consistent dose and type of surfactant used in these studies. Different types and doses of surfactant were used: poractant 50 mg/kg, calfactant 80 ml/m2, survanta/alveofact 100 mg/kg, lucinactant 175 mg/kg. Because studies involved administration of intratracheal surfactant, many of them were unblinded.6 ,8––10 Nevertheless, there were some studies that adopted an innovative way of carrying out the blinding process.7 ,11 ,12 These recent studies also used sham air instead of no intervention as placebo7 ,11 ,12
In conclusion, the use of surfactant in critically ill children with acute respiratory failure may not result in clinically significant outcome benefit. The use of surfactant can potentially be associated with adverse events. Larger studies with sufficient power are needed to assess the role of surfactant in reducing morbidity and mortality in this group of children.⇓
Clinical bottom line
The use of surfactant in critically ill children with acute respiratory failure may improve gaseous exchange but it has not been conclusively proven to shorten duration of mechanical ventilation, length of ICU stay and improve mortality.
Surfactant use is associated with adverse events.
We acknowledge the technical assistance of Peggy BY Fong and Venbagavalli MS in our literature search.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.