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Surfactant for acute respiratory failure in children

The use of exogenous pulmonary surfactant in the respiratory distress syndrome of the newborn is known to reduce mortality by almost half, as well as having other benefits. The use of surfactant in that setting is well understood, and forms part of several guidelines.

The benefits of using pulmonary surfactant in other settings is less clear, and the specific example of its use in acute respiratory failure in children [1] makes for interesting reading, with some lessons for decision-makers.

Systematic review

The review searched several databases (to about 2005), together with bibliographies, trial registries, and conference proceedings. Randomised trials were included comparing pulmonary surfactant plus standard care with standard care alone in intubated, mechanically ventilated patients with acute respiratory failure. Studies in neonates with respiratory distress syndrome were not part of the review. At least one dose of surfactant had to be used.

Outcomes sought were all case mortality, number of ventilator-free days to day 28, duration of mechanical ventilation, duration of stay on paediatric intensive care unit, and others, like adverse events.

Results

Six studies (311 patients) were found, two with blind intensive care teams. Three trials enrolled 79 infants aged mostly below one year with respiratory syncytial virus induced respiratory failure or severe bronchiolitis; there were no deaths in this group which we will call group A. Three other trials enrolled 226 children of average age four to seven years with acute respiratory distress syndrome or acute lung injury, including pneumonia, sepsis, and near drowning; in this group the mortality rate averaged 28% (group B).

The main results are shown in Table 1. For group A, there were more ventilator free days, fewer days of mechanical ventilation, and fewer days on the paediatric intensive care unit on average. For group B, older children, there were more ventilator free days and fewer days of mechanical ventilation. In addition, there was a 13% reduction in mortality (NNT to prevent one death 8 (95% confidence interval 4 to 220)). There were no adverse events directly related to the use of surfactant.



Table 1: Main outcomes of clinical trials of surfactant in paediatric patients with respiratory failure



Group A <1 year RSV
Group B 4-7 years ARDS
Number
79
226
Mean death rate (%)
0
28
Absolute difference surfactant - control
Mortality (%)
0
-13
Ventilator free days to day 28
2.2
1.9
Days of mechanical ventilation
-2.2
-1.1
Days on paediatric intensive care unit
-2.9
0.3


Comment

Surfactant is not inexpensive, running at several hundreds of pounds per dose, and most of these trials used one or two doses, though one could use up to four. Cost could be an issue in deciding whether or not pulmonary surfactant should be used.

So what does the evidence tell us? The first step might be to ask whether there are any further trials that can help us, and, indeed, one more [2] adds a further 42 children. The full story on mortality for trials with any deaths is shown in Figure 1. A brief glance, or more analysis, shows that the higher the baseline risk of death, the more use of surfactant is likely to prevent a death; in the two trials with death rates above 15%, the NNT to prevent a death was 6.



Figure 1: Mortality with surfactant and control in trials with any deaths





On other measures use of surfactant also produced benefits. In particular, a reduction of almost three days in paediatric intensive care for group A speaks to substantially lower costs, even where mortality was not an issue. In group B, these other benefits are not obvious, but the largest trial in group B did measure overall hospital costs, which were US$1,200 less per patient with surfactant. A cost-effectiveness analysis [2] agrees that costs were lower with surfactant.

The case looks pretty solid, though it is easily possible to take a 'glass half empty approach'. For instance, the statistical significance achieved for mortality was bare, with an upper confidence interval just below 1. A change of one or two deaths would remove statistical significance. Moreover, the two trials with the largest benefits on other outcomes have impossibly small standard deviations, and because of the way results are weighted by variance, these two trials carry 50% of the weight with only 20% of the patients. That doesn't make sense, but may influence our views. The results in Table 1 have used a more conservative approach, using weighting by trial size; the trouble is, though, that probably none of these results are now statistically significant.

All of which makes this [1] a most interesting paper and subject for discussion; it would certainly be a useful teaching paper. What's the bottom line? It may be that surfactant should be used despite no rigorous evidence of benefit, because it helps oxygenation, or for other technical reasons. It is a decision that requires a bit of wisdom, and shows the limitations of evidence without a bit of thought and wisdom.

References:

  1. M Duffett et al. Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Critical Care 2007 11: R66 (doi:10.1186/cc5944).
  2. NJ Thomas et al. Cost-effectiveness of exogenous surfactant therapy in pediatric patients with acute hypoxic respiratory failure. Pediatric Critical Care Medicine 2005 6: 160-165.

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