Extremely preterm infants who survive often develop bronchopulmonary dysplasia, which is characterised by severely impaired alveolarisation, which in turn results in a markedly reduced area for gas exchange.1 Infants with bronchopulmonary dysplasia often need long-term oxygen supplementation and frequent hospital re-admissions,2 with consequent high morbidity and health-care costs. Ventilator-induced lung injury is deemed one of the main pathogenic factors for the development of bronchopulmonary dysplasia and is mainly related to the magnitude of tidal volume.3, 4 Reduction of tidal volumes might result in alveolar hypoventilation with increased blood partial pressure of carbon dioxide (pCO2), which might be beneficial.5 The intentional reduction of the intensity of mechanical ventilation and allowing pCO2 values above 45 mmHg is referred to as permissive hypercapnia.
Increased respiratory drive through higher pCO2 has been used for decades to wean infants off mechanical ventilation. Early use of permissive hypercapnia in newborn preterm infants from the first day of life has been controversial, because it might increase cerebral perfusion, which can enhance oxygen delivery to the brain, but also increases the risk of intracranial haemorrhage.6 Furthermore, young rats have developed retinopathy when exposed to very high pCO2 values (roughly 100 mm Hg).7 Instead, because the susceptibility to ventilator-induced lung injury might be highest soon after birth,4 the reduction of tidal volumes with resultant permissive hypercapnia could be most beneficial when applied early.
Data from some retrospective analyses suggest an association between higher arterial pCO2 (PaCO2) values during the first days of life in preterm infants and a reduced incidence of bronchopulmonary dysplasia,8, 9 whereas others do not.10, 11 Furthermore, findings of a randomised trial12 comparing two different tidal volume settings in adults with acute respiratory distress syndrome showed increased survival and decreased morbidity in patients randomly assigned to the lower tidal volume, who also had higher PaCO2.
Research in context
Evidence before this study
Data from animal experiments suggested that permissive hypercapnia could be beneficial for subjects requiring mechanical ventilation because of lower tidal volumes and additional biochemical effects. We hypothesised that such benefits might also apply to preterm infants. We searchedPubMed from 1960 until 2014 for English language articles with the following search terms: “preterm infant”, “permissive hypercapnia”, and “minimal ventilation”. We also searched the reference lists of previous review articles. Several retrospective analyses were inconclusive. Three randomised trials were identified in which ventilator-dependent extremely low birthweight infants were allocated to different partial pressure of carbon dioxide (pCO2) targets. Two were small and monocentric and the third, the SAVE trial, was prematurely terminated for reasons unrelated to the mechanical ventilation. All three used different PCO2 targets and the pCO2 differences between the randomly allocated groups were small. None of the trials showed reduced incidence of bronchopulmonary dysplasia associated with permissive hypercapnia. One of the monocentric trials reported faster weaning off mechanical ventilation, the other, however, a worse neurodevelopmental outcome. Investigators of the SAVE trial reported a smaller number of infants requiring long-term mechanical ventilation beyond a postmenstrual age of 36 weeks. Results of a meta-analysis encompassing all three trials with 334 infants were calculated which showed trends but no significant differences between the results of different pCO2 targets. In another very large randomised trial, management differed between treatment groups in several aspects other than pCO2 target ranges.
Retrospective analyses also suggested an increased risk of intracranial haemorrhage that was not substantiated by the randomised trials. Animal experiments suggested an increased risk of retinopathy of prematurity associated with severe hypercapnia. Whether this risk also applied to human beings was unknown.
Added value of this study
With a sample size of 359, this multicentre trial did not show increased lung protection and improved outcomes associated with higher pCO2 targets, despite lower ventilator pressures. On the contrary, higher pCO2 targets were associated with an increased incidence of bronchopulmonary dysplasia or death in the subgroup of infants with the worst lung disease. Furthermore, there was an unexpected increased incidence of necrotising enterocolitis, but no increase in the incidence of intracranial haemorrhage or retinopathy of prematurity.
Implications of all available evidence
Mildly hypercapnic pCO2 targets as used in the control group of this trial and the hypercapnia group of the SAVE trial seem to be safe and are likely to be associated with small health benefits. Higher pCO2 targets as used in the high target group of this trial do not increase these benefits, and might cause harm.
Several trials have assessed how strategies to avoid mechanical ventilation can improve outcomes for preterm infants.13 For this approach to be successful, investigators need to accept higher than normal pCO2 values, but it is not clear whether lung protection is due more to the use of non-invasive support than to increased pCO2. In preterm infants already on mechanical ventilation, results of four previous randomised trials14, 15, 16, 17 of permissive hypercapnia and a meta-analysis18 did not show reduced incidences of bronchopulmonary dysplasia. However, two of these trials had small sample sizes,14, 15 and in the third with 220 infants, the PaCO2 difference between the groups was only 4 mm Hg.16 In the fourth trial, management differed between treatment groups in several aspects other than pCO2 target ranges.17 However, no significant increases in adverse events, especially the rate of intracranial haemorrhage, associated with permissive hypercapnia were reported, and some secondary analyses of the prematurely terminated SAVE trial17 suggest some beneficial effects.
In their efforts to improve outcome, many neonatologists have accepted permissive hypercapnia as their standard of care,19 despite the absence of clearly proven beneficial effects. Consideration has been given to even higher pCO2 targets as being of even greater benefit. Hence permissive hypercapnia has spread in today's neonatal intensive care without sufficient supporting evidence,20 with the optimum PaCO2 target range for ventilated preterm infants still to be established. This situation led us to do a large multicentre trial comparing two markedly different PaCO2 target ranges in extremely low birthweight infants. We aimed to study whether a higher pCO2 target range would reduce the rate of moderate to severe bronchopulmonary dysplasia 21 or death in extremely low birthweight infants needing mechanical ventilation. Furthermore, we aimed to find out whether hypercapnia would be most beneficial to the infants requiring the most ventilatory support.