Does permissive hypercapnia carry increased risk for neurodevelopmental sequelae?

Abstract

Despite advances in ventilatory support, it is not clear what levels of PaCO2 are safe in extremely premature infants. Permissive hypercapnia is a strategy that tolerates higher levels of PaCO2 with the expectation to reduce ventilator-induced lung injury. One potential downside of permissive hypercapnia is the association with intraventricular haemorrhages (IVH) and poor developmental outcomes (1,2). In the PHELBI trial (3), investigators studied the effects of permissive hypercapnia. Although the study had some limitations (4) and was stopped early due to no reduction in BPD or death, it remains a valuable study, showing that hypercapnia did not increase IVH or retinopathy of prematurity (ROP). Investigators assessed neurodevelopment at two years corrected age on infants who participated in the original trial (4). Follow-up evaluations were performed using German translations of accepted standard of care evaluation methods. Age and growth at the follow-up examinations were similar and not suggestive of confounding effects. Neurodevelopment of infants that participated in follow-up assessment was comparable between PaCO2 target groups. Child’s development per CDI questionnaire and cerebral palsy were evenly distributed, as well as rates of hearing or visual impairment. This study is limited as the original trial was not designed for detecting neurodevelopmental differences at two-year follow-up and the trial was stopped early after no evidence of treatment effect. Finally, 15% of infants were lost to follow-up (14% in High Target Group and 15% in Low Target Group) and 10% did not complete all follow-up examinations. Baseline characteristics of patients lost to follow-up and those who completed testing appeared similar; however, it would be beneficial for interpretation to see the characteristics of those who did not complete testing. The authors acknowledge that there is no formal German validation for the BSIDII, though results obtained are similar to American infants. There was no blinding to study arm allocation in the original trial, and masking of individuals involved in the neurodevelopmental follow-up testing is not specified. Conclusions drawn from these data must be considered in light of these limitations. Benefits of permissive hypercapnia, as defined by this trial, were not observed in the study findings. BPD is associated with adverse neurodevelopment (5), and optimal PaCO2 levels remainunclear.Observationalstudieshavefound that large fluctuations and higher than average PaCO2 increase risk (3,6,7),whileameta-analysis of randomised trials for permissive hypercapnia shows that morbidity and neurodevelopmental outcomes did not differ between PaCO2 target groups (8). The PHELBI trial did not identify the optimal target range of PaCO2, and data suggest that permissive hypercapnia does not grant lung protection in extremely low birthweight infants. One should consider that permissive hypercapnia as a strategy to decrease chronic lung disease is not supported by data from this randomised trial. However, based on the comparable neurologic development observed in the study, clinician angst is not warranted and aggressive ventilator adjustments should not be implemented in order to normalise PaCO2 in extremely premature patients who are otherwise clinically stable.