Permissive hypercapnia in extremely low birthweight infants (PHELBI)
Final Report Abstract
359 infants were randomised to different PCO2 target ranges, and a large amount of data was collected, including two substudies. Most importantly, the High PCO2 target reduced ventilatory intensity but did not reduce the primary outcome, which was moderate to severe bronchopulmonary dysplasia or death. Moreover, trends, although not significant, favoured the control group. If this trial with these trends had been continued to a larger sample size, a significant difference in favour of the control group may have resulted. Furthermore, we demonstrated deteriorations of microcirculation, as skin vessel density in preterm infants randomized to high PCO2 target levels was significantly reduced. The critical view on high PCO2 targets is corroborated by animal experiments, which demonstrated harmful effects and cell culture experiments, which demonstrated important epithelial cell functions to be impaired by higher PCO2 levels. All these effects may contribute to the arrest of lung development typical of BPD, and may explain why the rate of BPD was not reduced despite clearly reduced ventilator induced lung trauma. Furthermore, no subgroup was identified which benefited from the higher PCO2 targets. Especially, the infants with the most severe lung disease had the largest difference in favour of the control group, which even turned out statistically significant. Additional support to the short-term clinical results is given by the TA analyses. Obviously, being randomized to the High target group did not reduce inflammatory activity inside the lung, and oxidative stress may even have been increased according to the detected nitrite levels. Neurodevelopmental follow-up was reassuring, as there were no developmental 2 differences between infants randomized to the High target or Control groups. It appears that higher PCO2 levels were well tolerated by nerve cells and brain tissue, possibly in contrast epithelial cells. This finding is very important in view of the continuing trend towards non-invasive ventilatory support, which improves short term outcome of preterm infants but is generally accompanied by somewhat higher PCO2 levels. Our data indicates that there is no need to intubate an infant doing well on non-invasive ventilatory support just to avoid exposing the brain to somewhat higher PCO2 levels. Our recent analysis of actually achieved PCO2 levels and their relation to clinical status and outcome gave additional interesting insights. Whether PCO 2 actually 3 increased or not was related to the severity of lung disease. Infants who indeed became hypercapnic still required a similar intensity of mechanical ventilation as the infants who kept their PCO2 low, and had a worse outcome than infants who were able to compensate reductions in ventilator settings. Infants with a better lung function remained below the randomized high target ranges, whereas infants with poor lung function had rising PCO2 levels when ventilator settings were reduced. Consequently, PCO2 was identified as a marker of disease severity. The largest surprise encountered in this study was the fact that the high target did not reduce the rate of bronchopulmonary dysplasia despite clear reductions in ventilator settings and barotrauma. This was corroborated by impaired microcirculation in association with the high PCO 2 target group, which was shown for the first time. These findings indicate that impairment of vessel growth and impairment of epithelial cell functions may have nullified the benefits of the reduced barotrauma and thereby also induced BPD. Any other trends also favoured the control group. Therefore, overly high PCO2 levels may be harmful for the preterm lung. There is no linear dose response relationship between carbon dioxide and outcome, but rather, and optimal target range must exist. Using the data from this and previous trials, this optimal target range can now be pinpointed, giving valuable guidance to clinicians treating such infants. Another, reassuring, surprise was the absence of negative effects of the high target on neurodevelopmental outcome and the rate of retinopathy of prematurity.
Publications
- Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. Lancet Respir Med. 2015 Jul;3(7):534-43
Thome UH, Genzel-Boroviczeny O, Bohnhorst B, Schmid M, Fuchs H, Rohde O, Avenarius S, Topf HG, Zimmermann A, Faas D, Timme K, Kleinlein B, Buxmann H, Schenk W, Segerer H, Teig N, Gebauer C, Hentschel R, Heckmann M, Schlösser R, Peters J, Rossi R, Rascher W, Böttger R, Seidenberg J, Hansen G, Zernickel M, Alzen G, Dreyhaupt J, Muche R, Hummler HD; PHELBI Study Group
(See online at https://doi.org/10.1016/s2213-2600(15)00204-0) - Inflammatory mediators in tracheal aspirates of preterm infants participating in a randomized trial of permissive hypercapnia. Frontiers in Pediatrics 2017
Gentner S, Laube M, Uhlig U, Yang Y, Fuchs HW, Dreyhaupt J, Hummler HD, Uhlig S, Thome UH
(See online at https://doi.org/10.3389/fped.2017.00246) - Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Arch Dis Child Fetal Neonatal Ed. 2017
Thome UH, Genzel-Boroviczeny O, Bohnhorst B, Schmid M, Fuchs H, Rohde O, Avenarius S, Topf HG, Zimmermann A, Faas D, Timme K, Kleinlein B, Buxmann H, Schenk W, Segerer H, Teig N, Bläser A, Hentschel R, Heckmann M, Schlösser R, Peters J, Rossi R, Rascher W, Böttger R, Seidenberg J, Hansen G, Zernickel M, Bode H, Dreyhaupt J, Muche R, Hummler HD; PHELBI Study Group
(See online at https://doi.org/10.1136/archdischild-2016-311581) - Influence of PCO2 control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birthweight Infants. Neonatology 2018
Thome UH, Dreyhaupt J, Genzel-Boroviczeny O, Bohnhorst B, Schmid M, Fuchs H, Rohde O, Avenarius S, Topf HG, Zimmermann A, Faas D, Timme K, Kleinlein B, Buxmann H, Schenk W, Segerer H, Teig N, Ackermann B, Hentschel R, Heckmann M, Schlösser R, Peters J, Rossi R, Rascher W, Böttger R, Seidenberg J, Hansen G, Zernickel M, Bode H, Muche R, Hummler HD; PHELBI Study Group
(See online at https://doi.org/10.1159/000485828)
