Background: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

1.
Steenbergen C, Deleeuw G, Rich T, Williamson JR: Effects of acidosis and ischemia on contractility and intracellular pH of rat heart. Circ Res 1977;41:849-858.
2.
Lee KJ, Hernandez G, Gordon JB: Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets. Pediatr Pulmonol 2003;36:94-101.
3.
van Hulst RA, Hasan D, Lachmann B: Intracranial pressure, brain PCO2, PO2, and pH during hypo- and hyperventilation at constant mean airway pressure in pigs. Intensive Care Med 2002;28:68-73.
4.
Dix LML, Weeke LC, de Vries LS, Groenendaal F, Baerts W, van Bel F, et al: Carbon dioxide fluctuations are associated with changes in cerebral oxygenation and electrical activity in infants born preterm. J Pediatr 2017;187:66-72.
5.
Kaiser JR, Gauss CH, Pont MM, Williams DK: Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants. J Perinatol 2006;26:279-285.
6.
Fabres J, Carlo WA, Phillips V, Howard G, Ambalavanan N: Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics 2007;119:299-305.
7.
Greisen G, Vannucci RC: Is periventricular leucomalacia a result of hypoxic-ischaemic injury? Hypocapnia and the preterm brain (review) (74 refs). Biol Neonate 2001;79:194-200.
8.
Weeke LC, Dix LML, Groenendaal F, Lemmers PMA, Dijkman KP, Andriessen P, et al: Severe hypercapnia causes reversible depression of aEEG background activity in neonates: an observational study. Arch Dis Child Fetal Neonatal Ed 2017;102:F383-F388.
9.
Doerr CH, Gajic O, Berrios JC, Caples S, Abdel M, Lymp JF, et al: Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med 2005;171:1371-1377.
10.
Briva A, Vadasz I, Lecuona E, Welch LC, Chen J, Dada LA, et al: High CO2 levels impair alveolar epithelial function independently of pH. PLoS One 2007;2:e1238.
11.
Holmes JM, Zhang S, Leske DA, Lanier WL: Carbon dioxide-induced retinopathy in the neonatal rat. Curr Eye Res 1998;17:608-616.
12.
Saigal S, Doyle LW: An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet Lond Engl 2008;371:261-269.
13.
Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al: Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443-456.
14.
Doyle LW, Anderson PJ: Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009;14:391-395.
15.
Thome UH, Genzel-Boroviczeny O, Bohnhorst B, Schmid M, Fuchs H, Rohde O, et al: Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. Lancet Respir Med 2015;3:534-543.
16.
Thome UH, Genzel-Boroviczeny O, Bohnhorst B, Schmid M, Fuchs H, Rohde O, et al: Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Arch Dis Child Fetal Neonatal Ed 2017;102:F376-F382.
17.
McKee LA, Fabres J, Howard G, Peralta-Carcelen M, Carlo WA, Ambalavanan N: PaCO2 and neurodevelopment in extremely low birth weight infants. J Pediatr 2009;155:217-221.e1.
18.
Ambalavanan N, Carlo WA, Wrage LA, Das A, Laughon M, Cotten CM, et al: PaCO2 in surfactant, positive pressure, and oxygenation randomised trial (SUPPORT). Arch Dis Child Fetal Neonatal Ed 2015;100:F145-F149.
19.
Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A: Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol 2003;23:451-456.
20.
Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al: Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-1360.
21.
Papile LA, Burstein J, Burstein R, Koffler H: Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 g. J Pediatr 1978;92:529-534.
22.
International Committee for the Classification of Retinopathy of Prematurity: The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123:991-999.
23.
Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al: Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1-7.
24.
The International Neonatal Network: The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet Lond Engl 1993;342:193-198.
25.
Bayley N: Bayley Scales of Infant Development-II. San Antonio, The Psychological Corporation, 1993.
26.
Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B: Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214-223.
27.
Brandstetter G, Siebler V, Schneider H, Grässle A, Steinmacher J, Bode H: Elternfragebogen zur Entwicklung im Kleinkindalter (EFkE) - ein Screeninginstrument: I. Normierung. Kinderärztl Prax 2002;5:338-344.
28.
Brandstetter G, Bode H: Elternfragebogen zur Entwicklung im Kleinkindalter (EFkE) - ein Screeninginstrument: II. Praktikabilität und Reliabilität. Kinderärztl Prax 2002;5:345-350.
29.
Ireton H, Glascoe FP: Assessing children's development using parents' reports. The Child Development Inventory. Clin Pediatr (Phila) 1995;34:248-255.
30.
Thome UH, Carroll W, Wu T-J, Johnson RB, Roane C, Young D, et al: Outcome of extremely preterm infants randomized at birth to different PaCO2 targets during the first seven days of life. Biol Neonate 2006;90:218-225.
31.
Curley G, Laffey JG, Kavanagh BP: Bench-to-bedside review: carbon dioxide. Crit Care 2010;14:220.
32.
Ryu J, Heldt GP, Nguyen M, Gavrialov O, Haddad GG: Chronic hypercapnia alters lung matrix composition in mouse pups. J Appl Physiol 2010;109:203-210.
33.
Vadasz I, Hubmayr RD, Nin N, Sporn PH, Sznajder JI: Hypercapnia: a nonpermissive environment for the lung. Am J Respir Cell Mol Biol 2012;46:417-421.
34.
Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA, Shankaran S, et al: Minimal ventilation to prevent bronchopulmonary dysplasia in extremely low birthweight infants. J Pediatr 2002;141:370-374.
35.
Shankaran S, Johnson Y, Langer JC, Vohr BR, Fanaroff AA, Wright LL, et al: Outcome of extremely-low-birth-weight infants at highest risk: gestational age < or = 24 weeks, birth weight < or = 750 g, and 1-minute Apgar < or = 3. Am J Obstet Gynecol 2004;191:1084-1091.
36.
Struck A, Almaazmi M, Bode H, Sander S, Hay B, Schmid M, et al: Neurodevelopmental outcome of very low birth weight infants born at the Perinatal Centre in Ulm, Germany. Z Geburtshilfe Neonatol 2013;217:65-71.
37.
Polglase GR, Miller SL, Barton SK, Baburamani AA, Wong FY, Aridas JDS, et al: Initiation of resuscitation with high tidal volumes causes cerebral hemodynamic disturbance, brain inflammation and injury in preterm lambs. PLoS One 2012;7:e39535.
38.
Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al: Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362:1970-1979.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.