Permissive hypercapnia in neonates: The case of the good, the bad, and the ugly

There is significant controversy over the effects of hypercapnia on the human newborn brain. Previous studies have shown that 1 h of an arterial CO 2 pressure (PaCO 2 ) of 80 mm Hg alters brain cell membrane Na ϩ K ϩ -ATPase enzyme activity in the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypercapnia (either a PaCO 2 of 65 or 80 mm Hg) results in decreased energy metabolism and alters neuronal nuclear enzyme activity and protein expression, specifically Ca ϩϩ / calmodulin-dependent kinase (CaMK) IV activity, phosphorylation of cAMP response element binding protein (CREB), and expression of apoptotic proteins in cortical neuronal nuclei of newborn piglets. Studies were performed in 20 anesthetized normoxic piglets ventilated at either a PaCO 2 of 65 mm Hg, 80 mm Hg, or 40 mm Hg for 6 h. Energy metabolism was documented by ATP and phosphocreatine (PCr) levels. Results show ATP and PCr levels were significantly lower in the hypercapnic groups than the normocapnic. CaMK IV activity, phosphorylated CREB density, and Bax protein expression were all significantly higher in the hypercapnic groups than the normocapnic group. Bcl-2 protein was similar in all three groups, making the ratio of Bax/Bcl-2 significantly higher in the hypercapnic groups than in the normocapnic group. We conclude that hypercapnia alters neuronal energy metabolism, increases phosphorylation of transcription factors, and increases the expression of apoptotic proteins in the cerebral cortex of newborn piglets and therefore may be deleterious to the newborn brain. The long-term neurologic morbidity for preterm and ill term human newborns remains a serious concern. Among these infants, hypercapnia is a common occurrence. Current clinical practice often allows infants ventilated acutely or chronically to remain hypercapnic (undergoing "permissive hypercapnia") to limit ventilator-induced lung injury. The effects of hypercapnia on the newborn brain are controversial as there is not a known safe range of arterial CO 2 pressure (PaCO 2 ).Some recent clinical studies have not shown an immediate harmful effect of hypercapnia in human infants (1-3). However, in most of these studies, long-term neurologic outcomes were not reported. In addition, subtle alterations in brain structure and function may not be detectable in these clinical studies.Hypercapnia (PaCO 2 Ͼ60 mm Hg) results in increased CBF and decreased cerebral vascular resistance in newborn infants (4 -6) and has been associated with intraventricular hemorrhage in some studies (7-9) but not in others (10,11). There are some clinical data suggesting that hypercapnia may be harmful to the newborn brain even if it does not result in intraventricular hemorrhage (12)(13)(14). Moderate elevations in PaCO 2 (end tidal PCO 2 of 60 mm Hg) in healthy preterm (33-36 wk) infants significantly impeded brain stem auditory evoked responses (15). In other studies, very-low-birth-weight infants and term infants with impaired CBF reactivity during hypercapnia had poor neurologic...

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“…ATP levels (mol/g wet brain) were lower in the both the CO 2 65 (3.85 Ϯ 0.41) and 80 (4.0 Ϯ 0.14) groups than in the CO 2 …”

Section: Resultsmentioning

confidence: 95%

“…Some recent clinical studies have not shown an immediate harmful effect of hypercapnia in human infants (1)(2)(3). However, in most of these studies, long-term neurologic outcomes were not reported.…”

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confidence: 89%

Hypercapnia-Induced Modifications of Neuronal Function in the Cerebral Cortex of Newborn Piglets

et al. 2005

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“…Maintaining arterial partial pressure of carbon dioxide (PaCO 2 ) levels of 45 to 55 mm Hg is likely safe in ventilated premature infants, 25,26 but there are few data to determine a threshold PaCO 2 level that alone should prompt intubation. Our practice had been to intubate for any PaCO 2 level higher than 60 mm Hg.…”

Section: Strict Intubation Criteriamentioning

confidence: 99%

Impact of Implementing 5 Potentially Better Respiratory Practices on Neonatal Outcomes and Costs

et al. 2011

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OBJECTIVE:We implemented 5 potentially better practices to limit mechanical ventilation (MV), supplemental oxygen, and bronchopulmonary dysplasia in newborn infants born before 33 weeks' gestation. METHODS:The methods used in this study included (1) exclusive use of bubble continuous positive airway pressure (bCPAP), (2) provision of bCPAP in the delivery room, (3) strict intubation criteria, (4) strict extubation criteria, and (5) prolonged CPAP to avoid supplemental oxygen. We excluded outborn infants and those with major anomalies and obstetric complications from analysis. RESULTS:Demographics were similar in 61 infants born before and 60 born after implementation. For infants born at 26 to 32 6 ⁄ 7 weeks' gestation, intubation (first 72 hours) decreased from 52% to 11% (P Ͻ .0001) and surfactant use decreased from 48% to 14% (P ϭ .0001). In all infants, the mean Ϯ SD fraction of inspired oxygen requirement (first 24 hours) decreased from 0.27 Ϯ 0.08 to 0.24 Ϯ 0.05 (P ϭ .0005), days of oxygen decreased from 23.5 Ϯ 44.5 to 9.3 Ϯ 22.0 (P ϭ .04), and days of MV decreased from 8.8 Ϯ 27.8 to 2.2 Ϯ 6.2 (P ϭ .005). Hypotension decreased from 33% to 15% (P ϭ .03). The percentage of infants with bronchopulmonary dysplasia was 17% before and 8% after (P ϭ .27). Nurse staffing ratios remained unchanged. CONCLUSIONS:Implementation of these potentially better practices reduced the need for MV, surfactant, and supplemental oxygen as well as reduced hypotension among infants born before 33 weeks' gestation without adverse consequences. The costs for equipment and surfactant were lower. Pediatrics 2011;128:e218-e226 All the authors made substantive intellectual contributions to this report. Dr Levesque contributed to the conception and design of the study, implementation, data collection, analysis, and interpretation, drafted the article, and approved the version submitted; Dr Kalish contributed to the data analysis and interpretation and critical revising of the article for important intellectual content and approved the final version submitted; and Ms LaPierre, Ms Welch, and Ms Porter participated in the conception and design, implementation, data collection and interpretation, and revising of the article and approved the version submitted.www.pediatrics.org/cgi

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“…(e) Finally, several of the strategies employed today, such as permissive hypercapnea, 21 permissive acidosis, permissive hypotension, 22 and treatment of hypotension have not undergone rigorous evaluation. These evolving practices in neonatal intensive care may confer no benefit, or may even be harmful.…”

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confidence: 99%

Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern?

et al. 2011

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Unadjusted analyses revealed reduction in mortality (unadjusted odds ratio (UAOR): 0.83, 95% confidence interval (CI): 0.63, 0.98), severe retinopathy (UAOR: 0.68, 95% CI: 0.50 to 0.92), but increase in bronchopulmonary dysplasia (UAOR: 1.61, 95% CI: 1.39 to 1.86) and patent ductus arteriosus (UAOR: 1.22, 95% CI: 1.07 to 1.39). Adjusted analyses revealed increases in the later cohort for bronchopulmonary dysplasia (adjusted odds ratio (AOR): 1.88, 95% CI: 1.60 to 2.20) and severe neurological injury (AOR: 1.49, 95% CI: 1.22 to 1.80). However, the ascertainment methods for neurological findings and ductus arteriosus differed between the two time periods.Conclusion: Improvements in prenatal care has resulted in improvement in the quality of care, as reflected by reduced severity of illness and mortality. However, after adjustment of prenatal factors, no improvement in any of the outcomes was observed and on the contrary bronchopulmonary dysplasia increased. There is need for identification and application of postnatal strategies to improve outcomes of extreme preterm infants.

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Permissive hypercapnia in neonates: The case of the good, the bad, and the ugly

Cited by 50 publications

References 117 publications

Hypercapnia-Induced Modifications of Neuronal Function in the Cerebral Cortex of Newborn Piglets

Hypercapnia-Induced Modifications of Neuronal Function in the Cerebral Cortex of Newborn Piglets

Impact of Implementing 5 Potentially Better Respiratory Practices on Neonatal Outcomes and Costs

Outcomes of preterm infants <29 weeks gestation over 10-year period in Canada: a cause for concern?

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