PEDIATRICS Vol. 122 No. 3 September 2008, pp. e583-e589 (doi:10.1542/peds.2008-1016)
ARTICLE |
Permissive Hypercapnia and Risk for Brain Injury and Developmental Impairment
a Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
b Department of Pediatrics, Emory University, Atlanta, Georgia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Permissive hypercapnia is a respiratory-care strategy that is used to reduce the risk for lung injury. The goal of this study was to evaluate whether permissive hypercapnia is associated with higher risk for intraventricular hemorrhage and early childhood behavioral and functional problems than normocapnia among very low birth weight infants.
METHODS. Very low birth weight infants from a statewide cohort were eligible for this study when they were born at <32 weeks' gestational age and survived at least 24 hours. Infants were classified as receiving a permissive hypercapnia, normocapnia, or unclassifiable respiratory strategy during the first 24 hours after birth according to an algorithm based on PCO2 values and respiratory-treatment decisions that were abstracted from medical charts. Intraventricular hemorrhage diagnosis was also abstracted from the medical chart. Behavioral and functional outcomes were assessed by parent interview at 2 to 3 years. Logistic regression was used to evaluate the relationship between intraventricular hemorrhage and respiratory strategy; ordinary linear regression was used to evaluate differences in behavior and function scores between children by respiratory strategy.
RESULTS. Infants who received a permissive hypercapnia strategy were not more likely to have intraventricular hemorrhage than those with normocapnia. There were no differences in any of the behavioral or functional scores among children according to respiratory strategy. There was a significant interaction between care strategy and 1-minute Apgar score, indicating that infants with lower Apgar scores may be at higher risk for intraventricular hemorrhage with permissive hypercapnia.
CONCLUSIONS. This study suggests that permissive hypercapnia does not increase risk for brain injury and impairment among very low birth weight children. The interaction between respiratory strategy and Apgar score is a potential worrisome exception to this conclusion. Future research should further evaluate the effect of elevated PCO2 levels among those who are sickest at birth.
Key Words: permissive hypercapnia • developmental follow-up • intraventricular hemorrhage • very low birth weight
Abbreviations: VLBW—very low birth weight • BPD—bronchopulmonary dysplasia • IVH—intraventricular hemorrhage • PIP—positive inspiratory pressure • CPAP—continuous positive airway pressure • OR—odds ratio • SNAP-II—Score for Neonatal Acute Physiology II • CI—confidence interval • RR—relative risk
Very low birth weight (VLBW) (<1500 g) infants are often preterm with incompletely developed respiratory systems, and most require respiratory assistance for survival1; however, mechanical ventilation and other respiratory care can injure fragile, immature lungs and increase risk for bronchopulmonary dysplasia (BPD), a chronic form of lung disease.2 Permissive hypercapnia is a respiratory-treatment strategy that accepts levels of PaCO2 above normal, thereby allowing less aggressive respiratory care and, as a result, less trauma to the lung.3,4
Despite the suggested benefit of permissive hypercapnia for decreasing risk for BPD, it is not well understood whether it is associated with risk for brain injury, such as intraventricular hemorrhage (IVH), and subsequent developmental impairment. IVH was evaluated as a secondary outcome in 2 clinical trials of permissive hypercapnia.5,6 Neither trial found any relationship between permissive hypercapnia and risk for IVH, but the first5 had a small sample size (n = 49) and the second6 was terminated early with a smaller than planned sample (n = 220). A trial that targeted even higher PaCO2 levels found that, at 18 to 22 months, children in this minimal ventilation group had worse scores on the Bayley Mental Developmental Index than children who were randomly assigned to standard ventilation.7 Previous observational studies have found an association between high PaCO2 levels and IVH,8–12 and IVH is associated with increased risk for developmental impairments.13–24 Hence, it is not clear whether permissive hypercapnia is safe for immature brains.
Clinical trials are both difficult and expensive. It can be challenging to enroll sufficient numbers of subjects, and trials can be terminated early. In addition, trials tend to be conducted under circumstances different from those under which the general population receives care. Our detailed observational data on blood gases and ventilatory support in a large population of infants allows us to infer ventilation care strategy and address the impact of permissive hypercapnia. The objectives of this study were to evaluate (1) whether a permissive hypercapnia treatment strategy early in life is associated with higher risk for IVH than a normocapnia treatment strategy, and (2) whether permissive hypercapnia is associated with more behavioral and functional problems during early childhood.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Sample and Data Collection
The Newborn Lung Project Statewide Cohort is a prospective study of all VLBW infants who were admitted to the 16 level III NICUs in Wisconsin from January 1, 2003, to December 31, 2004, and Wisconsin residents who were admitted to a level III NICU in Duluth, Minnesota. Anonymous data on blood gases, ventilatory treatments, baseline characteristics, and neonatal diagnoses were collected from the medical charts of all admitted VLBW infants. Designated NICU nurses approached parents for consent to collect identifiable data from the medical chart and to obtain contact information for follow-up. Trained interviewers collected data on behavior, function, and socioeconomic status through parent telephone interviews when children were 2 to 3 years of age (mean [SD]: 32.2 [3.5] months' corrected age; range: 25.0–46.3 months).
Analyses were restricted to 24-hour survivors with gestational age <32 weeks, because classification of respiratory-treatment strategy was based on the first 24 hours after birth and BPD is rare among infants who are 
32 weeks' gestation. Hence infants who are <32 weeks' gestational age are the target population for BPD prevention and a permissive hypercapnia strategy of care.
Description of Algorithm to Classify Infants According to Permissive Hypercapnia or Normocapnia Treatment Strategy
An algorithm was devised to identify infants who could have been treated with either a normocapnia or a permissive hypercapnia strategy. The 2-part algorithm was applied to blood gas measurements and respiratory-treatment decisions that were made during the subsequent hour, between NICU admission (median: 16 minutes after birth [interquartile range: 11–24 minutes]) and 24 hours after birth.
First, each blood gas measurement was classified as indicative of permissive hypercapnia, normocapnia, or unclassifiable on the basis of the PCO2 value and the respiratory-care actions within 1 hour of the blood draw. The vast majority of blood gas values were from arterial samples (91% for infants in the normocapnia group, 82% for infants in the permissive hypercapnia group). Capillary PCO2 values were considered similar to those based on arterial samples. Venous values were interpreted as 5 mmHg higher than those from arterial samples and transformed accordingly. PCO2 values and subsequent treatment decisions that were targeted at keeping PCO2 values at >45 mmHg and 
55 mmHg were taken as indicators of a permissive hypercapnia strategy, and PCO2 values and treatment decisions that were targeted at keeping PCO2 values at >35 mmHg and 45 mmHg were considered indicators of a normocapnia strategy. The following treatment decisions were considered less aggressive, allowing PCO2 values to rise or stay the same: decreasing positive inspiratory pressure (PIP) settings, decreasing ventilator rate settings, switching from mechanical ventilation to either continuous positive airway pressure (CPAP) or oxygen only, or switching from CPAP to oxygen. Increasing PIP, increasing ventilator rate settings, and switching from CPAP to mechanical ventilation were considered more aggressive, with the potential to lower PCO2 values.
Blood gas measurements were considered unclassifiable when the infant was not receiving CPAP or mechanical ventilation at the time of the blood draw or when there was an indication that the infant was too ill to be considered for a choice between permissive hypercapnia and normocapnia. Blood gas measurements with PCO2 at <35 mmHg or >55 mmHg were unclassifiable, because these values are likely indicative of illness severity that precludes the choice of a permissive hypercapnia treatment strategy.
The second step was to determine the percentage of blood gas measurements that met the criteria for permissive hypercapnia or normocapnia for each infant. When >50% of the blood gas measurements led to actions that met the permissive hypercapnia or normocapnia criteria, the infant was classified as receiving that treatment strategy. When exactly 50% of the blood gas measurements fell into each of the permissive and normocapnia criteria, the infant was classified as receiving a permissive hypercapnia strategy (this was the case for 10 infants).
The algorithm classifications were validated against clinical judgments of 3 neonatologists. The charts of 30 infants were reviewed by 2 neonatologists each. The algorithm had good agreement with the neonatologists' judgment of whether an infant was treated with a strategy of permissive hypercapnia (
: 0.63–0.89; Table 1).
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Outcome Measures
Designated NICU nurses recorded onto standard forms the presence and grade of IVH and death before discharge. IVH was graded on a scale of 1 to 4 according Papile et al.25 Severe IVH refers to grades 3 to 4. Neonatal outcomes included any grade IVH, severe IVH, and severe IVH or death.
Parents were interviewed by 1 of 3 interviewers when children were 2 to 3 years of age. We evaluated total behavior problems, internalizing behavior, and externalizing behavior from the Achenbach Child Behavior Checklist26 and social function, self-care, and mobility from the Pediatric Evaluation of Disabilities Inventory.27 The mean (SD) for each of these scales is 50 (10).
Statistical Analysis
We used logistic regression to estimate odds ratios (ORs) for IVH comparing children with permissive hypercapnia and normocapnia. We used linear regression to estimate differences in behavior and function scores between the 2 groups. All models were adjusted for indicators of baseline illness severity: gestational age, gender, 1-minute Apgar score, outborn status (born at another hospital and transferred to 1 with a level III NICU), receipt of antenatal steroids, and the Score for Neonatal Acute Physiology, Version II (SNAP-II). SNAP-II is an index of newborn illness severity that is based on physiologic measurements from the first 12 hours after birth, including the lowest recorded pH value.28 Because pH is associated with PaCO2, a modified SNAP-II score was calculated excluding the pH scale. Birth weight and gestational age were collinear, and gestational age was a stronger predictor of IVH, so birth weight was not included. Models for behavioral and functional outcomes were also adjusted for interviewer and indicators of socioeconomic status: maternal education, household income, race, and single-parent household.
Interactions between respiratory strategy and each of the baseline severity variables were investigated for all outcomes. Because a relatively large percentage of infants were not classified by respiratory strategy, a sensitivity analysis was conducted to explore whether unclassifiable infants affected the results. Models were weighted by the inverse of a propensity score computed by logistic regression as the probability of being classified by the algorithm. Each of the early childhood behavioral and functional outcomes models was reweighted by the inverse probability of follow-up to determine whether participation bias may have affected the results.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Population
A total of 1479 VLBW infants were admitted to the study NICUs during the recruitment period, 1241 of whom were 24-hour survivors who were <32 weeks' gestational age. Of these, 1162 (94%) had blood gas data available. Of the infants with blood gas data, 371 (32%) were classified as having a permissive hypercapnia (n = 129) or normocapnia (n = 242) strategy of respiratory care. Of those classified, 256 survived to age 2 with consent for follow-up, and data were obtained from 184 (72%). The mean (SD) number of blood gas values during the first 24 hours after birth was 5.6 (2.2), 6.5 (1.7), and 6.3 (2.9) for infants who received permissive hypercapnia, received normocapnia, or were unclassifiable, respectively.
Infants who were classified as receiving a permissive hypercapnia strategy were similar to those with a normocapnia strategy with respect to birth weight and gestational age, but infants who received permissive hypercapnia had better 1-minute Apgar and SNAP-II scores. Infants who were not classified by respiratory strategy had lower mean birth weight and worse Apgar and SNAP-II scores. The permissive hypercapnia group had higher mean PCO2 values and lower mean PIP and ventilator setting rates than the normocapnia group (Table 2). The permissive hypercapnia group tended to have better respiratory outcomes, but only the difference in ventilation at 36 weeks' postmenstrual age reached statistical significance.
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Respiratory-Care Strategy and IVH
Infants who were classified as receiving a permissive hypercapnia treatment strategy were not more likely to develop IVH than those with a normocapnia strategy. Although the crude incidence rate of IVH was slightly lower among infants with permissive hypercapnia than among those with normocapnia (24% and 27%, respectively), adjusted analyses indicated no difference in risk of IVH by care strategy (adjusted OR: 1.00 [95% confidence interval (CI): 0.59 to 1.80]). In addition, severe IVH was not significantly more likely among infants with permissive hypercapnia, and the combined outcome of severe IVH or death indicated no higher risk associated with permissive hypercapnia (Table 3).
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There was a significant interaction between respiratory-care strategy and 1-minute Apgar score for any grade IVH. The interaction was not significant for severe IVH or the combined outcome of severe IVH or death. The interaction indicated that for infants whose Apgar scores were
4, a permissive hypercapnia strategy is associated with higher risk for IVH, whereas for Apgar scores 5, a permissive hypercapnia strategy is protective (Table 4). Weighting models by the inverse of the propensity scores, on the basis of the probability of being classified by respiratory-care strategy, did not substantially change results.
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Respiratory-Care Strategy and Early Childhood Behavior and Function
There were no significant differences in behavior or function scores between children who received a permissive hypercapnia treatment strategy and those with a normocapnia strategy (Table 5). There were no significant interactions between respiratory-care strategy and any of the baseline severity variables. Weighting models by the inverse of the probability of early childhood follow-up did not affect the conclusions for any of the behavioral or functional outcomes.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Infants whose respiratory-treatment pattern indicated a permissive hypercapnia strategy were not at higher risk for IVH than those whose respiratory treatment indicated a normocapnia strategy. There were no early childhood behavioral or functional differences by respiratory strategy. Permissive hypercapnia, a strategy of care in current use among neonatologists to reduce risk for lung injury, seems to be safe for immature brains.
An exception to this conclusion may be for infants with low Apgar scores. A significant interaction was found between respiratory-care strategy and 1-minute Apgar score for any grade IVH, indicating that for infants with lower Apgar scores, permissive hypercapnia is associated with higher risk for IVH, whereas for infants with higher Apgar scores, permissive hypercapnia is associated with lower risk. It is possible that infants who are very vulnerable at birth just cannot handle a less aggressive treatment strategy; however, because of the many interactions investigated, this significant result could have occurred by chance. The reason for higher risk for any grade IVH associated with permissive hypercapnia among infants with low Apgar scores remains unclear.
To our knowledge, no other observational study has evaluated outcomes that are associated with patterns of respiratory care that are indicative of a permissive hypercapnia or normocapnia treatment strategy. Two clinical trials have evaluated the association between permissive hypercapnia and IVH among VLBW infants.5,6 The first trial5 randomly assigned 49 infants to minimal (PaCO2 target 45–55 mmHg) or standard ventilation (PaCO2 target 35–45 mmHg). The results showed no relationship between permissive hypercapnia and any grade IVH (relative risk [RR]: 0.82 [95% CI: 0.43 to 1.52]) or severe IVH (RR: 1.46 [95% CI: 0.47 to 4.82]). The second trial6 randomly assigned 220 infants to PaCO2 targets >52 mmHg or <48 mmHg. They found no association between permissive hypercapnia and severe IVH (RR: 0.78 [95% CI: 0.48 to 1.27]). Another trial randomly assigned 54 infants to either PaCO2 levels targeted above the permissive hypercapnia range (55–65 mmHg) or within the normal range (35–45 mmHg).7 These researchers also found no association between respiratory strategy and severe IVH (OR: 0.82; P = .78). The difference in the mean PaCO2 level between infants in the permissive hypercapnia and normocapnia groups both in our study and in the trial that targeted higher PaCO2 levels was relatively small (6 mmHg in each study). Our conclusion that there is no association between a permissive hypercapnia treatment strategy and risk for IVH is consistent with the results of these trials.
The trial of higher PaCO2 levels investigated neurologic and developmental impairments at 18 to 22 months' corrected age.7 There was no association between respiratory strategy and cerebral palsy, hearing impairment, vision impairment, or low scores on the Bayley Psychomotor Developmental Index, but infants in the minimal ventilation group had worse scores on the Bayley Mental Developmental Index (mean [SD] for minimal ventilation group: 70 [21]; mean [SD] for standard ventilation group: 88 [26]; P = .054); however, these results were based on 12 children from the minimal ventilation group (36% of original group) and 17 children from the standard ventilation group (56% of original group).
Our behavioral and functional follow-up also suggests that infants who are treated with permissive hypercapnia are not at a disadvantage during early childhood. The age at follow-up was older in our study than in the clinical trial. Perhaps any slight disadvantage on the Mental Developmental Index at an earlier age has diminished by age 2.5 to 3.5 years; however, additional follow-up is warranted to confirm that this suggested lack of disadvantage continues into later childhood and beyond.
Our study has important strengths. The rich observational data set allowed us to investigate the risk for IVH associated with actions by neonatologists indicative of less aggressive versus more standard respiratory care, comparing infants who could have been eligible for either strategy. Our study adds to the existing literature by evaluating the effect of the kind of care delivered to infants across an entire state and across a variety of NICUs.
Because of the extensive amount of data collected on each infant during the NICU stay, analyses could be adjusted to take the illness severity of the infants into account. This adjustment is important to reduce the influence of confounding variables on the association between elevated PaCO2 levels and IVH. Several indicators of illness severity are associated with higher risk for IVH (eg, gestational age, SNAP-II score), as well as with high PaCO2 levels.
The early childhood follow-up in this study provides important information about the ramifications of respiratory care during the NICU stay. Although the immediate goal of neonatal intensive care is morbidity-free survival to discharge, the long-term goal should be to help infants grow into children as free from impairment as possible. Monitoring the long-term effects of neonatal treatments is important to understanding how these decisions affect the developmental course.
This study did have some limitations. We did not have a way to determine the neonatologists' target PaCO2 levels; however, although we cannot be certain of the physicians' intentions, we were able to identify and compare groups of infants by de facto pattern of care. We used medical chart review to ascertain IVH diagnosis, which may miss IVH among some infants; however, it is unlikely that the clinical signs of severe IVH would go undetected, unless the infant died before diagnosis. Because the associations with permissive hypercapnia are consistent across the outcomes any grade IVH, severe IVH, and severe IVH or death, it is unlikely that missed IVH diagnoses affected our conclusions.
Our early childhood outcomes are based on parent report. Although parents are likely the best reporters of how young children are doing in their everyday lives, the well-being of the interviewee (in almost all cases, the mother) can affect the way she answers questions about her child. Stress and depression have been associated with worse reports of children's well-being.29,30 Although mothers of VLBW children are at higher risk for stress and depression throughout the first years of their child's life,31 all mothers in this study had VLBW children. Because neonatal morbidity was similar among infants in the permissive and normocapnia groups, stress as a result of child illness among mothers in each of the groups should be comparable.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The results of this study suggest that permissive hypercapnia does not increase risk for IVH and subsequent developmental impairment among VLBW children. These findings are consistent with the findings of clinical trials that randomly assigned infants to a permissive hypercapnia or normocapnia respiratory-treatment strategy. Together, these studies suggest that permissive hypercapnia is a treatment strategy that is safe for infant brains; however, the significant interaction between permissive hypercapnia and Apgar score for any grade IVH provides a potential worrisome exception to this conclusion. Additional investigation should be undertaken to understand the effect of elevated PaCO2 levels on the brains of the sickest infants.
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ACKNOWLEDGMENTS |
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This study was funded by National Institutes of Health NHLBI grant 5 RO1 HL38149-17 ("Risk Factors in Bronchopulmonary Dysplasia").
The Newborn Lung Project involved the following investigators and project and center coordinators: coordinating center, University of Wisconsin (Madison, WI): Dr Mari Palta (principal investigator), Dr Mona Sadek-Badawi (project director), Aggie Albanese, Kathleen Madden, Lisa Loder, and Tanya Watson; Dr Christopher Green (University of Wisconsin, Madison, WI); Dr David Carlton and Karin Smylie (University of Wisconsin, Madison, Meriter Hospital, Madison, WI); Dr Jeffrey Garland, Roberta Einsiedel, Kathy Weaver, and Jackie Sevallius (St Joseph's Regional Medical Center, Milwaukee, WI); Dr Chandra Shivpuri, Susan Plachinski, and Karen Dorfler (Sinai Samaritan Medical Center, Milwaukee, WI); Dr James Opitz, Sandy Freeman, MaryAnne Lach, and Angie Linneman (St Joseph's Hospital, Marshfield, WI); Dr Marie Weinstein and Laura Ziebarth (St Mary's Hospital, Madison, WI); Dr Paul Meyers, Denise Turnmeyer, and Pamela Verhagen (Children's Hospital of Fox Valley, Neenah, WI); Dr Joseph Brand and Lana Reinke (St Vincent Hospital, Green Bay, WI); Dr John Wolf, Jane Friday, and Joan Hintz (Columbia-St Mary's Hospital, Milwaukee, WI); Dr Nancy Herrell and Sharon Nelson (Waukesha Memorial Hospital, Waukesha, WI); Dr P. Sasidharan (Children's Hospital of Wisconsin, Milwaukee, WI); Dr Gregory Milleville, Melissa Grooms, and Carolyn Kraly (Aurora Women's Pavilion, West Allis, WI); Dr David Sheftel, Michelle Stampa, Monica DaPra, Sandy Anderson, and Diane Fiebig (St Luke's Hospital, Racine, WI); Dr Jeffrey Thompson and Shawn Dunlap (Gunderson Lutheran Hospital-La Crosse, La Crosse, WI); Dr Dennis Costakos, Karen Smith, and Lynn Dahlen (Franciscan Skemp Hospital, La Crosse, WI); Dr Howard Kidd, Nicole Stephani, and Tracy Heiman (St Elizabeth Hospital, Appleton, WI); Dr Frank Mattia and Patti Davis (Aurora BayCare, Green Bay, WI); and Dr Lee A. Muscovitz and Deborah Peters (St Mary's Hospital, Duluth, MN).
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FOOTNOTES |
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Accepted May 23, 2008.
Address correspondence to Erika W. Hagen, PhD, University of Wisconsin, Department of Population Health Sciences, School of Medicine and Public Health, 610 Walnut St, WARF 662, Madison, WI 53726. E-mail: ewarkentien{at}wisc.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Permissive hypercapnia is a respiratory-treatment strategy that allows moderately elevated PaCO2 levels to decrease lung trauma. Very high PaCO2 levels increase risk for IVH and subsequent developmental impairment, but the effect of moderately elevated PaCO2 levels is unknown.
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| What This Study Adds We used a large set of observational data to compare permissive hypercapnia and normocapnia among infants in an entire state across a variety of NICUs.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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