EditorialEditor's Choice

Incidence of Hypocapnia, Hypercapnia, and Acidosis and the Associated Risk of Adverse Events in Preterm Neonates

Melissa K Brown, Deborah M Poeltler, Kasim O Hassen, Danielle V Lazarus, Vanessa K Brown, Jeremiah J Stout, Wade D Rich and Anup C Katheria
Respiratory Care August 2018, 63 (8) 943-949; DOI: https://doi.org/10.4187/respcare.05801

Abstract

BACKGROUND: Permissive hypercapnia is a lung-protection strategy. We sought to review our current clinical practice for the range of permissive hypercapnia and identify the relationship between PaCO2 and pH and adverse outcomes.

METHODS: A secondary analysis of a delayed cord-clamping clinical trial was performed on all arterial blood gas tests in the first 72 h in infants < 32 weeks gestational age. All arterial blood gas values were categorized into a clinical range to determine the percent likelihood of occurring in the total sample. The univariate and multivariate relationships of severe adverse events and the time-weighted PaCO2, fluctuation of PaCO2, maximal and minimal PaCO2, base excess, and pH were assessed.

RESULTS: 147 infants with birthweight of 1,206 ± 395 g and gestational age of 28 ± 2 weeks were included. Of the 1,316 total samples, < 2% had hypocapnia (PaCO2 <30 mm Hg), 47% were normocapnic (PaCO2 35–45 mm Hg), 26.5% had mild hypercapnia (PaCO2 45–55 mm Hg), 13% had moderate hypercapnia (PaCO2 55–65 mm Hg), and 6.5% had severe hypercapnia (PaCO2 ≥ 65 mm Hg). There were no adverse events associated with hypocapnia. Subjects with death/severe intraventricular hemorrhage had a higher mean PaCO2 of 52.3 versus 44.7 (odds ratio [OR] 1.16, 95% CI 1.04–1.29, P = .006), higher variability of PaCO2 with a standard deviation of 12.6 versus 7.8 (OR 1.15, 95% CI 1.03–1.27, P = .01), and a lower minimum pH of 7.03 versus 7.23 (OR 0, 95% CI 0–0.06, P = .003). There was no significant difference in any variables in subjects who developed other adverse events.

CONCLUSION: The routine targeting of higher than normal PaCO2 goals may lead to a low incidence of hypocapnia and associated adverse events. Hypercapnia is common, and moderate hypercapnia may increase the risk of neurologic injury and provide little pulmonary benefit.

Introduction

Permissive hypercapnia, or allowing the PaCO2 levels to rise above normal, is a commonly utilized lung-protection strategy in the management of premature neonates.1 However, the range of PaCO2 that provides benefit with the least risk is not yet known.1,2 Permissive hypercapnia may allow the maintenance of an adequate minute ventilation with lower tidal volumes (VT), and it may help avoid the lung injury that can occur from volutrauma and barotrauma.3 The resultant reductions of mean airway pressure may also prevent lung injury as well as improve the cardiac output, which is frequently compromised in the critically ill premature neonate.4 Enhanced delivery of oxygen to the brain and other vital tissues can also be facilitated by shifting the oxyhemoglobin dissociation curve to the right, with respiratory acidosis and increases in PaCO2 levels. Previous randomized, controlled trials have demonstrated a reduction in median ventilator days (2.5 vs 9.5) and the need for ventilator assistance at 36 week corrected gestational age (16% vs 1%)5 with a strategy of mild hypercapnia (PaCO2 45–55 mm Hg)4 when compared to a normocapnic group (PaCO2 35–45 mm Hg) in extremely low birthweight infants, without an increase in neurodevelopmental adverse effects. However, bronchopulmonary dysplasia (BPD) rates have not been significantly reduced by a strategy of permissive hypercapnia.4–7

Hypercapnia can increase cerebral vasodilation and cerebral blood flow; conversely, hypocapnia can lead to vasoconstriction and significantly decreased cerebral blood flow.8–10 Progressive increases in the PaCO2 level can also impair the autoregulation of cerebral blood flow and may lead to ischemic damage of the neonatal brain.2,8,9 Hypercapnia, hypocapnia, fluctuations in PaCO2, and acidosis have all been positively associated with intraventricular hemorrhage (IVH), periventricular leukomalacia, and poor neurodevelopmental outcomes in preterm neonates.10–13

Previous studies have questioned the safe ranges of permissive hypercapnia and the role that pH plays in the relationship. The acceptable limits for acidosis are poorly defined and difficult to isolate from the effects of hypercapnia. Moderate hypercapnia (PaCO2 > 55 mm Hg) has not yet been demonstrated to be either beneficial or safe, although it has been reported to be a common clinical practice. Randomized controlled trials investigating the safety and effectiveness of moderate hypercapnia have been difficult to complete due to infant subjects' ability to regulate their own ventilation and override the study PaCO2 targets. Two randomized clinical trials attempted to determine whether targeting moderate levels of hypercapnia is safe or beneficial. Both had negative results, and the authors did not recommend that they be attempted again in the future.7,14

Although most of the early positive trial results that lead to the adoption of permissive hypercapnia of neonates compared mild levels of hypercapnia to normal values, Thome at al randomized mechanical ventilated infants < 28 weeks within 6 h of birth to a higher PaCO2 target of 55–65 mm Hg or 35–45 mm Hg for the first 7 postnatal days.14 The primary outcome measure was BPD or death and neurodevelopmental outcome at 18–22 months corrected age. The trial was stopped early after enrolling 31% of the projected sample size. A PaCO2 target of 55–65 mm Hg was associated with trends toward higher mortality and higher incidence of neurodevelopmental impairment, and a significant increase in the combined outcome of mental impairment or death (P < .05). Higher ventilator rates to achieve gas exchange with low VT may have diminished the advantage of minimal ventilation. VT was kept similar in both groups (high-rate strategy pH > 7.25 with sodium bicarbonate administration). A strategy of reducing VT by increasing the PaCO2 target was not in effect in this cohort (as utilized in ARDSnet15), possibly negating any pulmonary impact between groups. The trial had difficulty achieving the high PaCO2 target in non-paralyzed infants, and although the PaCO2 difference was statistically significant (6 mm Hg, P < .001), it did not meet the study goal of 55–65 mm Hg.

The Permissive Hypercapnia in Extremely Low Birthweight Infants (PHELBI) trial enrolled 362 infants at 16 centers in Germany before being stopped early after an interim analysis.7 The authors hypothesized that a higher target PaCO2 55–65 mm Hg (day 1–3) as compared to 40–50 mm Hg and then escalating gradually over 14 d would reduce the rate of BPD or death. The trial was terminated when no benefit in the treatment group and a trend toward benefit in the control group was found. The high-target group had a significantly higher rate of necrotizing enterocolitis and did not have a shorter duration of ventilation. Although the high-target group did have lower ventilator pressures, it did not translate into better outcomes. The infants with severe disease in the high target group (PaCO2 55–65 mm Hg) had a higher incidence of BPD, necrotizing enterocolitis, and death. The PHELBI investigators were unable to reach the desired targets with the high PaCO2 group. The mean PaCO2 difference was only 6.2 mm Hg between days 2 and 11. The authors suggest that the high targets may be impossible to achieve in a randomized, controlled trial and probably should not be attempted either clinically or in future studies.7

Our goal was to review our current clinical practice for the range of permissive hypercapnia in premature neonates < 32 weeks gestational age, and to identify a relationship between PaCO2 and pH during the first 72 h and adverse neonatal outcomes. This information may then allow us to identify PaCO2 and pH values that are associated with adverse events, which may advise good clinical practice.

QUICK LOOK

Current knowledge

A strategy of mild hypercapnia (PaCO2 = 45-55 mm Hg) can lead to a reduction in ventilator days and the need for ventilator assistance at 36 week corrected gestational age when compared to a normocapnic group (35-45 mm Hg) in extremely low birthweight infants, without an increase in neurodevelopmental adverse effects. Bronchopulmonary dysplasia rates have not been significantly reduced by a strategy of permissive hypercapnia.

What this paper contributes to our knowledge

Moderate to high levels of permissive hypercapnia (> 55 mm Hg) in the first 72 h of life has found its way into neonatal clinical practice, which may increase neurologic risk and provide little pulmonary benefit. Targeting higher than normal PaCO2 levels may help avoid the adverse events associated with hypocapnia.

Methods

This is a secondary analysis of infants < 32 weeks gestational age previously enrolled in a prospective, randomized, controlled trial of delayed cord clamping (n = 150 subjects).16 Subjects were enrolled in the primary trial between August 2014 and October 2015 at Sharp Mary Birch Hospital for Women and Newborns, and written informed consent was obtained from the parents or guardians of each participant. Infants with severe placenta abruption or congenital anomalies were excluded from the original trial, as were cases in which the attending physician believed care was futile. The Sharp Institutional Review Board approved the secondary analysis. Subjects with arterial blood gas (ABG) tests were included in the secondary study (N = 147). All ABG values from the first 72 h after birth along with the associated mode of ventilation were included in the analysis. An experienced research team, as part of the original clinical trial, prospectively collected all subject demographic and outcome data (Table 1). ABGs and the corresponding mode of ventilation were collected retrospectively from the electronic medical record. Study data were collected and managed using REDCap (Research Electronic Data Capture, Vanderbilt University, Nashville, Tennessee). The trial data were exported from RedCap into SPSS version 23 for Windows (IBM, Armonk, New York) for the purpose of further analysis.

View this table:
Table 1.

Demographics and Neonatal Outcome Data

All PaCO2 and pH values were initially categorized into a clinical range to determine the percent likelihood of the value range occurring in the total sample (Table 2). The value ranges and associated mode of ventilation were described for the whole sample and a subset of the sample that was < 28 weeks gestational age. Value ranges were set to reflect areas of clinical interest: Moderate to severe hypocapnia (PaCO2 < 30 mm Hg), mild hypocapnia (PaCO2 30–34 mm Hg), normal values (PaCO2 35–44 mm Hg), mild hypercapnia (PaCO2 45–54 mm Hg), moderate hypercapnia (PaCO2 55–64 mm Hg), and severe hypercapnia (PaCO2 65 mm Hg or higher), as well as the percentage of ABG tests with a pH < 7.20. The mean PaCO2 and pH values were stratified by < 28 weeks gestational age and ≥ 28 weeks gestational age, and each group was analyzed with a Student t test with significance set at P < .05. The highest and the lowest PaCO2 values per subject over the first 72 h of life were identified and labeled PaCO2 maximum and PaCO2 minimum. Mean time-weighted PaCO2 was calculated as previously described by Fabres et al.17 The sum of all PaCO2 values were multiplied by the time interval from the previous blood gas divided by the overall time period. This method takes into consideration the time exposure for each PaCO2 value. We capped the time weighting to no more than 12 h per blood gas to reduce the possibility of any one ABG having an outsized effect. PaCO2 fluctuation was identified in 2 ways: by the standard deviation of the time weighted PaCO2 per subject, and by the difference between PaCO2 maximum and PaCO2 minimum (ΔPaCO2).

View this table:
Table 2.

Arterial Blood Gas Analysis of All Subjects vs Subjects < 28 Weeks Gestational Age

PaCO2 and other variables were compared for infants with and without each of 7 outcomes: any IVH, severe IVH (grade 3–4), BPD (defined as oxygen or mechanical ventilation at 36 weeks postmenstrual age), necrotizing enterocolitis, retinopathy of prematurity (ROP), pneumothorax, and the combined outcome of death and/or severe IVH. IVH was categorized according to Papile's grading system, and necrotizing enterocolitis was defined as modified Bells Stage IIa or greater. Severe ROP was defined as stage 3 or greater with “plus” disease. All of the ABG variables and the prenatal and postnatal variables collected as part of the original trial (Table 1) were analyzed with a Student t test and with univariate logistic regression. Those variables with P < .10 in the univariate analysis were retained to be examined in the stepwise logistic regression modeling.

Results

The 147 subjects included in the secondary analysis had a mean ± SD gestational age of 28 ± 2 weeks and a mean ± SD birthweight of 1,206 ± 394 g (Table 1). A total of 1,316 ABG samples (9.3 ± 4.9 samples per subject) were evaluated. Antenatal steroids, magnesium sulfate, chorioamnionitis, pregnancy-induced hypertension, maternal diabetes, premature rupture of the membranes, cesarean section, gender, and Apgar scores at 1 min were not significantly different between any of the outcome groups.

Of the total ABG samples, 10% had a pH < 7.20. The mean pH for the 48 subjects < 28 weeks gestational age was 7.26 ± .08 as compared to 7.27 ± .07 for the 99 subjects ≥ 28 weeks (P = .72). Infants with an outcome of death/severe IVH, severe IVH, and with any grade IVH had significantly lower values for minimum pH than those without the adverse outcomes (Table 3). There was a significant association between the minimum pH in subjects with the outcome of death/severe IVH that remained after adjusting for other variables (P = .003) (Table 3). There was no significant difference in the minimum pH in subjects who developed necrotizing enterocolitis, BPD, ROP, or pneumothorax.

View this table:
Table 3.

Univariate and Multivariate Logistic Regression Analysis of Arterial Blood Gas Variables to Predict Adverse Outcome

Less than 2% of all the PaCO2 values were < 30 mm Hg. Minimum PaCO2 was not significantly different for any of the outcomes, and none of the subjects included in this study were diagnosed with periventricular leukomalacia. Moderate hypercapnia of 55–64 mm Hg occurred in 13% of all samples, but in 18.5% of the samples of subjects < 28 weeks gestational age. PaCO2 ≥ 65 mm Hg occurred in 6.5% of all samples and in 8.2% of those < 28 weeks gestational age. Moderate levels of hypercapnia or higher were present in approximately 20–25% of the total samples and > 50% of those drawn during high-frequency ventilation (Table 2). PaCO2 values obtained without assisted respiratory support (nasal cannula ≤ 2 L/min or room air) were primarily in the normal range (35–45 mm Hg). Overall mean PaCO2 values obtained while on CPAP were lower and exhibited less fluctuation (smaller SD) than continuous mandatory ventilation and high-frequency ventilation. Table 2 provides the PaCO2 (mean ± SD) and the PaCO2 range by percent of the values for each category. The mean PaCO2 for subjects < 28 weeks gestational age was not significantly greater than subjects ≥ 28 weeks gestational age (P = .09). The mean PaCO2 on high-frequency ventilation was significantly greater than that on continuous mandatory ventilation (P < .001).

The multivariable models to predict the outcomes of interest included all parameters with P ≤ .10 in the univariate analysis (gestational age, birthweight, and 5-min Apgar score < 7) and confirmed the independent association of only gestational age.

Subjects with the outcome of death/severe IVH had a mean ± SD PaCO2 of 52.3 ± 11 as compared to a PaCO2 of 44.7 ± 5.8 (adjusted OR 1.16, 95% CI 1.04–1.29, P = .006) and a higher variability of PaCO2 as measured by the SD 12.6 ± 8.7 as opposed to 7.8 ± 4.5 (adjusted OR 1.15, 95% CI 1.03–1.27, P = .01) for those without the negative outcome (Table 3). Maximum PaCO2 for subjects with death/severe IVH and any IVH as well as time-weighted and PaCO2 fluctuations for subjects with any IVH were all significant with univariate analysis (Table 3) but were not significantly associated with those outcomes, after adjusting for the other variables in the model. There was no significant difference in any of the variables for those subjects who developed necrotizing enterocolitis, BPD, ROP, or pneumothorax in our cohort after adjusting for the other variables in the model.

Discussion

Permissive hypercapnia is a ventilation strategy widely used to minimize the iatrogenic lung injury that can occur with mechanical ventilation. It is theorized that the main benefits come from the avoidance of volutrauma with the lower VT values that can be utilized to maintain lower minute ventilation and a higher PaCO2.1 One of the possible advantages of a permissive hypercapnia strategy is the reduced incidence of hypocarbia and the avoidance of known hazards. Our study had a very low incidence of hypocarbia in our cohort (< 2% of all ABG samples had PaCO2 < 30 mm Hg), no cases of periventricular leukomalacia, and no adverse events associated with hypocarbia. In the past, many clinicians have attempted to keep PaCO2 < 40 mm Hg in ventilated neonates; this is, however, associated with an increased risk of developing BPD.17,18 An analysis of preterm infants < 29 weeks gestational age comparing PaCO2 levels during the first 96 h with the incidence of severe IVH, periventricular leukomalacia, and BPD demonstrated that infants whose PaCO2 fell below 30 mm Hg at any stage in the first 48 h of life had an increased risk of severe IVH or periventricular leukomalacia (OR 2.38, 95% CI 1.27–4.49, P = .007). Infants with at least 3 PaCO2 values < 30 mm Hg in the first 24 h of life had an increased risk of BPD (OR 2.21, 95% CI 1.05–4.57, P = .036).13 Our cohort's low incidence of hypocapnia and the absence of periventricular leukomalacia or other associated adverse events may be a direct result of routine targeting of higher than normal PaCO2 goals.19–21

Early randomized, controlled trials testing mild permissive hypercapnia in neonates found reduced ventilator days or ventilator dependence at 36 week corrected gestational age, although these differences did not reach statistical significance. There was also not a significant reduction in BPD rates with a mild hypercapnia strategy, but neither was there an increase in adverse neurologic events. The study by Mariani et al4 had PaCO2 goals of 45–55 mm Hg, but actual PaCO2 values in the permissive hypercapnia group were primarily 45–50 mm Hg. Carlo et al5 had PaCO2 goals of > 52 mm Hg, but actual PaCO2 values in the permissive hypercapnia group were primarily 45–50 mm Hg for the first 7 postnatal days. These 2 studies may be a reflection of possible neurologic safety of permissive hypercapnia of 45–50 mm Hg but not 50–55 mm Hg. In our cohort, 26.5% of all PaCO2 values fell in the mild hypercapnia range of 45–55 mm Hg. There was no statistical difference in any of the PaCO2 parameters between our subjects with BPD or pneumothorax and those without the adverse event after adjustment for gestational age. In a meta-analysis, permissive hypercapnia did not reduce the rate of BPD or air leaks in ventilated, extremely low birthweight infants.14

Vannucci et al22 postulated a neuroprotective effect of CO2 in preterm rats and that PaCO2 of 45–55 mm Hg offered significant neuroprotection. Possible explanations include a shift of the oxygen–hemoglobin dissociation curve to the right, resulting in increased delivery of O2 and increased cerebral blood flow preventing cerebral ischemia.13 Hypercapnic cerebral vasodilation can also cause an increase in cerebral blood flow that may contribute to the development of IVH.8 The most potent acute regulator of cerebral blood flow is PaCO2, and it can have more impact than increases in mean blood pressure.10,23 Cerebral autoregulation must be intact to maintain steady blood flow to the brain despite disturbances to cerebral perfusion pressure that can occur with critically ill neonates.8,23 Kaiser et al.8 investigated the effects that PaCO2 levels of 30–60 mm Hg and mean blood pressure have on cerebral autoregulation. Cerebral blood flow was not influenced by mean blood pressure when cerebral autoregulation was intact, but a progressive loss of autoregulation was found with increasing PaCO2, starting with PaCO2 ≥ 45. The autoregulatory slope increased with increasing PaCO2, which raises concerns about the use of permissive hypercapnia.8 Noori et al24 examined the effect of CO2 on cerebral blood flow in the first 3 postnatal days for neonates ≤ 30 weeks gestational age. They found the relationship was absent on day one, but a threshold existed on day 2 (52.7 mm Hg) and day 3 (51.0 mm Hg), at which point cerebral blood flow became reactive to PaCO2. The authors theorized that the enhanced cerebral blood flow response to PaCO2 contributes to the reperfusion injury and partly explains the association between hypercapnia and periventricular or intraventricular hemorrhage.24 We found a mean PaCO2 of 52.3 ± 11 mm Hg to be associated with the outcome of death/severe IVH (OR 1.16, 95% CI 1.04–1.29, P = .006). Severe hypercapnia (defined by Kaiser et al25 as a percentage of PaCO2 values ≥ 60 mm Hg, P = .009) has been associated with an increased risk of IVH, and most infants experience the IVH in the first week of life when PaCO2 levels may have been a factor. A causal relationship cannot be confirmed, however, because it is unclear whether hypercapnia precedes IVH or is a result of IVH.25

In neonates without intact cerebral autoregulation, the variability of PaCO2 may also be an important contributor to neurologic adverse events.8,17,23 In our cohort, subjects who exhibited fluctuations of the PaCO2 as represented by the SD were more likely to experience the adverse event of death/severe IVH (OR 1.15, 95% CI 1.03–1.27, P = .01). Infants evaluated as a secondary analysis of the SUPPORT trial26 also demonstrated that greater fluctuation in PaCO2 was significantly associated with IVH and neurodevelopmental impairment at 18–22 months corrected age and an independent predictor of worse outcomes for extremely low birthweight infants.

Almost 20% of our total ABG samples had PaCO2 values 55 mm Hg. Because our study is a retrospective cohort, subjects had similar ABG management, and we were thus unable to identify a possible positive association between higher PaCO2 and pulmonary adverse outcomes and necrotizing enterocolitis in our cohort. For subjects receiving high-frequency ventilation, 90% of the samples could be categorized as permissive hypercapnia > 45 mm Hg, and > 50% were in the moderate to severe range of > 55 mm Hg. It is possible that there is little pulmonary benefit to a permissive hypercapnia strategy in this mode of ventilation, because they are already receiving a low VT strategy and there may be in fact a neurologic risk at this level of PaCO2. Because high-frequency ventilation is often used as a rescue therapy or for active air leak, it is difficult to identify whether extremes of PaCO2 were due to extensive lung disease or to physician choice to allow permissive hypercapnia.

Acidosis may be an independent predictor of poor outcome or merely a reflection of the corresponding levels of CO2.6 Because the conditions are intertwined, it is difficult to separate their effects. The mean pH was more acidotic in samples taken during high-frequency ventilation as compared to conventional ventilation (P < .001), although the high-frequency ventilation samples also had higher levels of permissive hypercapnia. There was a significant association with minimum pH in the adjusted odds ratio for the outcome death/severe IVH (OR 0, 95% CI 0–0.06, P = .003). There was no significant difference in the minimum pH in subjects that developed necrotizing enterocolitis, BPD, ROP, or pneumothorax.

Our study cohort is a sample from a single institution and may not be generalizable to other populations. Higher PaCO2 levels may be correlated with a greater magnitude of lung disease or physician intent to allow permissive hypercapnia. Only 5 subjects in our cohort had severe IVH, and they were all < 28 weeks gestational age. A larger sample size with more immature infants may have yielded different results. The ventilation strategies and clinical course after the first 72 h are also likely to have a considerable effect on the risk of morbidities.

Conclusion

Moderate to high levels of hypercapnia were commonplace in our cohort. The low incidence of hypocapnia and the absence of periventricular leukomalacia or other associated adverse events may be a direct result of routine targeting of higher than normal PaCO2 goals. There was no significant difference in any of the pH or PaCO2 variables for those subjects who developed necrotizing enterocolitis, BPD, ROP, or pneumothorax. There was a significant association between the minimum pH, time-weighted mean PaCO2, and the fluctuations of PaCO2 in subjects with death/severe IVH. Although mild hypercapnia appears safe, moderate hypercapnia may increase neurologic risk and provide little pulmonary benefit.

Acknowledgments

The authors would like to thank the outstanding respiratory therapists and neonatal nurses of Sharp Mary Birch Hospital for Women and Newborns, whose efforts were essential to make this research possible.

Footnotes

  • Correspondence: Melissa K Brown RRT RRT-NPS, Neonatal Research Institute at Sharp Mary Birch Hospital for Women and Newborns, 3003 Health Center Drive, San Diego, CA 92123. E-mail: melissa.brown{at}sharp.com.

  • Ms Brown presented a version of this paper at the AARC International Congress, held October 15–18, 2016, in San Antonio, Texas.

  • Mr Rich discloses a relationship with Windtree Therapeutics. The other authors have disclosed no conflicts of interest.

  • See the Related Editorial on Page 1070

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