Thome UH, Genzel-Boroviczeny O, Bohnhorst B for the PHELBI Study Group, et al. Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Archives of Disease in Childhood – Fetal and Neonatal Edition 2017;102:F376-F382. PMID: 28087725
Pablo Lohmann, MD
Baylor College of Medicine
Clyde Wright, MD
University of Colorado Denver School of Medicine
(P) In infants born at gestational age between 23 0/7–28 6/7 weeks and birthweights between 400 and 1000 g birth who required endotracheal intubation and mechanical ventilation within 24 hours of birth, (I) is permissive hypercapnia (high PCO2) (C) compared to mildly elevated PCO2 targets (O) associated with worse neurodevelopmental outcomes as evaluated at (T) 2 years of corrected age?
- Design: Randomized multicenter trial.
- Allocation: Infants were randomly assigned (1:1) with a secure web-based randomization system. Randomization was done by a block randomization scheme with variable block sizes (2–6) stratified by site and birthweight (three strata: 400–499 g, 500–749 g, 750-1000 g).
- Blinding: Not feasible to mask caregivers and parents during trial. There is no description of blinding to evaluators at follow up.
- Follow-up Period: Initial study: Until death or at 36 weeks postmenstrual age. Neurodevelopmental follow up at 2 years +/- 3 months corrected age
- Setting: 16 tertiary care perinatal centers in Germany between March 1, 2008, and July 31, 2012.
- Patients: Follow up for patient initially enrolled in PHELBI
- Inclusion criteria: Birth weight between 400 g and 1000 g and gestational age 23+0 to 28+6 weeks, who needed endotracheal intubation and mechanical ventilation within 24 h of birth recruited in the period between March 1, 2008, and July 31, 2012.
- Exclusion criteria: neonates born outside the prenatal center’s delivery ward, chromosomal anomalies, congenital malformations requiring early surgery or otherwise compromising respiratory care or outcome, hydrops fetalis, air leaks before randomization, severe birth asphyxia, or a decision to provide compassionate care only.
- Intervention: Trial intervention was allocation to two distinct target PaCO₂ values, as described: Within 12 h of endotracheal intubation, infants were randomly assigned to either a high target or control group. The high target group aimed at PaCO₂ values of 55–65 mmHg (7.3-8.7 kPa) on postnatal days 1–3, 60– 70 mmHg (8.0-9.3 kPa) on days 4–6, and 65–75 mmHg (8.7-10 kPa) on days 7–14, and the control target at PaCO₂ 40–50 mmHg (5.3-6.7 kPa) on days 1–3, 45–55 mmHg (6.0-7.3 kPa) on days 4–6, and 50–60 mmHg (6.7-8.0 kPa) on days 7–14. Blood gases were to be measured at least every 12h, or more frequently if clinically indicated.
- Outcomes for initial PHELBI trial:
- Primary outcome: The composite of death or death or BPD before 36 weeks postmenstrual age according to the physiological definition of BPD—i.e., requiring mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age within ±2 days, including an oxygen reduction test for infants requiring less than 0.3 FiO₂ (BPD or death).
- Secondary outcomes: Severity of BPD, incidence and severity of intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC).
- Outcomes for Follow-up study (reported in this manuscript):
- Follow-up Study: Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) determined using Bayley Scales of Infant Development II (BSIDII) in validated German translation.
- Motor function by the modified Gross Motor Function Classification System (GMFCS)
- Child Development Inventory (CDI) questionnaire in its validated German translation.
- Blindness and deafness assessed by parent interviews.
- Statistical considerations: Statistical tests used were the χ2 test, Fisher’s exact test, Student’s t test and Mann-Whitney U test. Univariate logistic regression analyses were performed to identify possible risk factors associated with MDI<85, MDI<70, PDI<85 or PDI<70, neurodevelopmental impairment (NDI) or the end points mentioned combined with death. All analyses were performed on an intention-to-treat basis. A p value of <0.05 was considered to be statistically significant.
- Patients Included: The original trial had 359 patients randomized and included for the intention-to-treat analysis (180 in the control group, 179 in the high target group). During the course of the trial, 44 died (19 in control and 25 in high target group) and 315 completed the trial (161 control and 154 in high target group). There were four additional late deaths. One infant (control group with BPD) died 1 day after completing the trial, two others (1 high target, 1 control, both having BPD) died within the first year, and one infant, also high target, (without BPD per trial’s criteria), died at 2 years corrected age.
- Of the remaining 311 subjects, 46 were lost for reasons unknown and 265 participated in the follow-up evaluations. Attrition was 14% (22/152) in the intervention group and 15% (24/159) in the control arm. 233 had complete data for assessing neurodevelopmental impairment (NDI).The investigators propose that assuming that all lost infants were alive, the follow-up rate was at least 85% of survivors.
- There were no statistically significant differences in baseline demographic data and common important morbidities of premature birth between those followed-up and those lost to follow-up, as well as between both study groups. The rates of moderate-to-severe BPD and intraventricular hemorrhages were not significantly different. Weight at the time of discharge was also similar. More infants in the high target group had suffered from NEC, as described in the report of the main trial
The initial PHELBI trial was stopped prematurely after an interim analysis of 359 showing no benefit and a possible trend towards less BPD favoring the control rather than the high target group.
The study included 359 ELBW infants, all of whom were intubated in the first 24 h of life. In the main trial, PaCO₂ values were lower than intended in the high target group. This finding could be attributed either to the patient’s own respiratory drive, or to insuﬃcient adherence to the protocol by the clinicians. The PaCO₂ differences between groups however were statistically significant.
The results for the main trial showed that the combined outcome of BPD and death was not reduced by targeting hypercapnia. Although the differences in PaCO2 levels between groups were statistically significant, the achieved levels of PaCO2 in the intervention group were lower than the protocol intended, sometimes overlapping the control group targets. Furthermore, the authors could not identify a birthweight subgroup that might have beneﬁted from the high target. However, in infants with severe acute lung disease there were associations between those randomized to high target and the incidence of BPD or death [risk ratio (95% confidence intervals): 1·44 (1·01–2·04), p=0.04]. A similar association was found between NEC and the high target in infants with severe lung disease (p=0·06) and in infants with 500–749 g birthweight (p<0·01).
The incidence of intraventricular hemorrhage, retinopathy of prematurity, periventricular leukomalacia, hydrocephalus and air leaks was similar between both groups. Despite higher rate of NEC in infants in the high target group, weight gain was similar in both groups. The authors do not specify if the number of blood gases obtained differed in between PaCO2 target groups.
The follow up neurodevelopmental studies aimed to assess neurodevelopmental impairment, both by trained evaluators and parental interviews and questionnaires. There was no statistically significant difference in neurodevelopmental outcomes between infants allocated to a high target PaCO2 and a normal PaCO2.
The results for the assessed outcomes can be seen in this table (Table 3 from the referenced study).
|High target (n=130)||Control (n=135)||p Value|
|MDI*||82 (49–120, 122)||84 (49–118, 127)||0.79|
|MDI<85||67/122 (55)||64/127 (50)||0.47|
|MDI<70||37/122 (30)||41/127 (32)||0.74|
|PDI*||84 (49–114, 109)||84 (49–114, 117)||0.73|
|PDI<85||56/109 (51)||62/117 (53)||0.81|
|PDI<70||36/109 (33)||39/117 (33)||0.96|
|Total mortality by follow-up||27/179 (15)||21/180 (12)||0.34|
|Hearing impairment||8/127 (6)||5/132 (4)||0.35|
|Visual impairment||24/127 (19)||26/133 (20)||0.89|
|NDI (MDI<70 or PDI<70 or hearing impairment or visual impairment)||58/115 (50)||57/118 (48)||0.75|
|NDI or death||85/142 (60)||78/139 (56)||0.52|
|GMFCS level 0||64 (49)||69 (51)||0.23|
|GMFCS level 1||40 (31)||49 (36)|
|GMFCS level 2||13 (10)||4 (3)|
|GMFCS level 3||4 (3)||6 (4)|
|GMFCS level 4||7 (5)||6 (4)|
|GMFCS level 5||2 (2)||1 (1)|
|CDI score*||22 (1–50, 95)||23 (1–58, 88)||0.56|
|Percentiles for CDI scores†||5 (<2—>90)||10 (<2—>90)|
|Weight at follow-up (kg)*||10.5 (5·6–15.0, 122)||10.5 (7.0–17.2, 132)||0.84|
|Height at follow-up (cm)*||84 (66–96, 121)||85 (70–102, 132)||0.40|
|Head circumference (cm)*||47 (40–52, 123)||47 (43–50, 130)||0.54|
|Corrected age at follow-up (months)*||24 (18–28)||24 (19–31)||0.46|
Data are number of infants (%), χ2 test, *Median (minimum–maximum, n), Mann-Whitney U-test. †According to the standard sample: median (minimum–maximum).
CDI, Child Development Inventory; GMFCS, Gross Motor Function Classification System; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index.
Targeting a higher PaCO₂ did not decrease the rate of BPD or death in ventilated preterm infants and there were no significant differences in neurodevelopmental outcomes at 2 years. Permissive hypercapnia does not appear to confer any protection from severe lung disease or cause any adverse effect as a consequence. The risk factors for adverse neurodevelopment at follow-up remain in line with previous studies. In this study, higher PaCO2 levels seem to carry a potential risk of NEC.
Despite advances in ventilatory support, it is not clear what levels of PaCO2 are safe in extremely premature infants. Permissive hypercapnia is a strategy that tolerates higher levels of PaCO2 with the expectation to reduce ventilator‐induced lung injury. One potential downside of permissive hypercapnia is the association with intraventricular hemorrhages (IVH) and poor developmental outcomes (1, 2).
In the PHELBI trial (3) investigators studied the effects of permissive hypercapnia. Although the study had some limitations  and was stopped early due to no reduction in BPD or death, it remains a valuable study, showing that hypercapnia did not increase IVH or retinopathy of prematurity (ROP).
Investigators assessed neurodevelopment at 2 years corrected age on infants who participated in the original trial (4). Follow up evaluations were performed using German translations of accepted standard of care evaluation methods. Age and growth at the follow-up exams were similar and not suggestive of confounding effects. Neurodevelopment of infants that participated in follow-up assessment was comparable between PaCO2 target groups. Child’s development per CDI questionnaire, and cerebral palsy were evenly distributed, as well as rates of hearing or visual impairment.
This study is limited as the original trial was not designed for detecting neurodevelopmental differences at 2 years follow-up and the trial was stopped early after no evidence of treatment effect. Finally, 15% of infants were lost to follow-up (14% in High Target Group and 15% in Low Target Group) and 10% did not complete all follow-up examinations. Baseline characteristics of patients lost to follow-up and those who completed testing appeared similar, however it would be beneficial for interpretation to see the characteristics of those who did not complete testing. The authors acknowledge that there is no formal German validation for the BSIDII, though results obtained are similar to American infants. There was no blinding to study arm allocation in the original trial and masking of individuals involved in the neurodevelopmental follow up testing is not specified. Conclusions drawn from these data must be considered in light of these limitations.
Benefits of permissive hypercapnia, as defined by this trial, were not observed in the study findings. BPD is associated with adverse neurodevelopment (5) and optimal PaCO2 levels remain unclear. Observational studies have found that large fluctuations and higher than average PaCO2 increase risk (3, 6, 7), while a meta-analysis of randomized trials for permissive hypercapnia shows that morbidity and neurodevelopmental outcomes did not differ between PaCO2 target groups (8). The PHELBI trial did not identify the optimal target range of PaCO2 and data suggests that permissive hypercapnia does not grant lung protection in extremely low birth weight infants.
One should consider, that permissive hypercapnia as a strategy to decrease chronic lung disease is not supported by data from this randomized trial. However, based on the comparable neurologic development observed in the study, clinician angst is not warranted and aggressive ventilator adjustments should not be implemented in order to normalize PaCO2 in extremely premature patients who are otherwise clinically stable.
- 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: F145-9. PubMed PMID: 25425651. Pubmed Central PMCID: 4336211.
- 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: 217-21 e1. PubMed PMID: 19447409.
- 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: 534-43. PubMed PMID: 26088180.
- 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-F82. PubMed PMID: 28087725.
- 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: 1353-60. PubMed PMID: 16322158.
- Brown MK, Poeltler DM, Hassen KO, Lazarus DV, Brown VK, Stout JJ, et al. Incidence of Hypocapnia, Hypercapnia, and Acidosis and the Associated Risk of Adverse Events in Preterm Neonates. Respir Care 2018; 63: 943-9. PubMed PMID: 29615483.
- 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. PubMed PMID: 17272619.
- Ma J, Ye H. Effects of permissive hypercapnia on pulmonary and neurodevelopmental sequelae in extremely low birth weight infants: a meta-analysis. Springerplus 2016; 5: 764. PubMed PMID: 27386250. Pubmed Central PMCID: 4912505.