Thome UH, Genzel-Boroviczeny O, Bohnhorst B, et al. Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. The Lancet Respiratory medicine 2015;3:534-43. PMID: 26088180
Hesham Abdel-Hady, MD, PhD
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital
Basma Shouman, MD, PhD
Department of Pediatrics/Neonatology, Mansoura University Children’s Hospital
TYPE OF INVESTIGATION
In mechanically ventilated, extremely low-birthweight infants (ELBW) with birthweight between 400 g and 1000 g and gestational age 23–28 weeks plus 6 days, does the use of higher target ranges for PaCo2 in the first 14 days of life versus lower target ranges for PaCO₂, was compared regarding the primary outcome of death or bronchopulmonarydysplasia (BPD) at 36 weeks of gestational 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.
- Follow-up period: Until death or at 36 weeks postmenstrual age.
- Setting: 16 tertiary care perinatal centers in Germany between March 1, 2008, and July 31, 2012.
- Inclusion criteria: Birth weight between 400 g and 1000 g and gestational age 23+0 –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: Within 12 h of endotracheal intubation, infants were randomly assigned to either a high target or control group. The high target group aimed at PaCO₂values 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 PaCO₂40–50 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.
- Primary outcome: The composite of death or death or BPD before 36 weeks postmenstrual age according to the physiological definition of BPD—ie, 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).1
- Secondary outcomes: Severity of BPD, incidence and severity of intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC).
- Analysis and Sample Size:
- Authors used estimates of a outcome rate was found of death or BPD incidence of 47%. They proposed a 20% relative reduction (from 50% to 40%) with a power of 80% and a significance level of 5%, using a two-sided group sequential test with two interim analyses, which required a sample size of 830 patients.
- Predefined secondary analyses were done by X2 tests, Student’s t tests, Mann-Whitney U tests, survival analyses, and, for repeated measures, linear mixed effects regression models. Subgroup analyses were done to test the hypothesis that hypercapnia is of most benefit to infants at the highest risk of poor outcomes, by analyzing interactions with log-linear Poisson regression with robust estimation of error variance.
- The predefined subgroups were infants in the three birthweight strata (400–499 g, 500–749 g, 750-1000 g; small for gestational age infants (defined as birthweight less than 10th percentile for the gestational age), and infants with more severe lung disease (FiO2 >0.4 or mean airway pressure >10 mbar for >4 h). Sex was added post hoc to the subgroup analyses. All analyses were done on an intention-to-treat basis. A p value < 0.05 was deemed significant.
- Early in 2012, the study design was changed from a three-stage group sequential design into a two-stage adaptive group sequential design with one interim analysis requested by the review board of the funding agency.
- Patient Follow-Up:
- Of 1534 infants screened, 362 were recruited, of whom three had to be excluded: two because parental consent was withdrawn and one after being mistakenly randomly assigned despite meeting an exclusion criterion (malformation).
- 359 patients were included (179 in the high target group, 180 in the control group) for the intention-to-treat analysis.
The trial was stopped prematurely after an interim analysis of 359 (23%) infants screened in 53 months due to:
- The interim analysis showed no beneﬁt, and a possible trend favoring the control rather than the high target group. This ﬁnding suggested that it was futile to continue recruitment because a beneﬁt to the high target group showing over the remainder of the trial had become extremely unlikely.
- Proving the opposite, a worse outcome in the high target group, would not change current standard of care.
- Ethical concerns were raised about the need to randomly assign hundreds of additional patients to achieve the original sample size with limited further scientiﬁc gain, whereas other multicenter trials poised to test important hypotheses were held back.
- Too many changes to clinical standards can confound trial results if patient recruitment exceeds more than 3–5 years.
The study included 359 ELBW infants, all of them were intubated in the first 24 h of life, the median age at intubation was 0 (0–22) h in the high target group and 0 (0–21) h in the low target group, 31.2% were intubated > 1 h of age, 96.7% received surfactant, 22.3% had PROM, 93.6% received methylxanthines.
Randomization and assignment to the randomized target range was completed within 12 h of endotracheal intubation, the lowest PaCO₂ within that time of 12 h – was not mentioned by the authors.
The PaCO₂ values were lower than intended in the high target group, which could be attributed either to the patient’s own respiratory drive, or to insuﬃcient adherence to the protocol by the clinicians.
The main results of the study are shown in table.
|High target group
|Low target group
|Gestational age (weeks)||25·6 ± 1·4||25·7 ± 1·3|
|Birthweight (g)||713 ± 156||709 ± 153|
|Moderate or severe BPD or death at 36 weeks’ PMA||65 (36%)||54 (30%)||0·18|
|Moderate or severe BPD||40 (22%)||35 (19%)||0·44|
|Mortality to 36 weeks’ PMA||25 (14%)||19 (11%)†||0·32|
|Death before day 28||22 (12%)||16 (9%)||0·29|
|IVH all grades||50 (28%)||55 (31%)||0·46|
|PVL||16 (9%)||11 (6%)||0·31|
|PIE||25 (14%)||32 (18%)||0·32|
|Pneumothorax||8 (5%)||13 (7%)||0·27|
|ROP||78 (47%)||78 (47%)||0·92|
|NEC ≥ grade 2||20 (12%)||8 (5%)||0·02|
Data are n (%) with χ2 test, median with Mann-Whiney U test (min–max), unless stated otherwise. †One additional patient with severe BPD died 1 day after completing 36 postmenstrual weeks.
PMA= postmenstrual age, BPD= bronchpumonary dysplasia, IVH= intraventricular hemorrhage, PVL= periventricular leukomalcia; PIE= pulmonary interstitial emphysema, ROP= retinopathy of prematurity, NEC= necrotizing enterocolitis.
- In the predeﬁned analyses, the authors did not identify a birthweight subgroup that might have beneﬁted from the high target.
- Subgroup analysis showed that in infants with severe lung disease there were associations between the incidence of BPD or death and high target in infants [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).
Targeting a higher PaCO₂ did not decrease the rate of BPD or death in ventilated preterm infants. The rates of mortality, IVH, and ROP did not differ between groups. These results suggest that higher PaCO₂ targets than in the slightly hypercapnic control group do not confer increased beneﬁts such as lung protection.
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Ventilator-induced lung injury is an important cause of morbidity in ELBW infants as it may lead to the development of BPD.2 Permissive hypercapnia is a ventilator strategy used to reduce ventilator-induced lung injury, by employing low tidal volumes and accepting PaCO₂ levels above “normal” to decrease the risks of volutrauma.3 Permissive hypercapnia is considered one of the potentially better practices to reduce BPD in very-low-birthweight infants.4 The potential benefits of permissive hypercapnia are not only related to the reduced lung stretch, but also to the biological effects of CO₂ in the lungs, brain, cardiovascular and immune system.5
The PHELBI study did not show that higher PaCO₂ targets reduce death or moderate to severe BPD associated, despite using lower ventilator pressures. However, it was stopped early and we are unable to make any firm conclusions. Another 3 small RCTs6-8 addressed the clinical benefits and safety of high PaCO₂ targets in mechanically ventilated preterm infants and demonstrated heterogeneous results, with only one study showing a trend for a reduction in BPD/death.7 An interesting finding in the PHELPI study is that higher PaCO₂ targets were associated with an increased incidence in the combined outcome of BPD or death and an increased incidence of NEC in the subgroup of infants with severe lung disease.
On the other hand, the PHELBI study demonstrated that hypercapnia did not increase the risks for IVH and ROP. Previous studies showed conflicting results regarding the effect of hypercapnia on the incidence of IVH in preterm infants; a retrospective study of 849 infants weighing <1250 g revealed that severe hypocapnia, severe hypercapnia, and wide fluctuations in PaCO₂were associated with an increased risk of IVH.9 Mariani et al. (1999)6 reported a non-significant increase in IVH in hypercapnic [45-55 mmHg(6.0-7.3 kPa)] compared to normocapnic infants [35-45 mmHg(4.7-6.0 KPa)], Carlo et al. (2002)7 observed a non-significant increase in IVH in infants managed with lower targeted PaCO₂< 48 mmHg (6.4 KPa) vs.>55 mmHg (7.3 KPa), and Thome et al. (2006)8 reported worse mental development in ELBW infants managed with higher targeted PaCO₂ [55–65 mmHg (7.3-8.7 KPa)] vs. [35–45 mmHg (4.7-6.0 KPa)]. Secondary exploratory data analysis of Surfactant, Positive Pressure, and oxygenation Randomized Trial (SUPPORT) revealed that higher PaCO₂ in the first 2 weeks of life was an independent predictor of severe IVH/death, BPD/death and NDI/death.10 Only animal studies reported increased incidence of ROP with hypercapnia .11
Thome et al. are to be congratulated for an important study. As well as being the largest study to examine the question, they made some important adjustments to prior study designs. They included only intubated ELBW infants (23 to 28 weeks gestation) thus they included infants with pronounced respiratory distress syndrome who are more likely to develop worse outcomes. Finally, the high PaCO₂target group was planned with much higher PaCO₂targets to increase the difference in PaCO₂ between the groups and the planned difference between groups was kept constant.
However, the findings of this study should be interpreted with caution, putting in consideration some limitations such as:
- This RCT was stopped prematurely after an interim analysis (n=359) thus reducing statistical power to answer the pertinent questions;
- The caregivers were not masked to group allocations;
- The PaCO₂ values were lower than intended in the high target group;
- Clinical decisions on choosing ventilator settings did not always follow the study protocol;
- The varying use of bicarbonate was not significantly different between the two study groups, but resulted in lower pH values in the high PaCO₂ target group which could have influenced lung repair mechanisms and intestinal function;
- No available data on: PaCO₂ fluctuations in this study, whether the recruited infants received standardized delivery room management or not and on use of low tidal volume ventilation or patient synchronized ventilation which might have more effect than PaCO₂ concentrations in the first day of life;
- The study design might have inadvertently affected the clinician’s decision to ventilate newborn babies to achieve the PaCO₂ targets during the study period, as after 14 days, 25% of infants were still ventilated;
- The limitations of subgroup analysis;
- and finally the long duration of recruitment of more than 4 years as clinical practice might have changed during this time especially with the increasing use of non-invasive means of respiratory support.12
Where do we go from here? Should the ELBW infant require mechanical ventilation, while it is difficult to define the optimal target range of PaCO₂, normocapnic or mildly hypercapnic PaCO₂ targets as used in the control group of the PHELBI study seem to be safe, whereas higher PaCO₂ targets do not lead to further beneﬁts; and may even be harmful. Further studies are required to define if therapeutic hypercapnia has a role in specific situations and decide what is the optimal target for PaCO₂ in mechanically ventilated ELBW infants. It is essential in such studies that long-term follow-up assessment is included so that the benefits/adverse effects can be appropriately identified.
- Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. Journal of perinatology : official journal of the California Perinatal Association 2003;23:451-6.
- Attar MA, Donn SM. Mechanisms of ventilator-induced lung injury in premature infants. Seminars in neonatology : SN 2002;7:353-60.
- Miller JD, Carlo WA. Safety and effectiveness of permissive hypercapnia in the preterm infant. Current opinion in pediatrics 2007;19:142-4.
- Payne NR, LaCorte M, Sun S, Karna P, Lewis-Hunstiger M, Goldsmith JP. Evaluation and development of potentially better practices to reduce bronchopulmonary dysplasia in very low birth weight infants. Pediatrics 2006;118 Suppl 2:S65-72.
- Silvestre C, Vyas H. Is permissive hypercapnia helpful or harmful? Paediatrics and Child Health;25:192-5.
- Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999;104:1082-8.
- Carlo WA, Stark AR, Wright LL, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr 2002;141:370-4.
- Thome UH, Carroll W, Wu TJ, et al. Outcome of extremely preterm infants randomized at birth to different PaCO2 targets during the first seven days of life. Biology of the neonate 2006;90:218-25.
- 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.
- Ambalavanan N, Carlo WA, Wrage LA, et al. PaCO2 in surfactant, positive pressure, and oxygenation randomised trial (SUPPORT). Arch Dis Child Fetal Neonatal Ed 2015;100:F145-9.
- Holmes JM, Zhang S, Leske DA, Lanier WL. Carbon dioxide-induced retinopathy in the neonatal rat. Current eye research 1998;17:608-16.
- Rabe H, Fernandez-Alvarez JR. Permissive hypercapnia in preterm infants: the discussion continues. The Lancet Respiratory medicine 2015;3:499-501.