Articles
Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial

https://doi.org/10.1016/S2213-2600(15)00204-0Get rights and content

Summary

Background

Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.

Methods

In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23–28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55–65 mm Hg on postnatal days 1–3, 60–70 mm Hg on days 4–6, and 65–75 mm Hg on days 7–14, and the control target at pCO2 40–50 mmHg on days 1–3, 45–55 mm Hg on days 4–6, and 50–60 mm Hg on days 7–14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.

Results

Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3–4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).

Interpretation

Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.

Funding

Deutsche Forschungsgemeinschaft.

Introduction

Extremely preterm infants who survive often develop bronchopulmonary dysplasia, which is characterised by severely impaired alveolarisation, which in turn results in a markedly reduced area for gas exchange.1 Infants with bronchopulmonary dysplasia often need long-term oxygen supplementation and frequent hospital re-admissions,2 with consequent high morbidity and health-care costs. Ventilator-induced lung injury is deemed one of the main pathogenic factors for the development of bronchopulmonary dysplasia and is mainly related to the magnitude of tidal volume.3, 4 Reduction of tidal volumes might result in alveolar hypoventilation with increased blood partial pressure of carbon dioxide (pCO2), which might be beneficial.5 The intentional reduction of the intensity of mechanical ventilation and allowing pCO2 values above 45 mmHg is referred to as permissive hypercapnia.

Increased respiratory drive through higher pCO2 has been used for decades to wean infants off mechanical ventilation. Early use of permissive hypercapnia in newborn preterm infants from the first day of life has been controversial, because it might increase cerebral perfusion, which can enhance oxygen delivery to the brain, but also increases the risk of intracranial haemorrhage.6 Furthermore, young rats have developed retinopathy when exposed to very high pCO2 values (roughly 100 mm Hg).7 Instead, because the susceptibility to ventilator-induced lung injury might be highest soon after birth,4 the reduction of tidal volumes with resultant permissive hypercapnia could be most beneficial when applied early.

Data from some retrospective analyses suggest an association between higher arterial pCO2 (PaCO2) values during the first days of life in preterm infants and a reduced incidence of bronchopulmonary dysplasia,8, 9 whereas others do not.10, 11 Furthermore, findings of a randomised trial12 comparing two different tidal volume settings in adults with acute respiratory distress syndrome showed increased survival and decreased morbidity in patients randomly assigned to the lower tidal volume, who also had higher PaCO2.

Research in context

Evidence before this study

Data from animal experiments suggested that permissive hypercapnia could be beneficial for subjects requiring mechanical ventilation because of lower tidal volumes and additional biochemical effects. We hypothesised that such benefits might also apply to preterm infants. We searchedPubMed from 1960 until 2014 for English language articles with the following search terms: “preterm infant”, “permissive hypercapnia”, and “minimal ventilation”. We also searched the reference lists of previous review articles. Several retrospective analyses were inconclusive. Three randomised trials were identified in which ventilator-dependent extremely low birthweight infants were allocated to different partial pressure of carbon dioxide (pCO2) targets. Two were small and monocentric and the third, the SAVE trial, was prematurely terminated for reasons unrelated to the mechanical ventilation. All three used different PCO2 targets and the pCO2 differences between the randomly allocated groups were small. None of the trials showed reduced incidence of bronchopulmonary dysplasia associated with permissive hypercapnia. One of the monocentric trials reported faster weaning off mechanical ventilation, the other, however, a worse neurodevelopmental outcome. Investigators of the SAVE trial reported a smaller number of infants requiring long-term mechanical ventilation beyond a postmenstrual age of 36 weeks. Results of a meta-analysis encompassing all three trials with 334 infants were calculated which showed trends but no significant differences between the results of different pCO2 targets. In another very large randomised trial, management differed between treatment groups in several aspects other than pCO2 target ranges.

Retrospective analyses also suggested an increased risk of intracranial haemorrhage that was not substantiated by the randomised trials. Animal experiments suggested an increased risk of retinopathy of prematurity associated with severe hypercapnia. Whether this risk also applied to human beings was unknown.

Added value of this study

With a sample size of 359, this multicentre trial did not show increased lung protection and improved outcomes associated with higher pCO2 targets, despite lower ventilator pressures. On the contrary, higher pCO2 targets were associated with an increased incidence of bronchopulmonary dysplasia or death in the subgroup of infants with the worst lung disease. Furthermore, there was an unexpected increased incidence of necrotising enterocolitis, but no increase in the incidence of intracranial haemorrhage or retinopathy of prematurity.

Implications of all available evidence

Mildly hypercapnic pCO2 targets as used in the control group of this trial and the hypercapnia group of the SAVE trial seem to be safe and are likely to be associated with small health benefits. Higher pCO2 targets as used in the high target group of this trial do not increase these benefits, and might cause harm.

Several trials have assessed how strategies to avoid mechanical ventilation can improve outcomes for preterm infants.13 For this approach to be successful, investigators need to accept higher than normal pCO2 values, but it is not clear whether lung protection is due more to the use of non-invasive support than to increased pCO2. In preterm infants already on mechanical ventilation, results of four previous randomised trials14, 15, 16, 17 of permissive hypercapnia and a meta-analysis18 did not show reduced incidences of bronchopulmonary dysplasia. However, two of these trials had small sample sizes,14, 15 and in the third with 220 infants, the PaCO2 difference between the groups was only 4 mm Hg.16 In the fourth trial, management differed between treatment groups in several aspects other than pCO2 target ranges.17 However, no significant increases in adverse events, especially the rate of intracranial haemorrhage, associated with permissive hypercapnia were reported, and some secondary analyses of the prematurely terminated SAVE trial17 suggest some beneficial effects.

In their efforts to improve outcome, many neonatologists have accepted permissive hypercapnia as their standard of care,19 despite the absence of clearly proven beneficial effects. Consideration has been given to even higher pCO2 targets as being of even greater benefit. Hence permissive hypercapnia has spread in today's neonatal intensive care without sufficient supporting evidence,20 with the optimum PaCO2 target range for ventilated preterm infants still to be established. This situation led us to do a large multicentre trial comparing two markedly different PaCO2 target ranges in extremely low birthweight infants. We aimed to study whether a higher pCO2 target range would reduce the rate of moderate to severe bronchopulmonary dysplasia 21 or death in extremely low birthweight infants needing mechanical ventilation. Furthermore, we aimed to find out whether hypercapnia would be most beneficial to the infants requiring the most ventilatory support.

Section snippets

Study design and patients

In this randomised multicentre trial, infants were recruited from 16 tertiary care perinatal centres in Germany (appendix p 11). All infants who weighed 1000 g or less at birth were screened. Inborn infants with a gestational age of 23–28 weeks plus 6 days, weighing 400–1000 g and receiving endotracheal intubation and mechanical ventilation within 24 h of birth were eligible. Exclusion criteria were birth outside the prenatal centre's delivery ward, chromosomal anomalies, congenital

Results

Between March 1, 2008, and July 31, 2012, we screened 1534 infants and recruited 362, 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), leaving 359 patients (179 in the high target group, 180 in the control group) for the intention-to-treat analysis (figure 1). Table 1 shows baseline demographic and clinical characteristics of the two groups.

The primary endpoint of

Discussion

The high pCO2 target did not reduce the primary outcome. Our results should be interpreted in view of the protocol specifications for this trial. Infants were only eligible when they needed endotracheal intubation and invasive mechanical ventilation because pCO2 control is very limited in non-intubated infants. In combination with increasing clinical efforts to avoid invasive mechanical ventilation altogether,17, 33, 34 eligible infants were only a minor fraction of the admitted extremely low

References (49)

  • JM Holmes et al.

    Carbon dioxide-induced retinopathy in the neonatal rat

    Curr Eye Res

    (1998)
  • JS Garland et al.

    Hypocarbia before surfactant therapy appears to increase bronchopulmonary dysplasia risk in infants with respiratory distress syndrome

    Arch Pediatr Adolesc Med

    (1995)
  • LJ Van Marter et al.

    Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network

    Pediatrics

    (2000)
  • S Subramanian et al.

    Association of bronchopulmonary dysplasia and hypercarbia in ventilated infants with birth weights of 500-1,499 g

    Matern Health J

    (2011)
  • Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome

    N Engl J Med

    (2000)
  • HS Fischer et al.

    Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis

    Pediatrics

    (2013)
  • G Mariani et al.

    Randomized trial of permissive hypercapnia in preterm infants

    Pediatrics

    (1999)
  • UH Thome et al.

    Outcome of extremely preterm infants randomised at birth to different PaCO2 targets during the first seven days of life

    Biol Neonate

    (2006)
  • WA Carlo et al.

    Minimal ventilation to prevent bronchopulmonary dysplasia in extremely low birthweight infants

    J Pediatr

    (2002)
  • NN Finer et al.

    Early CPAP versus surfactant in extremely preterm infants

    N Engl J Med

    (2010)
  • PG Woodgate et al.

    Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants

    Cochrane Database Syst Rev

    (2001)
  • F Hermeto et al.

    Implementation of a respiratory therapist-driven protocol for neonatal ventilation: impact on the premature population

    Pediatrics

    (2009)
  • AH Van Kaam et al.

    Incidence of hypo- and hyper-capnia in a cross-sectional European cohort of ventilated newborn infants

    Arch Dis Child Fetal Neonatal Ed

    (2013)
  • RA Ehrenkranz et al.

    Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia

    Pediatrics

    (2005)
  • Cited by (84)

    • Respiratory Distress Syndrome

      2023, Principles of Neonatology
    • Neonatal Respiratory Therapy

      2023, Avery's Diseases of the Newborn
    • Cardiovascular Compromise in the Newborn Infant

      2023, Avery's Diseases of the Newborn
    • Diagnosis and management of pulmonary hypertension in infants with bronchopulmonary dysplasia

      2022, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      There are no studies that clearly establish optimal oxygen saturation or carbon dioxide targets for infants with BPD-PH. Intermittent episodes of hypoxemia may result in impaired lung mechanics and pulmonary vasoconstriction [33]. In addition, though permissive hypercapnia is widely employed in the prevention of BPD, it is not clear if it is beneficial or even harmful in the ventilatory management for infants with BPD-PH [34]. In general, a diagnosis of cPHi in an infant with BPD raises concern for chronic respiratory insufficiency and may suggest the need to ensure the infant has adequate respiratory support to avoid intermittent hypoxemia and facilitate pulmonary growth.

    • Respiratory support of infants born at 22–24 weeks of gestational age

      2022, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      These observations indicate a compromised cerebral autoregulation in preterm infants during the first day of life and a need to reduce variability in pCO2 maintaining it within “normal” limits of 35–50 mmHg (4.7–6.7 kPa). The PHELBI-study randomized infants born at <29 weeks GA and in need of MV within the first day of life into 40–50 mmHg (5.3–6.7 kPa) or 55–65 mmHg (7.3–8.7 kPa) targeted pCO2 with a successive increase in pCO2 by 5 mmHg in both groups during a two-week period until reaching 50–60 or 65–75 mmHg (6.7–8.0 or 8.7–10 kPa), respectively [97]. No difference could be identified between the groups in rates of extubation, re-intubation or incidence of BPD [97].

    View all citing articles on Scopus

    Members listed in the appendix

    View full text