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Early relapse during B lymphocyte depletion of children with frequently relapse steroid dependent nephrotic syndrome after rituximab treatment1 Topic1 Quiz
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Prophylactic hydrocortisone and the risk of sepsis in neonates born extremely preterm1 Topic1 Quiz
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Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants A Randomized Trial1 Topic1 Quiz
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PACULit Daily Literature Update: Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants A Randomized Trial
Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants A Randomized Trial
Late Permissive Hypercapnia for Mechanically Ventilated Preterm Infants A Randomized Trial
Travers CP, Gentle SJ, Shukla VV, Aban I, Yee AJ, Armstead KM, Benz RL, Laney D, Ambalavanan N, Carlo WA. Pediatr Pulmonol. 2025 Jun;60(6):e71165. doi:10.1002/ppul.71165. PMID: 40525736.
Introduction
Premature infants requiring mechanical ventilation frequently develop respiratory distress syndrome with significant morbidity, including bronchopulmonary dysplasia (BPD). Permissive hypercapnia, the strategy of allowing higher carbon dioxide levels to reduce lung injury, has been studied predominantly early after birth. However, the impact of later initiation of permissive hypercapnia remains unclear. This randomized clinical trial investigates whether targeting higher levels of pH-controlled permissive hypercapnia beginning between postnatal days 7 to 14 can reduce the duration of mechanical ventilation and improve respiratory outcomes in preterm infants.
The study’s findings are important given the delicate balance between ventilator management to avoid lung injury and the risks of elevated carbon dioxide in this vulnerable population. Understanding impacts on survival, ventilator-free days, and BPD incidence informs neonatal intensive care practice.
Study Overview
Study Type: Single-center randomized clinical trial with 1:1 parallel allocation
Population: 130 mechanically ventilated preterm infants (22 to 36 weeks gestation) with respiratory distress syndrome between postnatal days 7-14
Intervention: Targeting higher pH-controlled permissive hypercapnia (PCO2 60–75 mmHg, pH ≥ 7.20) vs Lower pH-controlled permissive hypercapnia (PCO2 40–55 mmHg, pH ≥ 7.25)
Duration: 28 days post-randomization
Primary Outcome: Days alive and ventilator-free over 28 days after randomization
Key Findings
- Mean gestational age: 24 weeks 5 days; mean birth weight: 657 grams ± 198
- Higher permissive hypercapnia group had significantly more ventilator-free days (11 ± 10) than lower group (6 ± 8); p = 0.009
- Mean PCO2 during study: 55 ± 10 mmHg (higher group) vs 52 ± 8 mmHg (lower group)
- Incidence of Grade 2–3 BPD or death: 44% (30/62) in higher group vs 59% (45/68) in lower group (adjusted OR 0.54; 95% CI 0.27–1.08; p = 0.08)
- Among survivors at 36 weeks PMA, Grade 2–3 BPD occurred in 35% (19/53) in higher group vs 50% (28/53) in lower group (adjusted OR 0.56; 95% CI 0.27–1.13; p = 0.12)
- Suggests a trend favoring lung protection, though statistical significance for morbidity outcomes not achieved
Evidence Synthesis & Clinical Context
The primary evidence for late permissive hypercapnia in mechanically ventilated preterm infants derives from this robust single-center randomized clinical trial. It demonstrates a meaningful increase in ventilator-free days, aligning with earlier pilot data supporting feasibility and safety.
Key Related Studies
- Travers et al., 2023 (Pilot Trial): Established feasibility and respiratory stability with late permissive hypercapnia among very preterm infants (PMID: 36914233).
- Thome et al., 2015 (Multicenter RCT on Early Permissive Hypercapnia): Found no significant benefit on BPD or death composite outcome, highlighting differences in timing and clinical decision-making (PMID: 26088180).
- Ozawa et al., 2022 (Systematic Review): Confirmed inconsistent benefits across multiple permissive hypercapnia studies, underscoring importance of this trial’s novel positive findings (PMID: 35945674).
- Gentner et al., 2017: Mechanistic data showed reduced inflammatory mediators in tracheal aspirates, supporting biological plausibility for lung protection (PMID: 29209598).
- Reiterer et al., 2017: Reviews emphasizing the role of lung-protective ventilation strategies contextualize this approach within current neonatal respiratory care standards (PMID: 27876355).
- Wong et al., 2022: Outline safe neonatal CO2 parameters reinforcing cautious application of permissive hypercapnia (PMID: 34230621).
- Thome et al., 2018 (Exploratory Analysis): Raised awareness that elevated PCO2 may correlate with illness severity, informing risk assessment (PMID: 29298438).
- Ou et al., 2014 (Follow-up Imaging): Suggests necessity for long-term neurodevelopmental outcomes evaluation after hypercapnia ventilation (PMID: 24671721).
Integration and Summary
The novel randomized trial extends the evidence base by demonstrating late permissive hypercapnia increases days alive and ventilator-free, an important clinical endpoint. While trends toward reduced BPD or mortality were noted, statistical significance was not met, necessitating larger trials. The biological rationale and safety data support cautious implementation with ongoing evaluation. This trial importantly informs neonatal ventilator management beyond early postnatal days, marking a paradigm shift in individualized respiratory support strategies.
Clinical Implications
- Targeting higher pH-controlled permissive hypercapnia starting from postnatal days 7–14 can increase ventilator-free days, potentially decreasing ventilator-associated lung injury risk.
- Though mortality and severe BPD rates were not significantly reduced, the trend toward lung protection indicates clinical potential requiring close monitoring.
- Clinicians should consider individualized ventilator management protocols integrating permissive hypercapnia with frequent blood gas measurements to optimize respiratory outcomes.
- Long-term neurodevelopmental follow-up is essential given uncertainties about prolonged hypercapnic exposure effects.
Strengths & Limitations
| Strengths | Limitations |
|---|---|
| Robust randomized clinical trial design with 1:1 parallel allocation | Single-center study may limit external generalizability |
| Well-defined inclusion criteria with narrow gestational range | Sample size insufficient for definitive conclusions on mortality/BPD differences |
| Detailed pH-controlled CO2 targeting with monitored ventilation parameters | Late enrollment after postnatal day 7 limits applicability to earlier or later phases |
| Careful protocol adherence with unblinded data after last enrollment reducing bias | Lack of long-term neurodevelopmental outcome data to assess safety comprehensively |
Future Directions
Further multicenter randomized trials with larger cohorts are needed to validate benefits on mortality and BPD and elucidate long-term neurodevelopmental outcomes associated with late permissive hypercapnia. Investigations into optimal PCO2 ranges balancing lung protection and systemic risks remain a priority for advancing neonatal care.
Conclusion
Targeting higher pH-controlled permissive hypercapnia from postnatal day 7–14 significantly increases ventilator-free days in mechanically ventilated preterm infants and may confer lung protection compared to lower PCO2 targets.
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