High-Intensity Noninvasive Ventilation May Reduce COPD Intubation

Among hospitalized COPD patients with persistent elevated blood carbon dioxide levels, treatment with high-intensity noninvasive positive pressure ventilation (NPPV) appeared to reduce the need for endotracheal intubation in the randomized HAPPEN clinical trial from China.

Following a 6 hour trial of low-intensity NPPV, 4.8% of patients moved to the high-intensity NPPV arm of the trial (tidal volume of 10-15 mL/kg of predicted body weight) met the prespecified criteria for needing endotracheal intubation, compared to 13.7% of patients continued on low-intensity NPPV (tidal volume of 6-10 mL/kg).

Between-group intubation rates were not significantly different, however, because low-intensity NPPV patients were allowed to cross over to the high-intensity group. High-intensity NPPV also resulted in more abdominal distention, but was not associated with a higher rate of removal from NPPV.

The study findings, published online Sept. 16 in JAMA, suggest a role for high-intensity NPPV in the treatment of COPD exacerbation and persistent hypercapnia, wrote researchers Zhixin Cao, MD, of Capital Medical University, Beijing, and colleagues.

In an accompanying editorial, Wolfram Windisch, MD, of Cologne Merheim Hospital, Cologne, Germany, and colleagues, wrote that the study provides "evidence for the first time that noninvasive ventilation techniques are successful in patients with persistent hypercapnia and COPD."

"The study also clearly demonstrates that different ventilator settings affect both physiology and outcomes," Windisch et al. wrote. "Although the overall role of noninvasive ventilation in patients with a COPD exacerbation with respiratory acidosis is undisputed, the current study…opens a discussion on the primary physiological goal of acute noninvasive ventilation and on how to best titrate ventilator settings in acutely ill patients with COPD and an evidence-based indication for noninvasive ventilation."

The HAPPEN trial was conducted at 30 Chinese hospital general respiratory, non–intensive care units from early January 2019, through January 2022, with the last 90-day follow-up occurring on April 22, 2022.

All hospitalized patients included in the study had COPD and PaCO 2 level greater than 45 mm Hg after receiving 6 hours of low-intensity NPPV.

In all, 147 patients were randomized to high-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume 10 mL/kg to 15 mL/kg of predicted body weight and 153 were initially randomized to continued low-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume of 6 mL/kg to 10 mL/kg of predicted body weight.

The mean age of the patients was 73 years, and 68% were men. Mean FEV1 at baseline was 36% predicted (n=243), and 86% of the patients were using long-acting inhaled bronchodilators and 79% were using inhaled corticosteroids.

Among the high-intensity group, 27 patients (18%) could not complete the bedside pulmonary function test due to dyspnea and 4 (3%) declined to participate, compared to 16% and 1%, respectively, in the low-intensity group.

Patients in the low-intensity NPPV group who met the prespecified criteria for the need for endotracheal intubation were allowed to crossover to high-intensity NPPV.

Need for endotracheal intubation, defined by prespecified criteria (arterial pH level of <7.25 Paco₂ having increased by 20% or more versus the baseline level or a ratio of Paco₂ to fraction of inspired oxygen <100 mm Hg and the presence of ≥ critical clinical sign). Fifteen prespecified secondary outcomes were also examined.

The trial was terminated by the data and safety monitoring board and trial steering committee after an interim analysis of the first 300 patients. All 300 patients were included in the analysis.

Among the main findings, the study authors wrote:

• "The primary outcome of meeting prespecified criteria for the need for endotracheal intubation occurred in 7 of 147 patients (4.8%) in the high-intensity NPPV group versus 21 of 153 (13.7%) in the low-intensity NPPV group (absolute difference, −9.0% [95%CI, −15.4%to −2.5%], 1-sided P = .004).
• "However, rates of endotracheal intubation did not significantly differ between groups (3.4%[5/147] in the high-intensity NPPV group versus 3.9% [6/153] in the low-intensity NPPV group; absolute difference, −0.5%[95%CI, −4.8%to 3.7%], P = .81).
• "Abdominal distension occurred more frequently in the high-intensity NPPV group (37.4%[55/147]) compared with the low-intensity NPPV group (25.5%[39/153])."

Study strengths included "large size, multi-center design, sealed randomization, clear enrollment criteria well-defined protocol, and strict criteria for defining the need for endotracheal intubation with external validation by 3 independent experts blinded to the intervention," the researchers wrote.

The premature termination was a study limitation, prompted by the determination of "a substantial and statistically significant (between-group) difference" in the primary outcome of need for endotracheal intubation, along with challenges associated with conducting the study during the Covid-19 pandemic.

In their editorial, Windisch and colleagues asked the question "Should all patients with an exacerbation of COPD receive high-intensity noninvasive ventilation?" and their answer was, "Probably not."

They noted that since all patients in the study had received low-intensity mask ventilation prior to receiving high-intensity NPPV, "it remains unclear if high-intensity NPPV would have been successful and comparably well tolerated if patients had never received NPPV."

They concluded that the study results "cannot be assumed to apply to patients with more severe respiratory distress, particularly those who are likely to develop dynamic hyperinflation."

"Nevertheless, this study clearly broadens the view on potential treatment strategies in patients with an exacerbation of COPD and respiratory acidosis," they wrote. "These results should also encourage the international research community to further investigate and confirm the effect of reducing Paco₂ level on both physiological and clinical outcomes in patients with an exacerbation of COPD receiving high-intensity NPPV."

Funding for this trial was provided by the Beijing Hospitals Authority Youth Program. The researchers reported no relevant disclosures. Windisch reported receiving grants from Löwentein Medical Open, GCE, and Great Britain Open and receiving personal fees from Boehringer Ingelheim, Novartis, Chiesi, BioNTech, AstraZeneca, and Sentec.

Luo Z, et al "Effect of high-intensity vs low-intensity noninvasive positive pressure ventilation on the need for endotracheal intubation in patients with an acute exacerbation of chronic obstructive pulmonary disease: the HAPPEN randomized clinical trial" JAMA 2024; DOI: 10.1001/jama.2024.15815.

Windsch W, et al "Noninvasive ventilation in COPD - pressure matters" JAMA 2024; DOI: 10.1001/jama.2024.0811.