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High-intensity noninvasive positive pressure ventilation (NPPV) might have reduced need for endotracheal intubation for persistent hypercapnia during acute exacerbation of chronic obstructive pulmonary disease (COPD), the randomized HAPPEN trial from China showed.

NPPV adjusted to a tidal volume of 10-15 mL/kg of predicted body weight led to 4.8% of patients meeting prespecified criteria for endotracheal intubation compared with 13.7% of patients randomized to continuation of NPPV at a tidal volume of 6-10 mL/kg, reported researchers led by Zhixin Cao, MD, of Beijing Chao-Yang Hospital at Capital Medical University, in .

However, the prespecified secondary endpoint of undergoing endotracheal intubation didn't differ between groups (3.4% in the high-intensity group vs 3.9% in the low-intensity group, P=0.81), in part because the low-intensity NPPV group was allowed to cross over in the open-label trial.

Despite problems with the trial, it has "convincingly shown for the first time that pressure matters when noninvasive ventilation is used in patients with COPD in the acute setting," wrote Wolfram Windisch, MD, of Cologne Merheim Hospital at Witten/Herdecke University in Cologne, Germany, and colleagues in an .

Previous trials have shown that high-intensity NPPV may improve in stable patients with hypercapnia and COPD when added to home oxygen therapy, and may delay within 12 months compared with home oxygen therapy alone after an acute exacerbation of COPD.

"Should all patients with an exacerbation of COPD receive high-intensity noninvasive ventilation? Probably not," the editorialists argued, noting that the "result may only apply to patients who had prior noninvasive ventilation use and have chronic hypercapnia with acute respiratory decompensation that is less severe. In addition, more important clinical benefits (such as reductions in actual intubation rates or mortality) need to be demonstrated prior to recommending high-intensity noninvasive ventilation as the preferred modality in the acute setting."

Rather, Windisch's group concluded that further studies should confirm the effect of reducing partial pressure of carbon dioxide (PaCO₂) level on both physiological and clinical outcomes in patients with an exacerbation of COPD receiving high-intensity NPPV.

The HAPPEN trial enrolled 300 patients in 30 general respiratory non-intensive care unit (ICU) wards in hospitals across China before it was terminated at half the planned enrollment when an interim analysis showed efficacy in the face of slow recruitment and COVID-19 pandemic disruptions. The trial was conducted from January 2019 through January 2022.

Enrollment required an acute exacerbation of COPD, an arterial pH level of less than 7.35, and a PaCO₂ level greater than 45 mm Hg after 6 hours on low-intensity NPPV. Thus, the results can't be extrapolated to apply to patients with more severe respiratory distress, "particularly those who are likely to develop dynamic hyperinflation," the editorialists cautioned.

The participants' mean age was 73 years, and 68% were men. The mean forced expiratory volume in the first second of expiration (FEV1) was 36% predicted, 86% of patients were taking long-acting inhaled bronchodilators, and 79% were using inhaled corticosteroids. Smoking and long-term oxygen therapy use were similar between groups.

Among the secondary endpoints, high-intensity NPPV improved both pH and PaCO₂ levels more substantially compared with low-intensity NPPV. Use of accessory muscles and dyspnea also favored high-intensity NPPV after 6 hours and 48 hours. Length of hospital stay dropped by a median of 1 day, although this difference was not statistically significant.

As to why high intensity might be better for NPPV, the researchers suggested that it provides more support for inspiratory effort, greater pressure support, and a higher tidal volume, augmenting alveolar ventilation. The high-intensity version also required continuous NPPV, which increased median daily duration of NPPV over the first 3 days.

Reduced airway edema and restoration of the depressed response of central chemoreceptors to an increase in PaCO₂ levels could also be mechanisms, they noted.

"Among patients in the low-intensity group who met criteria for the need for endotracheal intubation and who crossed over to high-intensity NPPV, most had improvements in pH and PaCO₂ levels with increases in IPAP [inspiratory positive airway pressure] level and tidal volume, and 11 of 13 (85%) avoided endotracheal intubation," Cao and colleagues noted. "In this regard, the current trial could be interpreted as showing no difference between the patients starting with a strategy of low-intensity NPPV who were allowed crossover to high-intensity NPPV and the patients starting with high-intensity NPPV."

Notably, high-intensity NPPV resulted in more abdominal distention (37.4% vs 25.5%) and more intolerance of NPPV due to abdominal distention (3.4% vs 0.7%), but not more severe intolerance or removal from NPPV. Severe alkalosis (pH >7.55) was "mildly higher" in the high-intensity NPPV group as well (4.1% vs 0%), but other severe adverse events "were rare and similar between groups," the researchers noted.

Although the trial used strict criteria for defining the need for endotracheal intubation with external validation by three independent experts blinded to the intervention, Cao and colleagues cautioned that their "findings may not be generalizable to patients with evident emphysematous bullae and presence of restrictive ventilatory dysfunction (e.g., pulmonary consolidation) because these patients were excluded from this trial."

Further, the editorialists noted that "the majority of patients had already been acclimatized to mask ventilation as used for noninvasive ventilation prior to randomization, and it remains unclear if high-intensity NPPV would have been as successful and comparably well tolerated if patients had never received NPPV, which is typical for many clinical trials."

Also, the trial treated patients in non-ICU wards, whereas patients with "COPD and acidemia requiring mechanical ventilation, and in particular those in whom intubation criteria are being monitored, are typically treated in the ICU," they added. Thus, it "remains to be elucidated if the results are transferrable to non-ICU conditions in other countries or to the ICU setting in general."

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