Editorial 

September 16, 2024

Noninvasive Ventilation in COPD—Pressure Matters

Wolfram Windisch, Sarah Bettina Stanzel, Christian Karagiannidis

JAMA. Published online September 16, 2024. doi:10.1001/jama.2024.0811

High-intensity noninvasive ventilation was first used more than 20 years ago in patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia.^1-3 High-intensity noninvasive ventilation aims to achieve normocapnia or to reduce elevated Paco₂ levels to the maximally achievable extent. For this purpose, the driving pressure, mainly achieved by modifying the inspiratory positive airway pressure, is individually titrated by a stepwise increase until normocapnia is established or the tolerated maximum pressure is reached (20-30 cm H₂O). This approach is in clear contrast to the classic approach of low-intensity noninvasive ventilation (<18 cm H₂O).⁴ Randomized crossover trials have established the physiological superiority of high-intensity vs low-intensity noninvasive ventilation in the chronic setting.^5,6

Subsequent randomized clinical trials have shown that high-intensity noninvasive ventilation is capable of improving 1-year survival in stable patients with hypercapnia and COPD,⁷ and in prolonging the time to readmission or death within 12 months in patients with persistent hypercapnia after an acute exacerbation of COPD.⁸ By contrast, former outcome studies have failed to establish clear benefits for low-intensity noninvasive ventilation.^4,9

In this issue of JAMA, Luo et al¹⁰ present their findings of a 30-center randomized clinical trial that included 300 patients and was conducted in China. High-intensity noninvasive positive pressure ventilation (NPPV) was compared with low-intensity NPPV for the first time in patients with an exacerbation of COPD and persistent hypercapnia (Paco₂ level >45 mm Hg) after a 6-hour trial of low-intensity NPPV.¹⁰ The need for endotracheal intubation during hospitalization after randomization served as the primary outcome (the need for endotracheal intubation was defined by prespecified criteria of arterial pH level <7.25 with Paco₂ level having increased by >20% vs the baseline level or a ratio of Pao₂ to fraction of inspired oxygen <100 mm Hg and the presence of ≥1 critical clinical sign).

Of 147 patients in the high-intensity NPPV group, 7 (4.8%) needed endotracheal intubation vs 21 of 153 patients (13.7%) in the low-intensity NPPV group (absolute difference, −9.0% [95% CI, −15.4% to −2.5%]; 1-sided P = .004); overall mortality was low in both groups. The between-group intubation rates did not significantly differ (3.4% of patients [5/147] in the high-intensity NPPV group vs 3.9% of patients [6/153] in the low-intensity NPPV group; absolute difference, −0.5% [95% CI, −4.8% to 3.7%]; P = .81), because crossover to high-intensity NPPV was allowed. A reduction in Paco₂ level occurred more rapidly and was more substantial during high-intensity NPPV, but also more frequently led to abdominal distension (37.4% of patients [55/147] in the high-intensity NPPV group vs 25.5% of patients [39/153] in the low-intensity NPPV group; absolute difference, 11.9% [95% CI, 1.5% to 22.4%]; P = .03). Despite this, severe intolerance to noninvasive ventilation because of abdominal distention or other safety outcomes did not significantly differ between the groups.

This study by Luo et al¹⁰ 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 outcome. Although the overall role of noninvasive ventilation in patients with a COPD exacerbation with respiratory acidosis is undisputed,¹¹ the current study by Luo et al¹⁰ 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.

A critique of the study by Luo et al¹⁰ might be that the predefined criteria for the need for intubation did not translate to actual intubation rates, because not all patients who met these prespecified criteria were eventually intubated, and crossover to high-intensity NPPV was allowed in the low-intensity NPPV group. From a clinical perspective, the need to demonstrate clear benefits in outcomes, including actual intubation rate or mortality, is justified. Based on this, the true clinical effect of high-intensity NPPV may be less than that reflected by the between-group difference for the primary outcome of need for intubation.

A strength of this study¹⁰ is the thorough and detailed documentation of both physiological and clinical parameters throughout application of NPPV; most of the 2-, 6-, 24-, 48-, and 72-hour data from baseline are displayed and illustrated in Supplement 3 of the article. Importantly, improvements in both pH and Paco₂ levels were more substantial in the high-intensity NPPV group vs the low-intensity NPPV group and occurred 2 hours after randomization; this trend remained statistically significant over the 72-hour observation period.¹⁰ In addition, the use of accessory muscles and dyspnea were also reportedly in favor of high-intensity NPPV vs low-intensity NPPV after 6 hours and 48 hours.¹⁰ Moreover, length of hospital stay after randomization was reduced by a median of 1 day (P = .08). In addition, patients spent more hours receiving high-intensity NPPV vs low-intensity NPPV (median of 20 hours vs 18 hours, respectively, on day 1; 18 hours vs 17 hours on day 2; and 17 hours vs 16 hours on day 3). Given these physiological and clinical advantages of high-intensity NPPV and the improved primary outcome, Luo et al¹⁰ have convincingly shown for the first time that pressure matters when noninvasive ventilation is used in patients with COPD in the acute setting.

Should all patients with an exacerbation of COPD receive high-intensity noninvasive ventilation? Probably not. Three major issues regarding the present findings need to be addressed. First, 19% of the patients in the high-intensity NPPV group had long-term noninvasive ventilation use prior to the study vs 21% of the patients in the low-intensity NPPV group, and 55% and 58%, respectively, of the patients had noninvasive ventilation use during previous hospitalizations. All patients included in the study by Luo et al¹⁰ received a 6-hour trial of low-intensity noninvasive ventilation prior to randomization. Therefore, 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.

Second, patients with COPD and acidemia requiring mechanical ventilation, and in particular those in whom intubation criteria are being monitored, are typically treated in the intensive care unit (ICU). In the study by Luo et al,¹⁰ patients had been treated on non-ICU wards, and it remains to be elucidated if the results are transferrable to non-ICU conditions in other countries or to the ICU setting in general.

Third, patients had acute respiratory deteriorations with respiratory acidosis, but this was apparently superimposed on substantial preexisting chronic hypercapnia. This is evidenced by relatively high mean baseline Paco₂levels of 79 mm Hg in both groups in view of rather mild respiratory acidosis (mean pH level of 7.31 in both groups) with substantial metabolic compensation of respiratory acidosis (mean bicarbonate level of 38 mm Hg in the high-intensity NPPV group and 39 mm Hg in the low-intensity NPPV group). The mean respiratory rates at baseline were 22 breaths/min in both groups. This is in clear contrast to most of the trials that have established the evidence for noninvasive ventilation using the classic approach.¹¹ For example, in the seminal paper by Brochard et al,¹² the mean baseline respiratory rate was 33 breaths/min both in the treatment (noninvasive ventilation) and in the standard group, and hypercapnia was less severe despite more severe acidemia. Such patients are more likely to develop dynamic hyperinflation with more aggressive forms of noninvasive ventilation compared with the patients in the study by Luo et al.¹⁰

Clinicians will recognize that there is no strict separation between acute and chronic hypercapnia in patients with COPD. Acute to chronic respiratory failure with hypercapnia has the potential to present with different degrees of acuity, ranging from predominantly acute to predominantly chronic. Based on the study by Luo et al,¹⁰ switching to high-intensity NPPV may be superior to continuing low-intensity NPPV in patients with an exacerbation of COPD and persistent hypercapnia despite 6 hours of low-intensity noninvasive ventilation; however, this 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.

The results reported by Luo et al¹⁰ 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. 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.