Noninvasive Ventilation for Acute Asthma: The Neglected Sibling

Invasive mechanical ventilation (IMV) is lifesaving for patients suffering from acute respiratory failure but is not without drawbacks. The introduction of noninvasive ventilation (NIV) revolutionized the management of acutely ill patients with respiratory failure and, when implemented in the appropriate patient population, offers a lifesaving alternative to IMV. Like any medical intervention, however, improper use or patient selection can result in significant harm. Since its introduction, NIV has become standard of care for multiple indications supported by robust randomized controlled trials, although evidence for other indications remains less certain (1). When used in respiratory failure due to acute cardiogenic pulmonary edema, NIV can reduce both need for endotracheal intubation and mortality (2–4). For patients with respiratory failure due to an exacerbation of chronic obstructive pulmonary disease (COPD), NIV offloads fatiguing respiratory muscles resulting from bronchial obstruction and hyperinflation. Thus, a well-established evidence base has demonstrated its efficacy in preventing intubation and reducing mortality in these patients (5, 6).

Although asthma shares a similar pathophysiology to COPD, evidence supporting the use of NIV for acute asthma has remained limited. The few randomized controlled clinical trials have shown some improvement in physiologic markers but were underpowered for more meaningful clinical outcomes (7–9). Although a Cochrane systematic review of five small randomized controlled clinical trials evaluating the effect of NIV in acute asthma showed an improvement in pulmonary function, respiratory rate, and hospital admissions, the aggregate analysis remained underpowered for in-hospital mortality and endotracheal intubation (10). Consequently, the 2017 combined European Respiratory Society/American Thoracic Society clinical practice guidelines on NIV for acute respiratory failure were unable to provide a recommendation for or against the use of NIV in acute asthma (11).

Given the uncertainty of available evidence and lack of consensus guidelines, the use of NIV in acute asthma has remained controversial. Despite this, it has been widely adopted with increased use over the past two decades (12). What might explain such pervasive use of an intervention without proven clinical benefit in this patient population? Various theories have been put forth including an assumed benefit given the pathophysiologic similarities between asthma and COPD coupled with growing comfort and familiarity with NIV (13). Regardless of the reason, this increased usage has facilitated a growing literature of large-scale observational studies assessing the clinical outcomes of patients with acute asthma managed with NIV, which has largely suggested an association with improved outcomes (12, 14).

In this issue of the Journal, Althoff and colleagues (pp. 1520–1530) add to this growing body of observational evidence with a large retrospective cohort study of adult patients with acute asthma admitted to the ICU examining the association between NIV use, need for endotracheal intubation, and in-hospital mortality and exploring their temporal trends (15). The authors used three unique multivariate models to assess this association and found that NIV was associated with a reduction in endotracheal intubation (adjusted generalized estimating equation odds ratio, 0.36; 95% confidence interval, 0.32–0.40) and in-hospital mortality (odds ratio, 0.48; 95% confidence interval, 0.40–0.58) across all models. The study also found patients failing NIV were more likely to have acute comorbidities such as pneumonia, sepsis, and acute renal failure. Interestingly, although those who failed NIV had a higher mortality than the overall population, their mortality was still lower than that of patients receiving IMV alone.

The study by Althoff and colleagues has many strengths and includes the largest cohort of adult patients who received NIV for acute asthma to date. The authors conducted a robust analysis using multiple statistical models, all of which support their main findings. These findings, although novel, align with the currently available evidence base. Despite the aforementioned strengths, the study is not without its limitations, first and foremost being its retrospective nature precluding randomization. Although the authors used propensity score matching to minimize selection bias, the variables used to match controls on acuity of illness and severity of asthma (including prior IMV) were limited. Furthermore, temporality of comorbid conditions could not be assessed owing to reliance on diagnosis codes, and conditions associated with NIV failure (pneumonia, acute renal failure, and severe sepsis) may have occurred as a complication of IMV as opposed to being a risk factor for NIV failure. Lastly, and perhaps most importantly, despite a marked increase in the proportion of patients with acute asthma managed with NIV over the study years, there was no significant change in the proportion of patients who received IMV or died. This finding is similar to other published data showing increased NIV use without a decrease in IMV in acute asthma (12). Taken together, this observation suggests that NIV is likely being used in lower-risk patients with acute asthma who may not require ventilatory support of any kind. To explore this, the authors performed a subgroup analysis of patients with a primary diagnosis of respiratory failure, thought to be a more critically ill group, and found that increased NIV use in this subgroup was accompanied by a decrease in IMV. However, more patients may have received a primary diagnosis of respiratory failure as a result of receiving NIV itself as opposed to objective measures of severity of respiratory illness, confounding this finding.

What comes next in the story of NIV for acute asthma? In light of widespread adoption and mounting observational evidence, it is unlikely that randomized controlled trials powered to detect an improvement in meaningful clinical outcomes are on the horizon. Thus, acute asthma may remain a neglected sibling in the robust clinical trial evidence for the efficacy of NIV. However, based on the in-depth and large-scale data provided by Althoff and colleagues, NIV appears to be a safe and well-tolerated intervention, possibly even in those who ultimately require IMV. Whether NIV reduces the need for endotracheal intubation or mortality, however, remains far from certain. Future studies may aim to determine whether NIV is a viable and effective alternative to IMV for patients presenting with severe acute asthma requiring ventilatory support, as these patients stand to suffer the most harm from a gap in the evidence base.