Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome.

Background Noninvasive ventilation (NIV) has been used in patients with the Middle East respiratory syndrome (MERS) with acute hypoxemic respiratory failure, but the effectiveness of this approach has not been studied. Methods Patients with MERS from 14 Saudi Arabian centers were included in this analysis. Patients who were initially managed with NIV were compared to patients who were managed only with invasive mechanical ventilation (invasive MV). Results Of 302 MERS critically ill patients, NIV was used initially in 105 (35%) patients, whereas 197 (65%) patients were only managed with invasive MV. Patients who were managed with NIV initially had lower baseline SOFA score and less extensive infiltrates on chest radiograph compared with patients managed with invasive MV. The vast majority (92.4%) of patients who were managed initially with NIV required intubation and invasive mechanical ventilation, and were more likely to require inhaled nitric oxide compared to those who were managed initially with invasive MV. ICU and hospital length of stay were similar between NIV patients and invasive MV patients. The use of NIV was not independently associated with 90‐day mortality (propensity score‐adjusted odds ratio 0.61, 95% CI [0.23, 1.60] P = 0.27). Conclusions In patients with MERS and acute hypoxemic respiratory failure, NIV failure was very high. The use of NIV was not associated with improved outcomes.


| INTRODUC TI ON
Middle East respiratory syndrome (MERS) has emerged as a cause of severe respiratory illness in humans. 1,2 As of March 1, 2019, 2279 cases of MERS have been reported including 806 deaths. 3 The disease presentation ranges from asymptomatic infection to severe respiratory illness, multiorgan failure, and death. [4][5][6] Acute hypoxemic respiratory failure (AHRF) develops in up to 70% of hospitalized patients with MERS and is associated with high mortality. 7,8 To date, there is no specific antiviral therapy for MERS of proven effectiveness; supportive therapy remains the cornerstone of management.
Noninvasive ventilation has been increasingly used in the management of AHRF with variable success. [9][10][11][12] While NIV may initially avoid the need for intubation and invasive mechanical ventilation (MV), several studies have reported high failure rates and the need for invasive ventilation among patients with severe acute respiratory distress syndrome (ARDS) and an association with increased mortality. 12 In a recent analysis from the LUNG SAFE study on unselected patients with ARDS, NIV was associated with higher intensive care unit (ICU) mortality in patients with the ratio of partial pressure of oxygen to the fraction of inspired oxygen (PaO 2 /FiO 2 ) lower than 150 mm Hg. 12 The role of NIV in AHRF secondary to viral respiratory infections is unclear. Although some uncontrolled studies suggested that NIV was effective and safe in management of patients with severe acute respiratory syndrome (SARS), [13][14][15] others have highlighted concern of increased transmission risk to healthcare workers when patients with SARS are treated with NIV. 16 Use of NIV in AHRF caused by pandemic H1N12009 virus (pdmH1N1) infection has been reported from several countries, [17][18][19] with reported NIV failure reaching up to 85%. 17 All studies were limited by their retrospective nature and, often, small sample size.
Noninvasive ventilation has been used in patients with MERS, 5,8 but its value in preventing intubation and impact on clinical outcomes has not been studied. The objective of this study was to assess the success of NIV in MERS patients with AHRF in avoiding intubation and its association with mortality and ICU and hospital length of stay. Our secondary objective was to identify factors associated with NIV failure in MERS patients.

| Study design and setting
We conducted this analysis on a multicenter retrospective cohort of critically ill MERS patients from 14

| Definitions
In this study, we included all patients with AHRF who required mechanical ventilation support in the ICU, whether invasively or noninvasively.
All patients who were managed initially with NIV were compared to those who were managed with invasive MV without NIV.

| Data collection
For this analysis, we extracted baseline data including demographics, comorbidities, duration from onset of symptoms to emergency room admission, ICU admission, and intubation. Arterial blood gases,

| Statistical analysis
Continuous variables were described as medians and interquartile ranges (Q1, Q3) or means and standard deviations and were tested We performed a secondary comparison of patients who had failed NIV to those who had been successfully treated with NIV. All statistical tests were two-sided with significance set at α < 0.05. Analyses were conducted using sas version 9.2 (SAS Institute, Cary, NC).

| Main interventions and outcomes
In 105 patients who were managed initially with NIV, NIV was used for a median duration of 1 (1, 3) day and 97 patients (92.4%) eventually required intubation and invasive MV (  [11,35], P = 0.6). There was no significant difference in the duration of invasive MV and total duration of NIV and invasive MV between the two groups, although invasive MV-free days and total NIV and invasive MV-free days were significantly longer among NIV patients compared to invasive MV patients (Table 2, Figure S2).

| Comparison of patients who failed NIV vs patients successfully treated only with NIV
Overall, only 8/105 (7.6%) of the NIV patients avoided subsequent intubation (Table S1). These patients were significantly younger than Tables S1 and S2). Crude 90-day mortality was significantly higher in patients who failed NIV compared with patients successfully treated only with NIV (Table S3 and Figure S3).

| D ISCUSS I ON
We have shown that among patients with MERS-related AHRF, NIV was commonly used, but nearly always resulted in subsequent transition to invasive ventilation. Our results suggest that while the initial NIV use in MERS patients was not associated with reduction of mortality or length of ICU or hospital stay, these patients had greater requirement for subsequent inhaled nitric oxide. A minority of patients were successfully managed with NIV-those who were young and had less severe disease. These findings have important implications for early management of patients infected with MERS, specifically, that there is little advantage to initial NIV treatment for most patients with MERS-related AHRF and that NIV may be associated with greater subsequent need for oxygenation rescue therapy such as inhaled nitric oxide.
Noninvasive ventilation has been proven to be useful as a means to avoid intubation and improve clinical outcomes in certain conditions, generally, with the possibility for rather rapid reversal of respiratory failure-for example, pulmonary edema due to congestive heart failure, and respiratory failure due to COPD exacerbations. 22,23 For conditions that typically worsen or do not improve in the range of many hours (eg, most causes of pneumonia), there appears to be little advantage in using NIV as a means to avoid intubation. 9,24,25 In choosing to use NIV for as initial treatment for patients with hypoxemic respiratory failure, there is a practical risk of patients worsening on NIV and requiring intubation at a time when they already have more advanced organ failure.
Few studies have assessed the effectiveness of NIV in patients with AHRF secondary to ARDS and acute lung injury. The overall effectiveness of NIV in reducing intubation rate or improving clinical outcome in these patients remains controversial. [26][27][28] Post hoc analysis of the LUNG SAFE study found that NIV was used in 15% of patients with ARDS and was associated with higher ICU mortality in subset of patients with severe ARDS. 12 A randomized controlled trial of patients NIV is generally not recommended for patients with hypoxia secondary to respiratory infections due to lack of efficacy and the potential for pathogen transmission. 16,31,32 It is also considered one of the aerosol-generating procedures that may increase risk of transmission to healthcare workers. 32 Broad dispersion of exhaled air during NIV via a face mask has previously been shown using a simulated patient encounter. 33  In conclusion, we report the results of NIV use in MERS patients from a large cohort of critically ill patients. We observed that there is little advantage to initial NIV treatment for most patients with MERS-related AHRF and that NIV may be associated with greater subsequent need for oxygen rescue therapy.

ACK N OWLED G EM ENT
We would like to thank the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) for their support in the database.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to disclose.

AUTH O R CO NTR I B UTI O N S
BMA: Conception and design, data acquisition, analytical plan, interpretation of data for the work, drafting of the manuscript, critical revi-