Introduction
Acute respiratory distress syndrome (ARDS) mortality ranges from 35 to 46%. Mortality is related to the severity of ARDS and remains high despite improvement in recent years [
1]. Noninvasive positive-pressure ventilation (hereafter, noninvasive ventilation, NIV) reduces the need for endotracheal intubation and mortality among patients with acute respiratory failure [
2,
3], but its use in ARDS is uncertain [
4].
Previous studies often included a heterogeneous population of patients with ARDS caused by pulmonary infection, sepsis, acute pancreatitis, or multiple trauma; this selection of patients could lead to an overestimation of the beneficial effects of NIV as compared with standard oxygen therapy. Pneumonia is a major cause of pulmonary ARDS. In observational ARDS studies, the rate of treatment failure with NIV was as high as 50% [
5‐
7] and associated with particularly high mortality in pulmonary infection-induced ARDS [
8]. Currently, NIV use in ARDS remains highly controversial [
9‐
11], especially in pneumonia-induced ARDS.
Although more than half of mild ARDS cases (arterial oxygen tension/inspired oxygen fraction [PaO
2/FIO
2] ≤ 300 mmHg but > 200 mmHg) rapidly evolve to moderate or severe ARDS [
12], many of these patients may not require invasive mechanical ventilation with the lower severity of mild ARDS. Our pilot study [
13] suggests that NIV for patients with mild ARDS reduced the need for intubation and the number of organ failures compared with conventional administration of oxygen through a Venturi mask. In this study, NIV also reduced the need for intubation in pneumonia-induced mild ARDS (10% vs. 50%). However, because of the small sample size and the etiological heterogeneity of this study, the benefit of NIV versus oxygen in pneumonia-induced early mild ARDS needs confirmation in a trial with a large sample size and homogeneous population [
14].
We hypothesized that more severe hypoxemia and comorbidities are the primary causes of NIV failures in pulmonary infection-induced ARDS. We therefore designed a multicenter randomized controlled trial to test the hypothesis that initiating NIV during early mild ARDS induced by pneumonia could prevent patients from evolving to moderate/severe ARDS and decrease the need for invasive mechanical ventilation compared with oxygen only.
Discussion
To our knowledge, the present study is the first and largest randomized controlled trial to evaluate NIV for patients with early pneumonia-induced mild ARDS. The main strength of our study is its high homogeneity with only pneumonia-induced mild ARDS patients included. The major finding of our study revealed that, compared to the Venturi mask, NIV did not reduce the need for intubation or mortality in pneumonia-induced early mild ARDS.
The rate of the need for intubation is lower than expected in our study. This may reflect patients being included in a very early stage of mild ARDS. In a previous study, timing for NIV application was based on a simple three-component early acute lung injury score (1 point for oxygen requirement > 2–6 L/min or 2 points for > 6 L/min; 1 point each for a respiratory rate ≥ 30 and immune suppression [EALI score]). A score greater than or equal to 2 points identified patients who progressed to ALI and requiring NIV [
16].The average respiratory rate in our early mild ARDS patients was 25, which suggests that our patients may had a less severe ARDS than that in the EALI study. RR used as selection criteria is helpful for including patients with more severity, especially with our finding that high minute ventilation was associated with NIV failure. Unfortunately, RR was not used as an inclusion criterion in our study which may be a reason for a low intubation rate and mortality.
Different pneumonia pathogens may be another reason for a relatively low intubation rate in our study. Bacterial pneumonia has a high possibility to progress to sepsis and related severe lung injury [
17]. Another study [
2] of pneumonia-induced hypoxemic acute respiratory failure (hARF) patients supported with CPAP included both CAP and HAP, a positive culture in about 50%, indicating bacterial infection. However, in our study, most cases were CAP, and only 10–15% were culture positive, suggesting a lower proportion of bacterial pneumonia-induced respiratory failure in our patients. Therefore, the type of pneumonia and the likelihood of bacterial etiology may result in different rates of progression to more severe ARDS and more need for intubation.
The primary outcome analysis of our study showed no difference in the need for intubation between the NIV and control groups. This may reflect the lack of recruitment responsiveness to NIV positive airway pressure in early mild ARDS patients. A meta-analysis revealed that higher airway pressure levels were associated with improved survival among the subgroup of ARDS patients with PaO
2/FIO
2 less than 200 mmHg [
18], who demonstrate better recruitment with positive airway pressure. In our study, we included patients with a PaO
2/FIO
2 higher than 200 mmHg, who may be less responsive to NIV, leading to a negative result for NIV compared to conventional oxygen therapy. PaO
2/FIO
2 was significantly higher in the NIV group than in the control group at 2 h after inclusion, and this trend remained for the first 72 h, similar to previous studies [
13,
19]. However, despite an initial improvement of arterial hypoxemia, the use of NIV did not result in changes of the intubation rate nor outcome variables in our study. In a recent large trial of immunocompromised patients admitted to the ICU with hARF, early NIV also did not reduce the incidence of intubation or mortality compared with oxygen therapy alone [
20]. However, the median duration of NIV in this study was 8 h within the first 24 h, 6 h on day 2, and 5 h on day 3. This negative study therefore may represent insufficient support time for NIV therapy. In our study, average NIV duration was more than 16 h per day. Despite this support time dose, we did not show a positive effect on avoidance of intubation. Finally, the management of continue NIV in the NIV group or crossover to NIV in the control group after the patients met the intubation criteria may influence the final outcome such as mortality, length of ICU or hospital stay, or complications.
Such a long period of NIV support through a facial mask may affect the patient comfort. A recent study showing that an NIV helmet could reduce intubation in patients with ARDS [
21]. The comfort of patients with face mask was evaluated in our study with a previously reported method [
2,
22,
23], and only one patient ceased the NIV because of intolerance.
Our results indicate that a minute ventilation exceeding 11 L/min may be a predictor of NIV failure. A recent clinical trial suggests that NIV administered to patients with severe lung injury could increase ventilator-induced lung injury by generating tidal volumes that exceeded 9 mL per kilogram predicted body weight [
24,
25]. However, the VT/PBW was between 7.7 and 9.4 mL/kg in the present study. A low expired tidal volume is almost impossible to achieve in the majority of patients receiving NIV for acute hypoxemic respiratory failure. The high tidal volume resulting from the high respiratory drive in these patients may lead to lung injury and NIV failure [
26]. High tidal volume and minute ventilation were also found in NIV patients in LUNG SAFE study [
10]. And in FLORALI study, NIV did not result in significantly different intubation rates compared to standard oxygen in patients with non-hypercapnic hARF, and the intubation rate in NIV was even higher than standard oxygen. This study suggests that high flow humidified nasal cannula (HFNC) may be more beneficial than NIV or standard oxygen [
24]. This may also be explained by lung injury caused by high driving pressure during NIV. Based on our data, the parameter of MV should be monitored for a limitation of less than 11 L/min in early mild ARDS.
The differences in PaO
2/FIO
2 and minute ventilation between NIV failure and success patients, shown after 12 to 48 h of NIV application, are similar to a failure time of 1 to 48 h after NIV initiation reported by Ozyilmaz et al. [
27]. In the NIV group of our study, mean delay between inclusion and failure was almost 5 days, and longer than 2.6 days in the control group. At the intubation time point, the NIV group has a worse state than the control group with lower PaO
2/FiO
2 (120 mmHg vs. 147 mmHg) and higher RR, which may suggest a delay in intubation by use of NIV. Furthermore, we noticed that, during the first 2 to 12 h after inclusion, PaO
2/FiO
2 ratio did not improve, and with a high MV trend for patients in the NIV failure group compared to the success group. This may be an early predictor for NIV failure for the pneumonia-induced mild ARDS. And recently, a HACOR score was proposed for patients with NIV failure in hypoxic patients [
28]. HACOR score improves in patients with NIV success and remains unaltered in patients with NIV failure, which also emphasized the trend of the five predictors from the score is important for predicting NIV failure.
Severe pneumonia is frequently of acute onset, demonstrates bilateral infiltrates on chest radiography, and causes severe acute respiratory failure not due to cardiac failure. Thus, differentiating severe bilateral pneumonia from ARDS is virtually impossible on clinical grounds alone. The differentiation of severe bilateral pneumonia from pneumonia-induced ARDS may be based on the measurement of decreased compliance in invasive ventilation, on a lung biopsy finding of diffuse alveolar damage (DAD), a complicated septic shock with pneumonia, or evidence of viral etiology. However, these criteria cannot be applied to the mild non-intubated ARDS patients included in our study. Therefore, we cannot exclude the possibility that specific sub-phenotypes of pneumonia patients are more or less responsive to NIV.
The last possibility for our findings is that early in pneumonia-induced mild ARDS, appropriate and effective anti-infection therapy may be more important than oxygenation and ventilation strategies. Greater culture positivity, and therefore presumed correctly adjusted antibiotics, is associated with improved outcomes with NIV for pneumonia. Others have demonstrated the early appropriate antibiotics are associated with less progression to ARDS in patients admitted with pneumonia [
29].
The main limitation of our study was that the definition of early mild ARDS was based on the American-European consensus conference criteria for ALI. Patients did not receive positive pressure at inclusion assessment. This results in our patients having lower severity of mild ARDS than those meeting the Berlin definition. Inclusion of pneumonia patients with very early stage of mild ARDS may have resulted in lower progression to ARDS and the need for intubation than expected. Although sputum culture was routinely performed for every patient, the positive culture rate is low. However, most patients were treated with guideline-compliant antibiotics and improved. The recruitment rate was also slower than expected because of a strict enrollment and exclusion criteria, potentially leading to time bias over the course of the study. Finally, based on the low incidence of intubation in our study, the sample size may be under power, and a sample size reevaluated as about 3000 cases in total may be needed for a settled conclusion.
Acknowledgements
We thanked professor Richard G Wunderink (from Pulmonary and Critical Care Division in Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA) for his advices and help for the manuscript revision.
A full list of investigators and study coordinators of ENIVA Study Group:
1. Hangyong He, Bing Sun, Lirong Liang (Beijing Chao-Yang Hospital, Beijing Institute of Respiratory Medicine)
2. Yanming Li, He Wang (Beijing Hospital)
3. Luqing Wei, Guofeng Li, Bin Liu (Affiliated Hospital of Logistics College of Chinese Armed Police Forces)
4. Shuliang Guo, Jun Duan (The First Affiliated Hospital of Chongqing Medical University)
5. Yuping Li, Ying Zhou (The First Affiliated Hospital of Wenzhou Medical University)
6. Yusheng Chen, Hongru Li, Rujun Hong, Xiujuan Yao, Fengfeng Lu (Fujian Province Hospital)
7. Jingping Yang, Xiyuan Xu, Hui Wang, Ling Wang, Hongjun Tian (The Third Affiliated Hospital of Inner Mongolia Medical College)
8. Liqiang Song, Jie Chen, Yunfu Wu (Xijing Hospital of the Forth Military Medical University)
9. Yong Bao, Feng Chen (The Third People’s Hospital of Chengdu)
10. Ping Wang, Lixi Ji, Xiaofang Huang, Min Sun (Chengdu Fifth People’s Hospital)
11. Yongxiang Zhang, Yanyan Ding (People’s Hospital of Beijing Daxing District)
12. Liangan Chen, Ying Wang, Zhixin Liang (Chinese PLA General Hospital)
13. Lan Yang, Tian Yang (The First Affiliated Hospital of Xi’an Jiaotong University)
14. Heng Weng, Hongyan Li, Xu Lin (Lung Disease Hospital of Fujian Fuzhou)
15. Daoxin Wang, Jin Tong, Wang Deng (The Second Affiliated Hospital of Chongqing Medical University)
16. Yongchang Sun, Ran Li, Jie Xu (Beijing Tongren Hospital)
17. Faguang Jin, Yandong Nan, Chunmei Li (Tangdu Hospital, the Fourth Military Medical University)
18. Bei He, Ning Shen, Lina Sun (Peking University Third Hospital)
19. Changzheng Wang, Mingdong Hu (Xinqiao Hospital Army Medical University)
20. Xiaohong Yang, Qin Luo, Mei Li (People’s Hospital of Xinjiang Uygur Autonomous Region)
21. Jin Zhang, Hai Tan (General Hospital of Ningxia Medical University)
22. Chen Wang (Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China. National Clinical Research Center for Respiratory Diseases, Beijing, China. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Department of Respiratory Medicine, Capital Medical University, Beijing, China)
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.