key: cord-0785204-fwpqzdxn
authors: Chang, Ko-Wei; Hu, Han-Chung; Chiu, Li-Chung; Chan, Ming-Cheng; Liang, Shinn-Jye; Yang, Kuang-Yao; Chen, Wei-Chih; Fang, Wen-Feng; Chen, Yu-Mu; Sheu, Chau-Chyun; Chang, Wei-An; Wang, Hao-Chien; Chien, Ying-Chun; Peng, Chung-Kan; Wu, Chieh-Liang; Kao, Kuo-Chin
title: Comparison of Prone Positioning and Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome: A Multicenter Cohort Study and Propensity-matched Analysis
date: 2021-10-16
journal: J Formos Med Assoc
DOI: 10.1016/j.jfma.2021.10.007
sha: d054be146d0dc687330efe2fe45f32392cb6f24f
doc_id: 785204
cord_uid: fwpqzdxn

Background Both prone positioning and extracorporeal membrane oxygenation (ECMO) are used as rescue therapies for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). This study compared outcomes between patients with severe influenza pneumonia-related ARDS who received prone positioning and those who received ECMO. Methods This retrospective cohort study included eight tertiary referral centers in Taiwan. All patients who were diagnosed as having influenza pneumonia-related severe ARDS were enrolled between January and March 2016. We collected their demographic data and prone positioning and ECMO outcomes from medical records. Results In total, 263 patients diagnosed as having ARDS were included, and 65 and 53 of them received prone positioning and ECMO, respectively. The baseline PaO2/FiO2 ratio, Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score did not significantly differ between the two groups. The 60-day mortality rate was significantly higher in the ECMO group than in the prone positioning group (60% vs. 28%, p = 0.001). A significantly higher mortality rate was still observed in the ECMO group after propensity score matching (59% vs. 36%, p = 0.033). In the multivariate Cox regression analysis, usage of prone positioning or ECMO was the single independent predictor for 60-day mortality (hazard ratio: 2.177, p = 0.034). Conclusions While the patients receiving prone positioning had better outcome, the causality between prone positioning and the prognosis is unknown. However, the current data suggested that patients with influenza-related ARDS may receive prone positioning before ECMO support.

and if a patient's PaO2/FiO2 ratio was <150 mmHg. According to the PROSEVA study 143 6 , prone positioning was performed for at least 16 hours in a day. Hemodynamic 144 instability is the main contraindication for prone positioning. 145

The initiation of ECMO was decided by critical care doctors and cardiovascular 147 surgeons, and ECMO was administered by cardiovascular surgeons. Venovenous 148 ECMO was used for patients with no improvement of refractory hypoxemia despite 149 optimal ventilator settings or severe hypercapnia. The venoarterial ECMO was used for 150 patients with no improvement of refractory hypoxemia despite optimal ventilator 151 settings combined with severe shock status despite high dose inotropic agent treatment 152 usage. 153 test was used to comparing continuous variables depending on the underlying 158 distribution. The Kaplan-Meier curve with log-rank statistic was used to compare 159 survival between the prone positioning and ECMO groups. In addition, we used the 160 propensity score to match the prone positioning and ECMO groups by using the PSI, 161 SOFA score and P/F ratio as predictors and a cutoff of 0.10 for match tolerance. We 162 used the univariate and multivariate Cox regression to analyze the predictive factors of 163 survival, and the variables with p value less than 0.10 in univariate analysis were 164 included for multivariate analysis. A p value of <0.05 was considered statistically 165 significant. We used SPSS (version 22.0; SPSS Inc., Chicago, IL), for statistical 166 analyses and database management. 167

In total, 336 patients with virology-proven severe influenza pneumonia were 169 admitted to the ICU during the study period (Fig. 1 who received prone positioning and ECMO, respectively, were included in the further 176 analysis. Of 65 patients who received prone positioning, 8 were shifted to ECMO 177 because the initial prone positioning failed, resulting in the deterioration of patients' 178 hypoxemia. These eight patients were excluded in both groups for analysis. In total, 179 40 patients (including 6 with prone positioning failure) received venovenous ECMO 180 and 13 patients (including 2 patients with prone positioning failure) received 181 venoarterial ECMO. 182

The characteristics of included patients at admission were similar between the 183 prone positioning group and ECMO group, except for the total bilirubin level (0.8 ± 0.8 184 mg/dL in the prone positioning group and 1.9 ± 1.9 mg/dL in the ECMO group, p = 185 0.002; Table 1 ). Influenza A virus infection was the main cause of severe ARDS, and 186 nonsignificant difference was observed in terms of the cause of severe ARDS between 187 the two groups (79% in the prone positioning group and 82% in the ECMO group). 188 groups. In all patients, the duration of receiving prone positioning and ECMO from 196 ARDS diagnosis was 1.9 ± 3.4 and 2.1 ± 3.5 days, respectively. 197

The 60-day mortality rate was significantly lower in the prone positioning group 199 than in the ECMO group (28% vs. 60%, p = 0.002; Table 3 ), and the statistical power 200 was 0.919. Figure 2A shows the cumulative survival rate between the prone 201 positioning and ECMO groups from the beginning of the follow-up period until day 202 60, and figure 2B shows the cumulative survival rate between the prone positioning, 203 venovenous ECMO groups and venoarterial ECMO groups. In eight patients who 204 developed prone positioning failure and were subsequently shifted to ECMO, 60-day 205 mortality and in-hospital mortality rates were 50% and 63%, respectively. For 206 J o u r n a l P r e -p r o o f survivors, the period of the prone positioning or ECMO usage was 4.1 ± 3.1 and 11.5 207 ± 7.0 days, respectively. The length of ICU and hospital stay did not significantly 208 differ between the two groups. However, ventilation-free days at day 60 were higher 209 in the prone positioning group than in the ECMO group (25.8 ± 22.1 vs. 13.7 ± 20.1 210 days, p = 0.004). No fatal complication related to prone positioning or ECMO was 211 recorded in all patients during the study period. 212

After matching, baseline characteristics and lung mechanics did not significantly 214 differ between the two groups; however, the 60-day mortality rate was still 215 significantly lower in the prone positioning group than in the ECMO group (36% vs. 216 59%, p = 0.033; Table 3 ). Figure 2C shows the cumulative survival rate from the 217 beginning of the follow-up period until day 60 between the matching prone 218 positioning and ECMO groups. 219

We also compared the prone positioning group with the venovenous ECMO 221 group (table 4). The baseline severity index, arterial blood gas data, ventilator 222 settings, and lung mechanics before prone positioning or venovenous ECMO were no 223 significant difference. The P/F ratio in venovenous ECMO was 93.0±52.2 mmHg. 224

However, the venovenous ECMO group had significant higher 60-day mortality rate 225 than prone positioning group (62% vs 28%, p = 0.002). 226

The predictors of 60-day mortality in patients with prone positioning or ECMO 228 are shown in Table 5 . In the univariate Cox regression analysis, the PSI (hazard ratio: 

The results of this multicenter retrospective cohort study revealed that patients 238 with severe influenza pneumonia-related ARDS who received prone positioning had 239 lower mortality rates than did those receiving ECMO at day 60 (28% vs. 60%, p = 240 0.001), and usage or prone positioning or ECMO was an independent predictor for 60-241 day mortality. Since further randomized controlled trial is needed to elucidate the 242 causality between prone positioning and better clinical outcomes, prone positioning can 243 be considered an adjunct therapy for refractory hypoxemia before administering ECMO 244 in patients with influenza pneumonia complicated by moderate to severe ARDS. 245

Pneumonia, the most common ARDS risk factor, is associated with a high 246 mortality 24 . Influenza (H1N1)-related ARDS can rapidly progress, resulting in life-247 threatening hypoxemia. The clinical course of influenza (H1N1)-related ARDS appears 248 to be substantially different from that of non-influenza-related ARDS, involving a 249 prolonged recovery of pulmonary gas exchange, a frequent demand for ECMO, and a 250 prolonged ICU stay. In the LUNG SAFE study, the overall 28-day mortality rate of 251 patients with ARDS was 34.8% (29.6%, 35.2%, and 40.9% with mild, moderate, and 252 severe ARDS, respectively) without focusing on any specific risk factor 2 . However, in 253 this study, the 30-day mortality rate of patients with severe influenza pneumonia-related 254 ARDS was relatively low (23.2%)-with it being 7.1%,19.0%, and 28.2% in patients 255 with mild, moderate, and severe ARDS, respectively. Compared with no treatment, 256 neuraminidase inhibitor treatment was associated with a reduction in mortality in 257 patients with H1N1 influenza admitted to hospitals (adjusted odds ratio, 0.81; 95% 258 confidence interval, 0.70-0.93; p = 0.0024) 25 . In this study, the relatively low mortality 259 rate in patients with severe influenza pneumonia with ARDS might partially be 260 attributed to early recognition of ARDS and the administration of empiric 261 neuraminidase inhibitor treatment to most patients, particularly during the epidemic. 262

Considering easy progression to severe ARDS but with a relatively low mortality rate 263 in some patients with severe influenza pneumonia, we must select an adequate adjunct 264 therapy, such as prone positioning or ECMO, earlier, if required. 265

Current guidelines suggest both prone positioning and ECMO as rescue therapies for 266 refractory hypoxia in patients with severe ARDS 26,27 . However, the guidelines suggest 267 the use of these therapies in different conditions; for example, prone positioning and 268 ECMO may be used when the PaO2/FiO2 ratio is <150 mmHg and <80 mmHg, 269 respectively 26 . In the PROSEVA study 6 , the 28-and 90-day mortality rates of patients 270 who received prone positioning were 16.0% and 23.6%, respectively; these values were 271 lower than real-world data observed in our study (30-and 60-day mortality rates were 272 26% and 31%, respectively, in our study). However, we focused on patients with severe 273 influenza pneumonia, and the mean PaO2/FiO2 ratio of patients in our study was lower 274 than that of patients in the PROSEVA study (95.9 vs. 100 mmHg). Moreover, the 275 mortality rate reported in Cochrane meta-analysis data 28 was higher than that observed 276 in our study both in the short term (33.4%) and long term (41.7%). By contrast, the 277 mortality rate of the ECMO group in our study was higher (30-and 60-day mortality 278 rates were 36% and 60%, respectively) than that reported in the EOLIA study (60-day 279 mortality rate was 35%) 16 or other studies including patients with influenza 29,30 . These study reported that patients with influenza who received late cannulation (after >7 days) 294 had significantly high mortality 32 . A previous study compared patients who received 295 ECMO with or without a prone positioning trial before the ECMO was initiated 33 . The 296 30-day mortality in patients who received prone positioning before ECMO was not 297 significantly higher than that in patients who did not receive prone positioning (21% vs. 298 41%, p = 0.098). In our study, eight patients received prone positioning before ECMO, 299 and the mortality rate of these patients who received prone positioning before ECMO 300 did not have a significantly higher 60-day mortality rate than did those who did not 301 receive prone positioning before ECMO (50% vs. 60%, p = 0.597). Therefore, a trial of 302 prone positioning before ECMO implementation is a suitable consideration in clinical 303

In the real-world, however, prone positioning may be underused in clinical practice 305 for ARDS management. In this study that the choice of prone positioning or ECMO 306 was mainly by the duty doctors' decision, or the equipment or experience in the unit or 307 hospital, 24.7% (65/263) of patients with severe influenza pneumonia-related ARDS 308 received prone positioning. However, in the LUNG SAFE study, only 16.3% (95% CI, Second, only patients who developed severe ARDS due to influenza were included in 327 this study. Thus, this might limit the applicability of results to patients with severe 328 ARDS caused by other risk factors. Whether these rescue therapies can result in the 329 same outcomes in patients with various causes of ARDS should be examined in the 330 future. Third, we did not analyze ECMO or ventilator settings after starting ECMO 331 support, and this might have affected the mortality of patients who received ECMO. 332 Additional studies are required to analyze optimal ECMO or ventilator settings in these 333 patients. 

ECMO 477 for ARDS: from salvage to standard of care?

Timing of ECMO Initiation 479

Prone positioning 482 before extracorporeal membrane oxygenation for severe acute respiratory distress 483 syndrome: A retrospective multicenter study

Unproven and Expensive before Proven and 485

Cheap: Extracorporeal Membrane Oxygenation versus Prone Position in Acute 486

Respiratory Distress Syndrome

Need renal replacement therapy 9 (16%) 9 (20%) 0.580 9 (21%) 9 (21%) >0.999 ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit. All values are expressed as number (percentage) or mean ± SD. Need renal replacement therapy 9 (16%) 6 (18%) 0.817 APACHE: Acute Physical and Chronic Health Evaluation; ARDS: acute respiratory distress syndrome; BMI: body mass index; VV ECMO: venovenous extracorporeal membrane oxygenation; PSI: pneumonia severity index; SOFA: sequential organ failure assessment. All values are expressed as number (percentage) or mean ± SD. * p < 0.05: Prone positioning vs VV ECMO