Impact of ventilator settings during venovenous extracorporeal membrane oxygenation on clinical outcomes in influenza-associated acute respiratory distress syndrome: a multicenter retrospective cohort study

Introduction

Influenza is a respiratory tract infection that is prevalent globally, affecting 1 billion adults every year (Global Influenza Strategy, 2019). Although most infected patients only experience mild illness, seasonal influenza epidemics result in approximately 3–5 million cases of severe illness annually  (Iuliano et al., 2018). In Taiwan, approximately 0.5% of influenza patients require hospitalization and 7% of patients hospitalized for influenza need intensive care (Influenza, 2014). Some hospitalized influenza patients may develop severe acute respiratory distress syndrome (ARDS) which requires venovenous extracorporeal membrane oxygenation (vv-ECMO) support.

Although vv-ECMO has been shown to be a promising treatment for patients with influenza-associated severe ARDS (Roch et al., 2010; Noah et al., 2011), the mortality of this disease is still high, ranging from 21% to 56% of patients (Roch et al., 2010; Davies et al., 2009; Pham et al., 2013). Vv-ECMO provides high-level gas exchange and oxygen support and enables clinicians to reduce ventilator settings to prevent further ventilator-induced lung injury from high mechanical forces (Schmidt et al., 2019; Abrams et al., 2020). However, a recent study of ECMO in ARDS showed that, despite most ECMO centers adopting ultra-protective lung ventilation, defined as a driving pressure ≤15 cm H2O and tidal volume of ≤4 ml/kg, this setting during ECMO did not significantly improve outcomes  (Schmidt et al., 2019). This unexpected finding may be related, in part, to a lack of defined optimal ventilator settings other than tidal volume during vv-ECMO (Schmidt et al., 2019; Abrams et al., 2020). Furthermore, a recent animal study (Araos et al., 2019) found that 24 h of near-apneic ventilation (respiratory rate of five breaths/min) significantly decreased histologic lung injury and fibroproliferation compared with both the nonprotective and protective lung strategies. Several previous experimental studies have also shown that decreasing respiratory rate may prevent ventilator-induced lung injury (Hotchkiss Jr et al., 2000; Retamal et al., 2016). Thus, we hypothesized that a lower mandatory respiratory rate during vv-ECMO in patients with ARDS might further reduce damage to the injured alveoli and result in better patient outcomes. In this multicenter study, we aimed to retrospectively investigate the association between mortality and mechanical ventilator settings, mechanical forces from mechanical ventilators, baseline characteristics and intensive care unit (ICU) management among patients with influenza-associated ARDS treated with mechanical ventilation and vv-ECMO support.

Patients and Methods

Results

From July 2009 to December 2019, a total of 93 patients with influenza-related ARDS receiving ECMO support were treated in the ICUs of the three study hospitals in Taiwan. Among these, 29 (31%) patients were excluded because they received venoarterial ECMO support for clinically suspected influenza-related myocarditis, 1 (1%) patient was excluded because he died on the day of vv-ECMO initiation, and 1 (1%) patient was excluded because he was transferred to the hospital 2 days after vv-ECMO initiation. After these exclusions, the remaining 62 (67%) patients receiving vv-ECMO support were enrolled in the study (Fig. 1). The clinical and demographic characteristics of the 62 study participants are shown in Table 1. The median patient age was 56 (46–63) years old, 42 participants (68%) were men, 15 (24%) were smokers, and the median Charlson comorbidity index score (Charlson et al., 1987) of the participants was 3 (1–4). Upon admission to the ICU, the median SOFA score was 11 (8–13), and the median APACHE II score was 19 (14–23). The median mean arterial pressure was 85 (70–98) mmHg, and 30 (48%) patients had septic shock.

The median duration from receiving mechanical ventilation to ECMO initiation was 22 (6–54) hours. Before ECMO, adjunctive therapies were used in 15 (24%) patients, prone positioning was used with 5 (8%) patients and 12 (19%) patients received inhaled nitric oxide. A neuromuscular blocker was administered to 33 (53%) patients.

The pressure control mechanical ventilation mode was used in these ARDS patients before and during ECMO. Before ECMO initiation, the median tidal volume was 6.9 (5.5–9.2) mL/kg predicted body weight, the median respiratory rate was 21 (16–28) breaths/min, the median PEEP level was 12 (10–15) cmH₂O, and the median PIP was 29 (26–32) cmH₂O.

After ECMO initiation (Table 2), 94% of patients were paralyzed using a neuromuscular blocker. The remaining 6% patients were sedated using benzodiazepine or propofol. Median blood flow was 3.0 (2.5–3.4) L/min and median sweep gas flow was 3.0 (2.0–3.0) L/min. From day 1 to day 3, the mean tidal volume was reduced to 5.1 (4.0–6.4) mL/kg predicted body weight and the mean respiratory rate was reduced to 13 (12–17) breaths/min, with a mean PEEP of 12 (10–14) cmH₂O. Mean dynamic driving pressure was reduced from 17 (14–21) to 15 (13–17) cmH₂O, and mean mechanical power was decreased from 23.9 (16.9–32.9) to 11.5 (8.3–15.8) J/min. Mean PaCO₂ decreased from 38 (33–54) to 31 (27–37) mmHg, and mean PaO₂ improved from 59 (44–65) to 73 (61–87) mmHg.

A total of 21 (34%) patients received steroids, and 25 (40%) patients underwent hemodialysis. Overall, 13 (21%) patients had one or more ECMO-associated complications, and 37 (60%) patients had secondary bacterial infections, with the most common pathogen being Acinetobacter baumannii. The median duration of ECMO for all 62 patients was 14 (7–20) days, median mechanical ventilator duration was 23 (15–38) days, the median ICU stay was 23 (16–41) days, and the median hospital stay was 36 (22–64) days.

Twenty-four patients (39%) died within the first six months after respiratory failure. All 24 of these patients died in the ICU. The most common cause of death was secondary bacterial pneumonia complicated by septic shock (75%). Compared with non-survivors, survivors were younger (52 vs. 59, p = 0.011) and had lower initial APACHE II scores (16 vs. 22, p < 0.001) and Charlson comorbidity index scores (2 vs. 4, p = 0.003). Inhaled nitric oxide and steroid use was lower in the survivor group compared to the non-survivor group.

Compared with non-survivors, during vv-ECMO support, survivors had a similar blood flow (3.0 vs. 3.0 L/min, p = 0.255), sweep gas flow (3.0 vs. 3.0 L/min, p = 0.451), mean tidal volume from day 1 to day 3 (5.1 vs. 5.2 mL/kg predicted body weight, p = 0.833), mean dynamic driving pressure (15 vs. 14 cmH2O, p = 0.146), mean mechanical power (11.3 vs. 11.8 J/min, p = 0.352), and mean PEEP (11 vs. 12 cmH2O, p = 0.538), but survivors had a lower mean respiratory rate (12 vs. 15, p = 0.013; Table 2 and Fig. 2). Using the receiver operating characteristic curve analysis (area under curve=0.69, 95% CI = 0.56−0.82), a cutoff point with a respiratory rate of 12 breaths/min could predict six-month mortality with 83% sensitivity and 57% specificity.

A univariate Cox proportional hazards regression analysis (Table 3) showed that older age (hazard ratio, HR = 1.05, 95% confidence interval, 95% CI = 1.01–1.1; p = 0.018), more severe respiratory acidosis before vv-ECMO support (HR = 1.04, 95% CI=1.02–1.06; p < 0.001), use of inhaled nitric oxide (HR = 2.49, 95% CI = 1.07–5.84; p = 0.035), and use of steroids (HR = 2.52, 95% CI = 1.13–5.62; p = 0.024) were associated with increased mortality. The Kaplan–Meier analysis showed that patients with a mean respiratory rate >12 breaths/min on the first 3 days after ECMO support had a higher six-month mortality rate (log-rank test, p = 0.003; Fig. 3A). Furthermore, the multivariable Cox proportional hazards regression analysis showed that a respiratory rate higher than 12 breaths/min (HR = 3.31, 95% CI = 1.10–9.97, p = 0.034), as an independent factor, was associated with six-month mortality (Table 3 and Fig. 4).

Discussion

In this multicenter retrospectively study, we found that a lower respiratory rate setting during vv-ECMO support was significantly associated with better survival among patients with influenza-associated severe ARDS. In addition to tidal volume and driving pressure, we suggest monitoring respiratory rate during ECMO support. The respiratory rate should be kept low.

The goal of mechanical ventilation in patients with ARDS is to maintain adequate gas exchange, but there are also many well-known complications of mechanical ventilation such as barotrauma, atelectrauma, oxygen toxicity, and hemodynamic compromise (Fan, Brodie & Slutsky, 2018; Slutsky & Ranieri, 2013). Vv-ECMO support during mechanical ventilation enables patients to ventilate with a very low tidal volume, low plateau pressure, and low respiratory rate, thereby minimizing ventilation-induced lung injury (Schmidt et al., 2019). However, the ideal mechanical ventilator settings for ECMO initiation are still not well defined (Peek et al., 2009; Extracorporeal Life Support Organization, 2017; Combes et al., 2018). Using a rat model of acid-induced lung injury, Frank et al. (2002) showed that a tidal volume reduction from 12 to six to three mL/kg, with the same level of PEEP (10 cmH2O), decreased pulmonary edema and lung injury. Recently, Del Sorbo et al. (2020) demonstrated that there was a linear relationship between the change in driving pressure and the plasma concentration of inflammatory mediators. The systemic inflammatory biomarkers increased with larger increases in inspiratory pressure in patients with severe ARDS on vv-ECMO, therefore, an ultra-protective lung ventilation strategy during ECMO support was proposed (Schmidt et al., 2019) that set the tidal volume less than four mL/kg or driving pressure less than 15 cmH₂O, plateau pressure less than 25 cmH₂O, and PEEP greater than 10 cmH₂O (Schmidt et al., 2019; Rozencwajg et al., 2019). Rozencwajg et al. found that ultra-protective ventilation for patients with vv-ECMO was associated with significantly decreased plasma sRAGE and other cytokine concentrations, which were biomarkers of lung injuries (Rozencwajg et al., 2019). Pham et al. (2013) studied 123 patients with influenza A (H1N1)-induced ARDS treated with ECMO and found that a reduction in plateau pressure (25 vs. 29, p < 0.01) on the first day of ECMO was significantly associated with survival.

Although the Extracorporeal Life Support Organization guidelines for patients with respiratory failure receiving ECMO support recommend a lung rest strategy (FiO2 <0.4, plateau pressure <25 cmH2O) (Extracorporeal Life Support Organization, 2017), a recent study by Schmidt et al. (2019) demonstrated a lack of association between mechanical ventilator settings during the first two days of ECMO and survival. In our study, we also did not find a significantly lower mortality rate among the 13 patients receiving ultra-protective ventilation (Fig. 3B) compared to those without ultra-protective ventilation (39% vs. 40%, p = 0.941). An animal study (Araos et al., 2019) found that a near-apneic ventilatory strategy, which sets the respiratory rate at five breaths/min, significantly decreased histologic lung injury and fibroproliferation compared with conventional protective lung strategies. Previous experimental studies have also shown that decreasing the respiratory rate may prevent ventilator-induced lung injury (Hotchkiss Jr et al., 2000; Retamal et al., 2016).

An analysis from a pooled database of 4,549 patients with ARDS found that higher respiratory rates could be injurious (Costa et al., 2021). A recent review by Abrams et al. also suggested setting the initial respiratory rate of ≤ 10 breaths/min during ECMO for ARDS (Abrams et al., 2020) adding that the recommendation for a respiratory rate below the lower limit of the EOLIA protocol is based on the presumption that lower respiratory rates may prevent lung injury (Abrams et al., 2020; Combes et al., 2018). In our study, we also found that a lower respiratory rate during vv-ECMO support was significantly associated with lower mortality, which supports the hypothesis that a near-apneic strategy with a low respiratory rate during vv-ECMO support could improve outcomes. Accordingly, to achieve lung protection for patients receiving vv-ECMO for ARDS, gas exchange could be primarily supported by the ECMO. In our opinion, optimal ventilator settings during ECMO should be guided by best available evidence from previous studies, such as the ultra-protective strategy. (Schmidt et al., 2019; Extracorporeal Life Support Organization, 2017) The initial settings could be as follows: Tidal volume ≤ 4 ml/kg, driving pressure ≤ 15 cmH2O, inspiratory plateau pressure <25 cmH2O, FiO2 <0.4 and PEEP ≥ 10 cmH2O. Furthermore, based on our study results, respiratory rate should be set lower than 12 breaths per minute.

Similar to patient populations in previous studies, our patients with influenza-associated ARDS treated with vv-ECMO (Roch et al., 2010; Davies et al., 2009; Pham et al., 2013; Patroniti et al., 2011) were relatively young, not obese, and had extensive viral pneumonia with extremely severe lung injury. However, some differences should be highlighted: less patients in this study received inhaled nitric oxide or prone positioning (19% and 8%, respectively) before vv-ECMO support compared with patients in previous studies from Australia (32%), New Zealand (20%) (Davies et al., 2009), and France (72% and 45%) (Pham et al., 2013); and the duration of mechanical ventilation before ECMO was shorter in our study (22 h) than in previous studies (from 2 to 4 days) (Noah et al., 2011; Davies et al., 2009; Pham et al., 2013; Patroniti et al., 2011). This finding suggests that vv-ECMO is more readily available as a rescue therapy in Taiwan than it is in other countries. In a previous cohort study, ECMO outcomes were highly variable with short-term mortality ranging from 29% to 56% (Roch et al., 2010; Noah et al., 2011; Davies et al., 2009; Pham et al., 2013; Patroniti et al., 2011), reflecting heterogeneity in the patient population, disease severity, and treatment received.

Initiation of antiviral treatment is recommended for patients with influenza. Oseltamivir administration within 48 h of symptom onset has been demonstrated to improve outcomes (Hernu et al., 2018). Conversely, steroid use in influenza patients has consistently been found to be predictive of poor outcomes in several studies, and a meta-analysis by Ni et al. (2019) showed that steroid use could increase mortality (risk ratio = 1.75, 95% CI [1.30–2.36], p = 0.0002). Consistent with the results from previous studies, we found that steroid use was associated with poor outcomes (HR = 2.29, 95% CI=1.06−4.96, p = 0.04).

This study has several limitations. First, there was no universal ventilator protocol for patients on ECMO. The primary attending physicians adjusted ventilator settings according to the patient’s clinical condition after ECMO initiation. Respiratory rate might be a marker of disease severity in ARDS but not a causal factor. Second, our study may be affected by type I error inflation because of the multiple comparisons used in our analysis, so our results should be interpreted with caution. Third, the sample size was small and the possibility of unobserved confounders explaining the differences in outcomes cannot be eliminated.

Conclusions

Patients with influenza-related severe ARDS receiving vv-ECMO support have a high mortality rate. The findings from this multicenter retrospective study suggest that patients with lower respiratory rates during vv-ECMO support have better outcomes. However, owing to the limitations of the study, it is necessary to conduct a prospective randomized control trial to verify these findings.

Supplemental Information