Removal of Mechanical Ventilation During Veno-Venous ECMO May Improve Outcome of Patients with Acute Respiratory Failure Due to Adult Community-Acquired Pneumonia

Background: As a life-saving therapy for patients with acute respiratory failure (ARF)Mechanical ventilation has catalyzed the development of modern emergency medicine and intensive care units.Another way to support respiratory or cardiac functions is extracorporeal membrane oxygenation (ECMO).Based on previous studies, the increased pre-ECMO time of mechanical ventilation is a signicant independent predictor of the poorer outcome . Removal or maintaining of mechanical ventilation during ECMO is still debatable. Methods: We analyzed the clinical data of 23 patients veno-venous ECMO therapy with acute respiratory failure due to adult community-acquired pneumonia.They were divided into two groups: group A (removed of mechanical ventilation, n=10) and group B ( maintaining of mechanical ventilation,n=13).Demographic data, including gender, age, smoking habits were collected. General characteristics and Clinical characteristics of patients were also recorded, in order to discuss whether the retention or removal of trachea cannula and continued mechanical ventilation during ECMO can affect patients’ prognosis. Results: After analysis, patients in the Group B were older than the Group A (61.0 y [54.5-67.5] vs 39.0 y [24.0-61.8], P=0.021). The median APACHE (cid:0) score of 23 patients before ECMO therapy was 25.0 (IQR, 21.0-28.0), and the Group A had a lower initial APACHE (cid:0) score than the Group B (21.5 [20.8-24.3] vs 28.0 [24.0-29.0], P=0.005)(Table 1).The group A with a survival rate of 80% , and the group B presenting a survival rate of 23.1%.The difference in the survival rate between the two groups was statistically signicant (P=0.012).No differences in other items were found between the two groups. Conclusions: The nal results showed that the removing of mechanical ventilation during ECMO can improve the survival rate and prognosis in patients with ARF.


Introduction
Mechanical ventilation as a life-saving therapy for patients with acute respiratory failure (ARF) has catalyzed the development of modern emergency medicine and intensive care units (1). However, mechanical ventilator is a double-edged sword that not only provide effective breathing for the patients, but also associates with a host of complications to exacerbate lung injury (1,2). Another means of supporting respiratory or cardiac functions is extracorporeal membrane oxygenation (ECMO). Although the use of ECMO in cardiopulmonary disease is evolving rapidly, many questions about the optimal patient populations and the timing for initiation of ECMO remain to be solved (3). Based on previous studies, the increased pre-ECMO time of mechanical ventilation is a signi cant independent predictor of the poorer outcome (4). Especially for patients with severe acute respiratory distress syndrome, the pre-ECMO mechanical ventilation lasting at least 7 days has been associated with higher mortality (5,6).
Removal or maintaining of mechanical ventilation during ECMO is still debatable. Thus, we analyzed the clinical data of 23 patients veno-venous ECMO therapy with acute respiratory failure due to adult community-acquired pneumonia.

Selection of participants
There were all 103 patients who received extracorporeal support in the emergency care unit at the First A liated Hospital, School of Medicine, Zhejiang University between November 2014 and September 2019. Patients who met any of the following criteria were excluded: (1) cardiac failure resulting in venoarterial ECMO, (2) ECMO provided for other indications than ARF,(3) pregnancy,(4) long term chronic respiratory insu ciency treated with oxygen therapy or noninvasive ventilation.Following the inclusion and exclusion criteria, 80 parents were excluded and 23 parents were included, and the speci c screening process was shown in Fig. 1. All included cases were severe pneumonia, including 12 cases of viral pneumonia and 11 cases of unde ned pathogen infection (Fig. 1).

Data collection
Demographic data, including gender, age, smoking habits were collected. The clinical parameters were also recorded, such as ECMO duration, and initial acute physiology and chronic health evaluation (APACHE) score. Also, we collected many basic characteristics: The patients' heart rate(HR), mean arterial pressure (MAP), temperature (T) were continuous recorded by the monitors; ECMO parameters: rotational speed Flow, sweep gas ow, fraction of inspired oxygen(FiO2);Artery blood gas analyzer was used for recording partial pressure of arterial carbon dioxide (PaCO2), partial pressure of arterial oxygen (PaO2), lactic acid (Lac) and potential of hydrogen (pH) value of patients. These indicators were used to monitor the hemodynamics, the patient's internal environment and whether the ECMO machine was working well in two groups, in order to look for the in uence on the prognosis.

ECMO operation conditions and deployment
We selected patients with ARF who with mechanical ventilation less than 7 days by one of three criteriaa ratio of partial pressure of arterial oxygen (PaO 2 ) to the fraction of inspired oxygen (FiO 2 ) of less than 50 mmHg for more than 3 hours, a PaO 2 ∶ FiO 2 of less than 80 mmHg for more than 6 hours, or an arterial blood potential of hydrogen (pH) of less than 7.25 with a partial pressure of arterial carbon dioxide (PaCO 2 ) of at least 60 mmHg for more than 6 hours-to receive immediate ve novenous ECMO. ARF was de ned as clinical evidence of respiratory distress (tachypnea, dyspnea) and hypoxemia at supplementary oxygen rates greater than or equal to 10 L/min (high-ow oxygen or non-invasive ventilation) or mechanical ventilation.
ECMO deployment: all patients were using silica membrane lungs (manufacturer: MAQUET; model: Rota ow, made in Germany) in veno-venous mode. Percutaneous cannulation was performed using the Seldinger technique. The right internal jugular vein and right femoral vein were used for venous cannula.
Under deep sedation and after the successful deployment of ECMO, the perfusion ow should be improved; the membrane oxygenation concentration was set at 70%-80%, and the ratio of gas ow and blood ow was 0.5-0.8:1. Then parameters were adjusted according to the heart rate (HR), blood pressure, central venous pressure (CVP), and blood gas. At the same time, the mechanical ventilation was adjusted to low voltage and low frequency mode with 20-24 cmH 2 O peak pressure, 10mmHg positive end-expiratory pressure (PEEP), 5-10 times/min frequency, and 21%-40% FiO 2 .Unfractionated heparin (UFH) was used in all patients, with a bolus at the dose of 50-100 U/kg before cannulation. Then a continuous intravenous infusion of UFH was increased at a rate of 2-to-20 U/kg/h, with a target activated clotting time (ACT) level of 180-to-200 seconds or an activated partial thromboplastin time (APTT) of 60to-80 seconds. Point-of-care monitoring was conducted for ACT or APTT(every 4 hours), and the APTT, thrombin time, prothrombin time, brinogen, D-dimer, and platelet count were monitored every 24 hours. Early mechanical ventilation removal can be considered for ECMO patients who meet the following conditions: the primary disease has been controlled to a certain extent;Be conscious;Airway protection was strong, and there was no obvious airway secretions or airway in ammation in bronchoscopy.Hemodynamic stability, no serious arrhythmia;In the auxiliary ventilation mode, peak pressure ≤ 20 cmH2O, PEEP ≤ 10 ~ 12 cmH2O, FiO2 ≤ 0.5. High risk or suspected possibility of Ventilatorassociated pneumonia (VAP);The presence or high risk of barotrauma;ECMO operation was normal, coagulation and brinolysis indexes were stable, there were no obvious signs of infection at the vascular puncture site, and there were no inclusions of serious complications. according to whether patients were removed of mechanical ventilation or not during ECMO, 23 cases were divided into two groups: group A (removed of mechanical ventilation, n = 10) and group B ( maintaining of mechanical ventilation,n = 13). This study was approved by the Ethical Committee of First A liated Hospital, School of Medicine, Zhejiang University. We obtained the consent of all patients or their relatives.

Statistical analysis
Continuous variables were described as medians with interquartile ranges (IQR). Categorical variables were shown as numbers and percentages. Mann-Whitney U-test was performed for evaluating continuous data and Chi-square test for categorical variables. Survival analysis was performed by the Kaplan-Meier method and evaluated by the log-rank test. The level of statistical signi cance was set at P < 0.05. All analyses were conducted with SPSS software (version 25.0, SPSS Inc., IBM, Chicago, IL, USA) 3. Results

General characteristics of patients
Of 23 participants we recruited, there were 13 males and 10 females, while, no differences in sex ratio were found between the two groups (P = 0.768). Patients in the Group B were older than the Group A (61.0 y [54.5-67.5] vs 39.0 y [24.0-61.8], P = 0.021). The rate of smoker was higher in the group B, but there was no signi cant difference between the two groups(P = 0.673). The median duration of ECMO of 23 patients was 12 days (range 5-47 days), and its difference between the two groups was not statistically signi cant (P = 0.483). APACHE was a classi cation system to measure the severity of disease for adult patients admitted to Intensive Care Unit (ICU). The median APACHE score of 23 patients before ECMO therapy was 25.0 (IQR, 21.0-28.0), and the Group A had a lower initial APACHE score than the Group B  Table 1).

Clinical characteristics of patients
Basic characteristics, ECMO parameters, and blood gas parameters during ECMO and 24 hours after ECMO are shown in Fig. 2. No signi cant difference between the two groups was found in all parameters (all P > 0.05). Table 2 shows the basic characteristics, blood gas, and ECMO parameters of the group A 24 hours before and after removing of mechanical ventilation. The signi cant increases in ECMO parameters (rotational speed, ow of ECMO, sweep gas ow, and FiO 2 ) were noted 24 hours after removing of mechanical ventilation in the group A, but no difference was found (P > 0.05). Compared to the group A, the group B had a higher Lac at all three times, but no difference was found (P > 0.05).  Figure 3 shows the survival curve of all patients, the group A with a survival rate of 80% (8 out of 10 patients were survived), and the group B presenting a survival rate of 23.1% (3 out of 13 patients were survived). The difference in the survival rate between the two groups was statistically signi cant (P = 0.012).

Discussion
The ARF is characterized by lung injury caused by either indirect or direct insults, which could be worsened by the way mechanical ventilation is applied (7). ECMO has been used in clinical medicine for over 40 years but remains controversial. As a result, it is considered a rescue therapy when conventional management fails (8). With ECMO, it is possible to rest the lungs by using lower tidal volumes, lower airway pressures, and lower FiO 2 , thereby decreasing the iatrogenic consequences of mechanical ventilation (9). Initiation of ECMO allows reductions in the tidal volume size, PEEP, and plateau pressure levels, as well as FiO 2 (9)(10)(11), which all may help to improve outcome via prevention of additional lung injury (12,13).
This study is to discuss whether the retention or removal of trachea cannula and continued mechanical ventilation during ECMO can affect patients' prognosis. It is generally accepted that the retention of trachea cannula and continued use of mechanical ventilation in the low voltage and low frequency mode during ECMO can improve alveolar oxygen partial pressure and decrease pulmonary vascular resistance, and the higher PEEP can prevent atelectasis.
Technically, the ECMO should be able to provide enough oxygen patients need. According to previous clinical practices and research, the removal of trachea cannula during ECMO can help patients with ARF to gain comfort, to reduce the stress level, use of sedatives and interference to circulation, and to promote cough and sputum. However, the removal of mechanical ventilation can also bring some disadvantages: for patients with poor lung compliance, it may lead to large atelectasis; for patients with ARF infected by the high aggressive pathogenic microorganism, it can result in partial alveolar collapse and may spread infection in lungs; due to the reduced oxygen supply by mechanical ventilation, ECMO needs to be enhanced, thereby increasing the incidence and intensity of adverse reactions, such as blood damage caused by excessive ow.
All in all, 23 patients with ECMO had no neuromuscular diseases and no signi cant abnormality in their respiratory center and respiratory drive. After patients with ARF were extubated tracheal cannula and stopped mechanical ventilation for 24 hours, ECMO-supported parameters slightly improved, while patients' HR, T, MAP, and Lac improved better than those before removing of mechanical ventilation. Thus, tracheal extubation during ECMO seems to greatly increase the tissue oxygenation level of patients, which may be related to the improvement of balance between oxygen supply and consumption. The nal results also showed that the removing of mechanical ventilation during ECMO seemed to improve the survival rate and prognosis in patients with ARF. Of course, patients in the two groups have a statistically signi cant difference in terms of age and APACHE score, which is consistent with the clinical practice. Young and mild patients are more likely to remove tracheal intubation.
Given the small sample capacity, this study is unrealistic and unscienti c to get de nite results. It is expected to draw clear conclusions from subsequent multicentric and large-scale clinical research and to make in-depth discussions on various mechanisms involved, in order to use ECMO more scienti cally and save more patients.

Conclusions
We found that the elimination of mechanical ventilation during ECMO can improve the survival and prognosis of ARF patients,tracheal extubation during ECMO seems to greatly increase the tissue oxygenation level of patients. Of course,there were statistically signi cant differences in age and APACHE score between the two groups, which was consistent with clinical practice. Young and mild patients are more likely to pull out endotracheal intubation.

Declarations
Funding Not applicable.

Con ict of interest
All the authors have declared that no con ict interest exists.

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors. Figure 1 Enrollment of patients. Basic characteristics, ECMO parameters and blood gas parameters of patients during ECMO and 24h after ECMO