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Abstract
Introduction While limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute respiratory distress syndrome (ARDS) is widely accepted, the best setting for positive end-expiratory pressure (PEEP) is still controversial. This study is being conducted to investigate whether a higher PEEP setting (15 cmH2O) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting.
Methods and analysis The study is an investigator-initiated, multicentre, open-label, two-arm, randomised controlled trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The subjects of the study are patients with severe ARDS who require V-V ECMO support. Eligible patients will be randomised equally to the high PEEP group or low PEEP group. Recruitment to the study will continue until a total of 210 patients with ARDS requiring V-V ECMO support have been randomised. In the high PEEP group, PEEP will be set at 15 cmH2O from the start of V-V ECMO until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmH2O. Other treatments will be the same in the two groups. The primary endpoint of the study is the number of ECMO-free days until day 28, defined as the length of time (in days) from successful libration from V-V ECMO to day 28. The secondary endpoints are mortality on day 28, in-hospital mortality on day 60, ventilator-free days during the first 60 days and length of ICU stay.
Ethics and dissemination Ethics approval for the trial at all the participating hospitals was obtained on 27 September 2022, by central ethics approval (IRB at Hiroshima University Hospital, C2022-0006). The results of this study will be presented at domestic and international medical congresses, and also published in scientific journals.
Trial registration number The Japan Registry of Clinical Trials jRCT1062220062. Registered on 28 September 2022.
Protocol version 28 March 2023, version 4.0.
- clinical trial
- adult thoracic medicine
- respiratory infections
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is the first randomised controlled trial (RCT) performed to investigate whether a high PEEP setting can shorten the ECMO-free days until day 28 as compared with a low PEEP setting in patients with severe acute respiratory distress syndrome (ARDS) requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO).
This study could be the largest RCT conducted to date in patients with severe ARDS requiring V-V ECMO.
This study includes a subgroup analysis for evaluating the outcomes by the index of lung recruitability.
Some limitations of the study include its open-label study design and assessment of the endpoints by the attending intensive care unit physicians.
Introduction
Background and rationale
Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by widespread inflammatory lung injury, and is encountered in an estimated 23% of mechanically ventilated patients.1 Of the three severity scales of ARDS categorised in the Berlin criteria, the reported mortality of severe ARDS, defined by a arterial oxygen tension (PaO2)/fractional inspired oxygen (FIO2) ratio (P/F ratio) of ≤100 mm Hg, is as high as 45%, and these patients often need respiratory support with veno-venous extracorporeal membrane oxygenation (V-V ECMO).2
As compared with ventilation strategies in patients not requiring V-V ECMO, optimal strategies for patients requiring V-V ECMO support have received relatively little attention. Based on a previous prospective study conducted with the participation of 23 ECMO centres from 10 countries, a tidal volume of ≤6 mL/kg and plateau pressure not exceeding 30 cmH2O have been widely accepted as lung protective strategies; however, there is still a large variability in the setting of positive end-expiratory pressure (PEEP); for example, the reported PEEP setting on day 1 of ECMO ranges from 5 cmH2O to 20 cmH2O.3 Thus, the optimal settings for mechanical ventilation during ECMO in patients with ARDS have not been established yet.
A high PEEP setting can be beneficial for preventing lung injury by reducing atelectrauma. The ExPress trial conducted in mechanically ventilated patients with ARDS not requiring ECMO support showed that a higher PEEP (approximately 15 cmH2O on day 1) tended to improve the lung function and reduced the needed duration of mechanical ventilation.4 The results of a previous systematic review and meta-analysis suggested that the beneficial effect of a higher PEEP setting may be more pronounced in the subgroup of patients with relatively more severe ARDS,5 which may imply that the effect may be most noteworthy in patients with severe ARDS who require ECMO support. In fact, a single-centre randomised controlled trial (RCT) conducted in patients with ARDS requiring V-V ECMO showed that the proportion of patients who could be successfully weaned from V-V ECMO was higher in the patient group in which a transpulmonary pressure-guided ventilation strategy, including a higher PEEP setting (approximately 15 cmH2O), had been used, as compared with that in the conventional lung rest strategy group.
On the other hand, however, a high PEEP setting can also have a harmful influence on the haemodynamics by reducing the venous return,6 as well as on the lung condition by inducing lung injury due to overdistention7 and increasing the mechanical power.8 Considering that the PEEP setting during ECMO can be adjusted without limiting oxygenation, because oxygenation is mainly accomplished by ECMO rather than by mechanical ventilation, and patients with severe ARDS likely have concomitant right heart failure, a low PEEP setting, such as 5 cmH2O, which is considered to be the minimum PEEP setting for patients with ARDS,9 may be more beneficial. While a recent guideline published by the Extracorporeal Life Support Organization (ELSO) recommends a PEEP setting of ≥10 cmH2O during ECMO,10 the Consensus Conference 2014 recommends that ‘mechanical ventilation be adjusted to minimise the plateau pressure, while administering a minimum positive expiratory pressure’.11 It remains unclear whether a higher or lower PEEP setting during V-V ECMO might be more beneficial for ameliorating the lung injury in patients with severe ARDS .12
Therefore, we designed this open-label, multicentre RCT to examine the beneficial effect of a higher PEEP setting (15 cmH2O) as compared with a lower PEEP setting (5 cmH2O) in patients with severe ARDS requiring V-V ECMO support.
Aim and objectives
This study is being conducted to investigate whether a higher PEEP setting (15 cmH2O) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting (5 cmH2O).
Methods and analysis
Trial design
The Expiratory Pressure for Severe ARDS requiring V-V ECMO Respiratory Support Trial (ExPress SAVER trial) is a randomised controlled, parallel-group, open-label, multicentre, superiority trial that is proposed to be conducted in patients with severe ARDS requiring V-V ECMO. Eligible patients will be randomised equally to the high PEEP (15 cmH2O) group or low PEEP (5 cmH2O) group.
Study setting
This 3-year study is expected to run from 1 November 2022 to 31 March 2026. The study is an investigator-initiated, multicentre, open-label, two-arm, randomised trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The flow chart for patient recruitment into the trial is shown in figure 1. Among the 20 participating hospitals, 11 were academic hospitals and 9 were non-academic hospitals. The trial is registered in the jRCT (Japan Registry of Clinical Trials; https://jrct.niph.go.jp, trial registration number: jRCT1062220062).
Flow chart for patient recruitment into the ExPress SAVER Trial. ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; EF, ejection fraction; ICU, intensive care unit; PEEP, positive end-expiratory pressure; V-A ECMO, veno-arterial extracorporeal membrane oxygenation; V-V ECMO, veno-venous extracorporeal membrane oxygenation.
Eligibility criteria
Adult patients (18–80 years old) with ARDS requiring V-V ECMO will be included. The diagnosis of severe ARDS was made on the basis of the Berlin definition criteria (P/F ratio ≤100 mm Hg).13 Respiratory support using ECMO is considered if the patients are assessed as having a high risk of mortality (≥50%) and is considered as being indicated when the risk is ≥80% in accordance with the guideline.14 A P/F ratio of <150 mm Hg on a high FIO2 of >0.9 and/or a Murray score of 2–3 indicates a mortality risk of ≥50%, while a P/F ratio of <80 mm Hg on a high FIO2 of >0.9 and/or a Murray score of 3–4 indicates an 80% mortality risk.
Patients were excluded if they were cases of conversion from initial veno-arterial ECMO, had been on a mechanical ventilation for longer than 7 days at the time of initiation of the ECMO support, had haemodynamic instability with a reduced left ventricular ejection fraction (<40%), had pneumothorax or air leak syndrome, had ARDS due to thoracic trauma, had ARDS due to extrapulmonary triggers, are known to be pregnant, or are judged by the ICU attending doctors as being unsuitable to participate in this study based on their medical condition.
Since eligible patients are expected to be unconscious, the trial information will be given to a proxy in person by physicians before enrolment in the study, and both written and verbal informed consent will be obtained. When the patient becomes alert, the attending physicians will obtain informed consent. If enrolment is rejected, the data of that patient will not be used for the analyses. Physicians will attempt to obtain informed consent from the patient even if consent has already been provided by the proxy. An example of the participant consent form is shown in online supplemental material. Approval from the local ethical committee will be needed for ancillary studies of the patient data, unless this is waived based on prior approvals or the design of the studies.
Supplemental material
Interventions
Explanation for the choice of comparators
There is poor evidence as to the optimal PEEP setting in patients with ARDS requiring V-V ECMO support. In this study, which is being conducted to investigate beneficial effects of a high PEEP setting, we set the group with a low PEEP setting during ECMO as the control group. We will use 5 cmH2O as a low PEEP setting, which is considered a the minimum PEEP for patients with ARDS, based on previous literature.9
Intervention description
Within 24 hours after the start of V-V ECMO support, registration will be performed by electronic data capture (EDC) on a personal computer. Then, patients will be randomised to the high PEEP group and low PEEP group. In the high PEEP group, the PEEP will be set at 15 cmH2O from the start of V-V ECMO support until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmH2O. Other treatments will be the same in the two groups.
In both groups, the invasiveness of mechanical ventilation, except for the PEEP, will be reduced for lung protection. The preset goals for oxygenation are a PaO2 of 55–65 mm Hg. Accordingly, the tidal volume will be decreased to ensure that the plateau pressure does not exceed 30 cmH2O. Also, the settings of FIO2, respiratory rate and driving pressure were adjusted to <0.5, 10 times/min and 8 cmH2O, respectively. Hypercapnia is allowed for lung protection (arterial carbon dioxide tension (PaCO2) ≥70 mm Hg).
During the period of intervention, it is left to the charge of the ICU physicians to judge whether the lung injury has improved sufficiently to attempt a weaning trial from ECMO, based mainly on the findings of daily blood gas examinations (eg, P/F ratio and PaCO2) and daily chest X-rays, and where needed, chest CT.
After the lung function improves, the sweep gas flow will be gradually tapered and finally switched off for 4–24 hours. In the weaning trial, the settings for mechanical ventilation will be adjusted to achieve the following criteria: FIO2 ≤0.6 and plateau pressure ≤30 cmH2O. If the arterial blood gases and respiratory parameters remain stable (eg, PaO2 >70 mm Hg), the ECMO system will be disconnected.
When the participant does not satisfy the eligibility criteria after registration before liberation from V-V ECMO, the intervention described above will be discontinued and the PEEP setting will be decided according to the clinical preference. Then, they will be excluded from the analyses and labelled as dropouts.
Relevant concomitant care permitted or prohibited during the trial
All treatments will be allowed, and there will be no prohibited treatments in either group.
Provisions for post-trial care
All patients who will suffer harm from participation in the trial will be covered by the Japanese public healthcare system.
Outcomes
The primary endpoint is ECMO-free days (EFDs) on day 28, defined as the number of days from successful weaning from V-V ECMO to day 28. The concept is similar to ventilator-free days (VFDs).15 EFDs are typically defined as follows. EFD=0, if the subject dies within 28 days after the start of ECMO support. EFDs=28 × in patients who are successfully liberated from ECMO × days after initiation of ECMO. EFD=0, if the subject is on ECMO for >28 days (figure 2). The 28-day time frame was initially chosen because most subjects with ARDS either die or are extubated by day 28.16 We defined EFDs as the primary endpoint, because we believe that it is a more appropriate index for evaluating improvement of lung injury as compared with mortality.
Calculation of EFDs at 28 days. ECMO, extracorporeal membrane oxygenation; EFDs: ECMO-free days.
The secondary endpoints are the mortality rate on day 28, the in-hospital mortality on day 60, number of VFDs during the first 60 days and length of ICU stay.
In the subgroup analysis, we propose to analyse the effects of high PEEP versus low PEEP setting separately according to indices of lung recruitability at the start of ECMO support. The indices of lung recruitability include the recruitment-to-inflation ratio (R/I) and the static lung compliance (Cst). Regarding the measurement for recruitability, we follow the method described in previous reports.17 18 In brief, all measurements were performed in the supine position after confirming a stable respiratory status in ventilated, deeply sedated patients (Richmond Agitation- Sedation Scale [RASS] ≤−3). If necessary, neuromuscular blockade was also used to maintain adequate levels of sedation. To measure the R/I ratio, alveolar derecruitment was evaluated by the first expired volume immediately after lowering the PEEP level from 15 cmH2O to 5 cmH2O.
Participant timeline
The main timeline of this study is shown in figure 3.
Time schedule for the trial. ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; PEEP, positive end-expiratory pressure; SOFA Score, Sequential Organ Failure Assessment Score.
Patient and public involvement
There was no patient or public involvement in the design and conduct of this study.
Sample size
For the primary outcome measure, we assumed a mean number of EFDs of 10.5 days, with a SD of 10 in the placebo group, based on past sample data of patients admitted to our ICU (53 cases from 2014 to 2021). Referring to the results of the ExPress Trial,4 we set 4.0 days as a difference in the number of EFDs between the high PEEP group and low PEEP group (10.5 days vs 6.5 days). It was estimated that a sample size of 100 per group would be needed to obtain at least 80% statistical power at a two-sided significance level of 5% by a Student’s two-sample t-test. To compensate for the loss of participants to follow-up (5%), we decided to enrol 105 patients per group (total study sample, 210 subjects).
Recruitment
This study will be conducted with the participation of 19 ICUs in Japan. The ICU physicians at each hospital will provide the patients with adequate information about the study.
Assignment of interventions: allocation
Sequence generation
The randomisation will be performed using stratified block randomisation with a block size of two or four on the EDC site. The randomisation list was automatically generated with a random sequence in each hospital on the EDC, based on stratification according to the age of the subjects (≥60/<60 years). Therefore, stratification will be performed for two factors (facility and age). Once physicians input the inclusion of a new participant on the EDC site, his/her allocation is immediately noted on the EDC site.
Concealment mechanism
The results of the allocation will be shown on the EDC site of each hospital and researchers at one hospital will be blinded to the assignments and outcomes of the patients at the other hospitals.
Implementation
The allocation will be performed on the EDC. Clinicians and investigators will enrol patients and assign them to the high PEEP or low PEEP group according to the allocation.
Assignment of interventions: blinding
Due to the type of the study design, it is impossible to blind keep the investigators, patients and care providers blinded to the group allocation. However, the data analysts will be kept blinded to the group allocation.
Data collection and management
Assessment and collection of outcomes will be performed by the ICU physicians at the participating hospitals. As for the mortality at 28 days, if a patient has been already discharged by 28 days, the outcome will be collected by a phone call to the patient’s general practitioner or to any medical staff involved in the care of the patient after discharge from the ICU.
Patients included are expected to stay in the ICU until they are liberated from ECMO, which means the primary outcomes (EFDs at 28 days) of almost all included patients could be expected to be collected by ICU physicians without any extra effort. However, if a patient is transferred to another hospital before he/she is liberated from ECMO, the outcomes will be collected by a phone call to the patient’s general practitioner or to any medical staff involved in the care of the patient.
Patient data will be stored as raw medical records at each participating hospital and remain anonymised on the EDC for at least 5 years. Changes in the EDC will be preserved on a log showing information about who changed the information and when.
All patient data will be anonymised in the EDC system. Only the chief investigator at each participating hospital, who has in his/her possession the original ID and password for accessing the EDC can input data on patients at his/her facility. The Statistician and Central Monitor will have exclusive access to all participants’ data on the EDC.
Statistical methods
Statistical methods for primary and secondary outcomes
Statistical analyses will be performed using an intention-to-treat analysis with a full analysis set (FAS). FAS is defined as all subjects for whom there were no violations of the main eligibility criteria (selection and exclusion criteria) or conflicts with the discontinuation and dropout criteria. Student’s t-test will be used to evaluate the significance of differences in the log-transformed values of the number of EFDs at 28 days. For analysis of the secondary endpoints, Fisher’s exact test will be used to analyse differences in the categorical variables (mortality on day 28 and in-hospital mortality on day 60), and Student’s t-test will be used to analyse differences in the continuous variables (VFDs during the first 60 days and length of ICU stay).
Interim analyses
Safety monitoring will be conducted in a timely manner by the Safety Monitoring Committee, comprising Kei Suzuki, Yusuke Okazaki and Yuya Yoshino of Hiroshima City North Medical Center Asa Citizens Hospital. As this study is being conducted in the ICU, attempts will be made to identify signs of any serious adverse events as early as possible through daily chest X-rays and blood examinations. If serious adverse events associated with the trial are identified, the chief investigator at the corresponding hospital will immediately report them to the director of that hospital and the primary investigator. The primary investigator will then take appropriate actions under the guidance of the Ethics Committee for Clinical Research of Hiroshima University and the Safety Monitoring Committee. The Safety Monitoring Committee will discontinue the study if a marked difference in safety is noted based on the severe adverse events. We do not propose to conduct any interim analysis of the efficacy.
Methods for additional analyses (eg, subgroup analyses)
We propose to conduct a subgroup analysis to determine the effects of a high PEEP setting as compared with low PEEP setting separately according to the indices of lung recruitability at the start of ECMO support. The indices of lung recruitability include the R/I and Cst.
Methods of analysis to handle protocol non-adherence and any statistical methods to handle missing data
In this study, we will perform FAS analysis as the main analysis. Any patients with missing data on the primary or secondary outcomes will be excluded. The safety analysis will be performed including all patients, even if there are missing data.
Plans to give access to the full protocol, participant level-data and statistical code
Both the protocol and data will be available on reasonable request and approval from the relevant authorities after the trial is completed.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee
The principal investigator and study coordinator is Shinichiro Ohshimo, Hiroshima University Hospital. The data manager is Mitsuaki Nishikimi, Hiroshima University Hospital. The statistical analysis manager is Kunihiko Takahashi, Tokyo Medical and Dental University. The Certification of the Ethics Committee for Clinical Research is established at Hiroshima University Hospital as the Coordinating Center and Trial Steering Committee.
Composition of the data monitoring committee, its role and reporting structure
Central monitoring will be performed by the Data Monitoring Committee, which consist of Kazuya Kikutani, assistant professor, Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University. On-site monitoring will be performed at each hospital by monitors appointed by the Data Monitoring Committee if the committee judges that such monitoring is needed based on the results of central monitoring.
Adverse event reporting and harms
If serious adverse events associated with the trial are identified, the chief investigator at the corresponding hospital will immediately report them to the director of that hospital and to the primary investigator. The primary investigator will then take the appropriate actions under the guidance of the Ethics Committee for Clinical Research of Hiroshima University and the safety monitoring committee. All serious adverse events associated with the trial will be shared among all researchers by the primary Investigator.
Frequency and plans for auditing trial conduct
An independent party will audit and report the results.
Plans for communicating important protocol amendments to relevant parties (eg, trial participants, ethical committees)
Any protocol modifications will be reviewed by the Ethical Committee for Clinical Research of Hiroshima University and then registered at jRCT (https://jrct.niph.go.jp). All relevant information will be shared among the researchers.
Dissemination plans
The results of this study will be presented at national and international medical congresses, and also published in a scientific journal.
Discussion
The ExPress SAVER Trial is the first large multicentre RCT being conducted to investigate whether a high PEEP setting or low PEEP setting is more beneficial for ameliorating the lung injury in patients with severe ARDS requiring V-V ECMO. As compared with ventilation strategies in the absence of V-V ECMO, those in patients needing ECMO have received relatively little attention, and the optimal PEEP setting in patients receiving ECMO has not been established yet. We believe that this trial can help clarify the most beneficial mechanical ventilation strategies for patients with severe ARDS receiving V-V ECMO support.
In this study, we also plan to conduct a subgroup analysis according to the indices of lung recruitability at the start of ECMO support. Recently, several studies have reported on the heterogeneity of ARDS, and the most appropriate management for ARDS might differ according to the subclinical phenotype.19–21 We consider it not surprising that the beneficial effects of high PEEP settings differ according to differences in the lung recruitability at the start of ECMO support. In this sub-group analysis, we will use R/I, which has been reported as a useful index of lung recruitability in several previous studies.
There are several limitations of the ExPress SAVER Trial. First, this is an open-label study and the endpoints will be assessed by ICU physicians. However, the criteria for liberation from ECMO are already set prior to the start of the study, and outcomes which cannot be influenced by the physicians’ judgement, including the mortality on day 28 and in-hospital mortality on day 60, will be also evaluated as secondary endpoints. Second, we decided not to use novel monitoring devices for the PEEP setting, such as electrical impedance tomography and oesophageal balloon catheter for measuring the oesophageal pressure, because these devices are used only at a limited number of ECMO centres in Japan. Both have the potential to help estimate the most appropriate PEEP setting for individual patients with ARDS requiring ECMO, although the benefits of personalising PEEP settings have not yet been established.
Trial status
This study protocol was approved by IRB at Hiroshima University hospital on 27 September 2022 (C2022-0006). This study protocol is version 4 made on 28 March 2023. The recruitment period is between 15 November 2022, and 31 March 2026. The first patient was randomised on 18 November 2022.
Ethics statements
Patient consent for publication
Acknowledgments
We acknowledge and honour all of our team members who consistently put themselves in harm’s way during the COVID-19 pandemic. We dedicate this manuscript to them, as their vital contribution to knowledge about COVID-19 and sacrifices on the behalf of patients made it possible. We also want to thank all study participants for making this work possible.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors MNishikimi and SO: conception and design of the study, interpretation of data and drafting of the manuscript. JH, KF and YH: coordination and conduction of the study and interpretation of data. TAnzai and KT: drafting of the manuscript (statistical part) and statistical analysis. JI, YO, TAokage, TIkeda, TYagi, GS, KI, KK, DKonno, NH, TN, YM, DKasugai, HK, TIino, SK, HH, YI: conduction of the study and critical revision of the manuscript for important intellectual content. TYoshida, TO, KM, KS, MNakamura, SI: supervision of the study and critical revision of the manuscript for important intellectual content. NS: conception and design of the study and supervision of the study.
Funding This work was supported by JSPS KAKENHI (Grant Numbers JP 22K09120 and JP 20K08541), the TSUCHIYA MEMORIAL MEDICAL FOUNDATION (Grant Numbers N/A), a Grant-in-aid for multicenter clinical research from the Japanese Association for Acute Medicine (Grant Numbers N/A), Japan Agency for Medical Research and Development (Grant Number JP22fk0108654).
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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