Sedation (painkillers and sedative drugs) treats pain, reduces suffering, and helps patients in the intensive care unit (ICU) receiving extracorporeal membrane oxygenation (ECMO) remain comfortable. ECMO is a life support machine that provides oxygen and removes waste gases (carbon dioxide) in very sick patients with severe heart or lung failure. About 300-400 patients per year receive ECMO in the UK. These patients are younger and generally more healthy compared to other critically ill patients. However patients that survive ECMO have long-term health problems. These include anxiety, memory problems, withdrawal from medicines, and mobility issues. These problems issues could all be related to the type and amount of sedation given.

A sedation protocol is a way of guiding healthcare professionals how much sedation is given to patients in ICU. Too much sedation can cause confusion, hallucinations, excessive sleepiness, and longer time in hospital. Too little sedation can cause pain, distress, and also a longer time in hospital. Using a sedation protocol in non-ECMO patients has been shown to reduce these complications.

However, there are no protocols for giving sedation to ECMO patients in research papers. Investigators know healthcare staff find it difficult to manage sedation, and higher amounts of sedation is given to ECMO patients.

Aims:

To see whether it is possible to run a trial that compares using a sedation protocol against usual care.

Design/methods:

Thirty to 60 ECMO patients will be chosen and will be put into one of two groups. One group will receive usual care, and the other will receive care using the sedation protocol. The investigators will collect information from both groups to find out if the study design works and how many patients agree to take part.

Patient and public involvement/engagement:

The investigators received feedback from patients and family member participants which helped to design this proposal, the lay summary and what to measure in a trial. They will advise how the investigators should review study findings, and support sharing of results to the public.

Impact/dissemination:

The investigators will share findings through social media, patient charities, research papers and conferences.

Research questions

1. Is a cluster randomised controlled trial (cRCT) of a co-designed analgosedation protocol for adult ECMO patients feasible to conduct in terms of intervention delivery and data collection?
2. What are the barriers and facilitators to the conduct of a cRCT of a co-designed analgosedation protocol?

STUDY AIM AND OBJECTIVES Overall aim and purpose • The overall aim is to test the feasibility of a cRCT of a co-designed analgosedation protocol for use with adult extracorporeal membrane oxygenation (ECMO) patients.

Objectives

Overall objective

• To evaluate the feasibility of a cRCT of a co-designed analgosedation protocol for ECMO patients in terms of intervention delivery and data collection. This will inform the design of a future adequately powered cRCT.

Feasibility objectives

1. To assess fidelity of intervention delivery (adherence to the study protocol)
2. To establish barriers and facilitators to trial conduct and intervention delivery
3. To assess the feasibility of data collection methods
4. To assess the acceptability of the co-designed analgosedation protocol from the perspectives of nursing, medical, and pharmacy staff using it.

Exploratory clinical objectives include

1. Duration of mechanical ventilation
2. Occurrence, and duration of delirium (days)
3. Duration of ECMO treatment
4. Daily analgosedation doses (enteral and intravenous opioids and sedatives)
5. Average Pain (Critical Care Pain Observation Tool - CPOT), sedation (Richmond Agitation and Sedation Scale - RASS) and delirium (Confusion Assessment Method for the Intensive Care Unit - CAM-ICU) scores
6. ICU and hospital length of stay
7. ICU and hospital mortality
8. Accidental removal of the endotracheal tube
9. Accidental removal of other tubes and invasive lines
10. Use of physical restraints

STUDY DESIGN

The investigators will conduct a feasibility cRCT in two tertiary adult ECMO centres within Guy's & St Thomas' NHS Foundation Trust (St Thomas' Hospital (cluster 1) and Royal Brompton Hospital (cluster 2)). The investigators have chosen a cRCT study design to reduce intervention contamination by healthcare professional participants delivering care in the intervention or control arms. This is important to ensure all patients within the same cluster receive the same treatment.

Study procedures

Control arm: Will comprise the standard of care for delivery of analgosedation and all other medical treatment while in the ICU. Standard of care includes use of pain (Critical-Care Pain Observation Tool - CPOT), and sedation (Richmond Agitation and Sedation Scale - RASS) scores to assess pain and sedation levels, and the use of opioids and sedatives to keep patients comfortable and pain-free with drug type and dosing selected by the ICU clinical team. One cluster (ICU) will be randomly assigned to this arm.

Intervention arm: Will comprise the use of the previously co-designed analgosedation protocol. The analgosedation protocol will focus on setting a daily target for pain using the CPOT score, and sedation using the RASS score. The protocol will include recommended opioid and sedative medicines and their dose ranges, guidance on titration of opioid and sedative doses based on pain and sedation scores, daily interruption of sedation, use of non-pharmacological approaches to keep patients calm and to promote sleep, and methods of weaning opioids and sedatives. Patients will also be assessed daily for delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). All other treatments will be as per standard care and at the discretion of the treating clinical team. The sedation protocol will be used for up to 10 days after commencement of ECMO. One cluster (ICU) will be randomly assigned to this arm.

Randomisation and blinding

The ECMO unit will be the unit of randomisation, with patients allocated to treatment or control according to their assigned cluster. Participants will be included if they meet the inclusion criteria. Randomisation will be performed via the Sealed Envelope online randomisation module following ethics approval to provide enough time to organise staff training on the use of the protocol. Each cluster will be informed ahead of time as to which arm they will be allocated to for the purposes of training on the protocol. Given the nature of the intervention, neither the treating clinicians, patients, nor data collectors can be blinded. However, exploratory outcome measures are objective and documented in the patient's medical record.

Staff training on the use of the protocol

Healthcare professionals (doctors, nurses and pharmacists) will receive training from the research team on the use of the protocol prior to the study launching and during trial recruitment in the centre allocated to the intervention arm. The investigators will provide training (in-person and virtually) on elements of the trial protocol, including analgosedation dose titration, targeted Richmond Agitation and Sedation Scale (RASS) scores, and the duration of protocol use. The investigators will also provide refresher training to staff in both arms of the study on the use of CPOT, RASS, and CAM-ICU assessments. A training log will be used to determine who has been trained and the date of training.

Success criteria

The investigators will assess the following criteria to inform progression to seeking funding for a future cRCT.

Progression criteria

1. Adherence to the protocol as intended.
2. Acceptability of the protocol by staff delivering the intervention.

The investigators will use a traffic light system to guide progression criteria as recommended in best practice guidelines.

Green: Progress to apply for trial funding, with review of screening logs and protocol revision to address any barriers to recruitment and delivery of the intervention.

Amber: Consider progression to apply for trial funding with consultation with key stakeholders, review of screening logs, and protocol revision to address any barriers to recruitment, delivery of the intervention and harness facilitators.

Red: Unable to progress to trial funding application.

Assessment of protocol adherence

The investigators will assess protocol adherence daily using a fidelity checklist. Adherence to the protocol will be deemed good if 70% of daily fidelity checklist items have been met over the study period.

• Daily RASS target recorded in electronic health record
• RASS score recorded in electronic health record at least once per 12-hour nursing shift
• CPOT behavioural pain score recorded in electronic health record at least once per 12-hour nursing shift
• Delirium screen (CAM-ICU) recorded in electronic health record if RASS >-3
• Fentanyl used as continuous opioid infusion
• Fentanyl continuous infusion dose within recommended range over the 24 hours
• Propofol and/or midazolam used as continuous infusion sedative
• Propofol and/or midazolam continuous infusion dose within recommended range over the 24 hours

Assessment of acceptability of the protocol

Staff participants will complete the validated Acceptability of Intervention Measure (AIM)/Feasibility of Intervention Measure (FIM) questionnaires and will be offered the opportunity to participate in an interview. The questionnaire will include questions including whether the analgosedation protocol meets staff approval and is appealing for ECMO patients, and if it is liked and welcomed for use in clinical practice. The AIM/FIM questionnaire will be administered daily to staff, who have used the protocol, before they go home after their day or night shift. The investigators will use codes to track if staff have answered the AIM questionnaire more than once during the study period. The analgosedation protocol will be deemed acceptable if all participants rated the acceptability questions as a mark of 4 (agree) or 5 (completely agree) in 70% of cases across all completed questionnaires.

Fidelity

The investigators will use the Theoretical Domains Framework (TDF) to guide both the measurement of fidelity and to understand factors affecting trial delivery. The progression criteria for protocol adherence are based on at least a 70% fidelity rate in line with a previous study.

Data to be collected

Feasibility and fidelity trial data

The direct care team will enter de-identified data on to the electronic case report form (e-CRF). The investigators will develop an e-CRF to collect de-identified patient demographic characteristics, analgosedation management and patient outcomes in the intervention and control arms. The investigators will develop an additional e-CRF to allow the collection of feasibility data (assessment of protocol adherence). The research team will enter de-identified data to the electronic data capture system (REDCap). This is to ensure participant confidentiality. The investigators will ensure a delegation log is completed.

Data collected will include baseline characteristics and severity scores (age, gender, height, weight, body mass index, worst documented PaO2/FiO2 (P/F) ratio prior to ECMO cannulation, APACHE II scores, admission SOFA scores, admission C-reactive protein, pregnancy or postpartum, ECMO modality, primary reason for ECMO, admission type, past medical history), and exploratory clinical objectives from the patient's medical notes. The research team will record all patients who were enrolled into the study using a Site Master Log sheet and Screening Log, and record any concerns relating to the intervention. The investigators will collect sedation data up to 10 days for the intervention and control arms.

The investigators will collect data on intervention fidelity at the site using the sedation protocol using the fidelity checklist.

The investigators will conduct semi-structured interviews online via Microsoft Teams with staff participants to explore their perceptions of barriers and facilitators to use of the co-designed sedation protocol and their views on its acceptability during the feasibility trial. The investigators will use a interview guide and a questionnaire, which will be based on the TDF and the AIM/FIM Questionnaire. The investigators will use purposive sampling (based on years of ICU experience and the number of patient participants they have managed using the protocol) to interview doctors, nurses, and pharmacists involved in protocol delivery. The investigators will collect basic demographic characteristics, professional role, years of ICU experience. All interviews will be digitally recorded and transcribed by a professional transcription company.

Data analysis

Quantitative analysis

Fidelity analysis

The investigators will sum the scores of the daily checklist to a maximum score of 8 (if an item on the checklist is ticked yes, a score of 1 is added). The investigators will average the scores of all the daily checklists completed per patient during study enrolment. Protocol adherence will be defined as at least 70% of the daily checklist score.

Acceptability questionnaire analysis

The investigators will review all completed AIM/FIM questionnaires and if at least 70% of responses are recorded as 4 (agree) or 5 (completely agree), acceptability will be achieved.

Exploratory patient outcomes

The investigators will calculate the mean (standard deviation) and median (interquartile range) of duration of mechanical ventilation, occurrence and duration of delirium, duration of ECMO, daily (24-hour period) dose of each analgosedation drug, ICU and hospital length of stay, and ICU and hospital mortality. The investigators will also calculate counts (%) for occurrence of delirium, accidental removal of the endotracheal tube, accidental removal of other tubes and invasive lines, and use of physical restraints. The investigators will convert all opioids (enteral and intravenous) to morphine dose equivalents; benzodiazepines (enteral and intravenous) into midazolam dose equivalents using opioid and benzodiazepine conversion tables (47,48). The investigators will calculate daily doses by dividing the sum of all analgosedation doses received during the data collection period by the number of days of collected data. Data will be analysed using R Studio.

Qualitative analysis

To analyse data on barriers, facilitators and acceptability, the investigators will use the Framework Method informed by the AIM/FIM Questionnaire and Theoretical Domains Framework (TDF). The investigators will dual-code transcripts coding data within the domains of the TFA and the TDF. The investigators will group and mark codes from the transcripts with one or more short descriptors to organise the raw data. The codes will then be grouped, summarised and categorised within the framework. The investigators will use NVIVO to support the coding and the analysis of the qualitative data.

Inclusion Criteria:

• Aged 18 years and older
• Receiving IV continuous infusions of analgosedation medication
• Receiving ECMO treatment

Exclusion Criteria:

• There will be no exclusion criteria as analgosedation management is routine for all adult ECMO patients.

The King's Open Research Data System (KORDS) at King's College London will be used as a data repository, which will provide long-term storage and access for anonymised data and study protocol at project-end and to support publications. KORDS uses the Figshare data repository platform, providing a simple, self-deposit way for researchers to upload and share their data, and a publicly accessible showcase of datasets from King's research. It supports Open Research, enabling researchers to make datasets discoverable, accessible and citeable. All datasets have a DOI and a structured metadata record so that they can be shared and cited when re-used. Depositing meets the policy requirements of funders for data retention and sharing, and the requirements of many publishers for access to datasets supporting publications.

The data will be made available following publication of research findings in peer-reviewed manuscripts and presentation at international conferences.

Institution access will be needed to access any data. This includes permission to access the specific university and hospital servers. Potential users will require tools including Microsoft Excel and Microsoft Word to access and use the data, which are widely adopted in many institutions and sustainable. The data will be shared via the University repository KORDS but it will not be openly accessible. Requests for access to the data will be handled directly by the research team in line with local policies.