==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0287470 PONE-D-22-25386 Study Protocol Medicine and Health Sciences Health Care Health Care Facilities Hospitals Intensive Care Units Biology and Life Sciences Neuroscience Cognitive Science Cognitive Neuroscience Cognitive Neurology Neuropsychological Testing Biology and Life Sciences Neuroscience Cognitive Neuroscience Cognitive Neurology Neuropsychological Testing Medicine and Health Sciences Neurology Cognitive Neurology Neuropsychological Testing Biology and Life Sciences Neuroscience Neuropsychology Neuropsychological Testing Biology and Life Sciences Psychology Neuropsychology Neuropsychological Testing Social Sciences Psychology Neuropsychology Neuropsychological Testing Medicine and Health Sciences Mental Health and Psychiatry Mental Health Therapies Biology and Life Sciences Neuroscience Cognitive Science Cognitive Psychology Clinical Psychology Biology and Life Sciences Psychology Cognitive Psychology Clinical Psychology Social Sciences Psychology Cognitive Psychology Clinical Psychology Research and Analysis Methods Research Design Survey Research Surveys Medicine and Health Sciences Clinical Medicine Clinical Trials Randomized Controlled Trials Medicine and Health Sciences Pharmacology Drug Research and Development Clinical Trials Randomized Controlled Trials Research and Analysis Methods Clinical Trials Randomized Controlled Trials Medicine and Health Sciences Health Care Quality of Life Medicine and Health Sciences Mental Health and Psychiatry A protocol for a pilot randomised controlled trial of an Early Psychiatric Assessment, Referral, and Intervention Study (EPARIS) for intensive care patients Protocol for Early Psychiatric Assessment, Referral and Intervention Study https://orcid.org/0000-0002-4094-5936 Flaws Dylan Conceptualization Funding acquisition Methodology Project administration Supervision Writing – original draft Writing – review & editing 1 2 3 4 * Allen Chelsea Conceptualization Methodology Project administration Writing – review & editing 5 Baker Stuart Conceptualization Methodology Supervision Writing – review & editing 6 https://orcid.org/0000-0001-6339-0374 Barnett Adrian Conceptualization Formal analysis Methodology Supervision Writing – review & editing 5 Metcalf Olivia Conceptualization Methodology Supervision Writing – review & editing 7 Pollock Hamish Conceptualization Methodology Writing – review & editing 6 https://orcid.org/0000-0003-4509-4015 Ramanan Mahesh Conceptualization Methodology Supervision Writing – review & editing 8 9 10 11 Tabah Alexis Conceptualization Methodology Supervision Writing – review & editing 2 4 6 Varker Tracey Conceptualization Methodology Supervision Writing – review & editing 7 1 Critical Care Research Group, The Prince Charles Hospital, Queensland, Australia 2 School of Clinical Sciences, Queensland University of Technology, Queensland, Australia 3 Metro North Mental Health, Caboolture Hospital, Queensland, Australia 4 Faculty of Medicine, University of Queensland, Queensland, Australia 5 Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health & Social Work, Queensland University of Technology, Queensland, Australia 6 Department of Intensive Care, Redcliffe Hospital, Queensland, Australia 7 Phoenix Australia, Centre for Posttraumatic Mental Health, Department of Psychiatry, University of Melbourne, Victoria, Australia 8 Department of Intensive Care, Caboolture Hospital, Queensland, Australia 9 Adult Intensive Care Services, The Prince Charles Hospital, Queensland, Australia 10 Mayne Academy of Critical Care, University of Queensland, Queensland, Australia 11 Critical Care Division, The George Institute for Global Health, University of New South Wales, New South Wales, Australia D’Agostino Armando Editor Università degli Studi di Milano, ITALY Competing Interests: The authors have declared that no competing interests exist. * E-mail: Dylan.flaws@health.qld.gov.au 29 6 2023 2023 18 6 e028747021 9 2022 2 6 2023 © 2023 Flaws et al 2023 Flaws et al https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Up to 80% of Intensive Care Unit patients experience physical, cognitive, and/or psychological complications post-discharge, known as ‘Post Intensive Care Syndrome’ (PICS). Early diagnosis and intervention are a priority, but while current post-intensive care follow-up processes endorse a multidisciplinary model, incorporating a psychiatric consultation has not been studied. Methods A pilot, open-label randomised controlled trial was developed by a multidisciplinary team to evaluate the feasibility and acceptability of incorporating a psychiatric review into an existing post-ICU clinic. The study will run for 12 months and aim to recruit 30 participants. Inclusion criteria for participants: a) ICU admission greater than 48 hours, b) no cognitive impairment that prevents participation, c) ≥ 18 years old, d) residing in Australia, e) fluent in English, f) able to provide GP information, and g) likely to be contactable in 6 months. Patient recruitment will be at Redcliffe Hospital, Queensland, Australia, and will involve patients attending the Redcliffe post intensive care clinic. Participants will be allocated to intervention or control using block randomisation and allocation concealment. Participants allocated to the control arm will receive the standard cares provided by the clinic, which involves an unstructured interview about their ICU experience and a battery of surveys about their psychological, cognitive, and physical function. Those allocated to the intervention arm will receive these same cares as well as an appointment with a psychiatrist for a single session intervention. The psychiatric intervention will involve a comprehensive review, including comorbid disorders, substance use, suicidal ideation, psychosocial stressors, social/emotional supports. Psychoeducation and initial treatment will be provided as indicated and recommendations given to the patient and their GP about how to access ongoing care. In addition to surveys conducted as part of standard clinic cares, all participants will complete additional questionnaires about their history, hospital experience, mental and physical health as well as employment circumstances. All participants will be followed up 6 months after their appointment and will be invited to complete follow-up questionnaires about their mental and physical health, as well as health service use and employment circumstances. The trial has been registered with ANZCTR (ACTRN12622000894796). Results To evaluate the feasibility and acceptability of the intervention to the patient population. Differences between groups will be assessed using an independent samples t-test. Resource requirements to administer the intervention will be evaluated by reporting the mean duration of the EPARIS assessment and approximate cost per patient to provide this service. To estimate the effect size of any treatment effects, changes in secondary outcome measures between baseline and 6 months will be compared between intervention and control groups using Analysis of Covariance regression. As this is a pilot, we will not use p-values or test a null hypothesis, but will give confidence intervals. Conclusions This protocol provides a pragmatic evaluation of the acceptability of introducing early psychiatric assessment into an existing post-ICU follow-up process, and if considered acceptable will inform future research into the efficacy and generalisability of the intervention. The strengths of EPARIS are the prospective, longitudinal design with a control population, and its use of validated post-ICU outcome measures. http://dx.doi.org/10.13039/100017511 Metro North Hospital and Health Service Clinician Research Fellowship https://orcid.org/0000-0002-4094-5936 Flaws Dylan Finlay http://dx.doi.org/10.13039/100017511 Metro North Hospital and Health Service Clinician Research Fellowship https://orcid.org/0000-0003-4509-4015 Ramanan Mahesh DF, MR Metro North Hospital and Health District Clinician Research Fellowship https://metronorth.health.qld.gov.au/research/grants/crf The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityNo datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. Data Availability No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. ==== Body pmc1. Introduction Novel technology, and clinical research have consistently improved Intensive Care treatment to the point where around 90% of patients admitted to an Intensive Care Unit (ICU) today will be discharged alive [1]. This rise in survival rates has precipitated a shift in focus from mere survival, to the quality of life after survival. It is now known that post ICU recovery is often complicated and partial [2], with as many as 80% of patients experiencing some form of physical, cognitive, and/or psychological complication which can persist for up to 15 years after their ICU discharge [3–5]. This complicated recovery trajectory following an ICU admission has been described in literature as ‘post intensive care syndrome’ (PICS). Mental illness is a common feature of PICS. A large UK cohort study of nearly 5,000 ICU survivors found the prevalence of anxiety, depression, and PTSD to be 46%, 40% and 22% respectively, with 18% meeting criteria for all three [6]. An increased prevalence of mental illness treatment and psychotropic medication use was also recently found in the 5 years following an ICU admission when compared to the 5 years prior [7]. The prevalence and burden of PICS may vary between populations, but it is demonstrably associated with substantial personal and financial burden for patients and families [8]. Disrupting social engagement and employment, the health and social costs are immense [3, 9, 10] and post-ICU psychological morbidity is associated with poor quality of life (QoL) across all domains regardless of aetiology [11]. Further research into prevention, early diagnosis and intervention of PICS is internationally considered a priority [12]. Many post-ICU clinics review patients after discharge, often with nursing, allied health, and psychologist input, but to our knowledge the effect of a consultation with a psychiatrist soon after ICU discharge on PICS outcomes has not been investigated. This is despite a recent meta-analysis demonstrating benefit from early psychological intervention targeted to symptomatic individuals following recent trauma [13] and a recent overview of PICS emphasising early screening and treatment of psychological morbidity to prevent longer term impairment, and advocating for a more targeted approach to intervention delivery [14]. The aim of the current paper is to describe the protocol for the Early Psychiatric Assessment, Referral, and Intervention Study (EPARIS). This randomised controlled trial will compare early psychiatric assessment and referral to treatment as usual. It is hypothesised that an early psychiatric consultation involving evaluation, initial treatment (such as psychoeducation and pharmacotherapy), recommendations on how to access ongoing care will be feasible to implement in a post-ICU clinic and acceptable to that population. Secondary aims include testing whether an intervention may improve a patient’s sense of self-efficacy, improve access of ongoing therapy, and reduce the long-term burden of PICS. 2. Objectives The primary objective of this study is to: To evaluate feasibility (cost and practicability) and acceptability of an early psychiatric intervention in a post-ICU clinic. Secondary objectives are: Assess the impact of early psychiatric assessment and provision of referral options on self-efficacy and rates of health service access for patients requiring psychological intervention post-ICU. Measure the change in symptom severity for anxiety, depression, and PTSD between presentation, and 6 months after presentation. Measure the impact on work, income, and independence in activities of daily living (ADL). 3. Materials and methods 3.1 Protocol version Version 3 dated 06/09/2022 3.2 Ethical and research approvals Ethics approval has been obtained by The Prince Charles Hospital Human Research Ethics Committee (Approval number: HREC/2020/QPCH/86123) and protocol is reported in accordance with SPIRIT-PRO guidelines [15]. The trial has been registered with ANZCTR (Approval number: ACTRN12622000894796) 3.3 Study design The EPARIS study is a prospective, parallel, single site, pilot, two-arm randomised controlled trial. The effectiveness of early psychiatric assessment, referral and intervention will be compared with treatment as usual. Data will be collected with consent from routinely kept hospital records, and from participants at two times (pre-intervention and six months post intervention). This trial will be conducted and reported according to the pilot trials extension of the CONSORT statement: http://www.consort-statement.org/extensions/overview/pilotandfeasibility. 3.3.1 Setting This study will be conducted in the Redcliffe Hospital, Queensland, Australia. The Redcliffe Hospital ICU has 10 beds and admits 500 patients per year. It provides general intensive care management for a broad spectrum of critical illnesses, apart from tertiary cardiothoracic, neurosurgical, trauma and burns management. Redcliffe Hospital has an established ICU follow-up clinic, where ICU survivors are reviewed around three months after discharge from hospital and data pertaining to physical, cognitive, and psychological functioning, quality of life and disability is collected to monitor for PICS. Where specific issues are identified, appropriate counselling and referrals are provided. Patients are referred predominantly from the Redcliffe Hospital ICU, but also from other local hospital ICUs. The clinic reviews approximately 80 patients per year. All ICU discharges meeting eligibility criteria are contacted by telephone between 1 and 3 months after ICU discharge and offered a post-ICU clinic appointment. The clinician makes initial contact with patients recently discharged from ICU who meet engagement criteria (ICU admission over 48 hours and able to provide informed consent). 3.4 Study team, participants and sample size The study team was created through and existing academic partnership between the Psychiatrist (DF) intended to deliver the intervention and ICU staff operating the current Post-ICU Clinic (SB, CA, AT, HP) who will be responsible for recruitment and data collection. Content experts OM and TV were approached to ensure intervention fidelity and best-practice. Methods and process expertise was sought from statistician AB and Intensivist MR. Participants will be sourced from patients attending the clinic. This study is aiming for a convenience sample of 40 participants. The feasible recruitment window is 12 months, with an estimated maximum possible sample size of 80. Assuming a 50% recruitment percentage (with 70% agreeing to participate and 70% of those completing the follow-up survey), it is estimated that data will be collected from a sample of approximately 30 to 40 patients attending the Redcliffe ICU follow-up clinic over 12 months, with 15 to 20 allocated to the control and intervention arms respectively. 3.5 Inclusion and exclusion criteria People discharged from the participating ICU will be eligible to participate if they meet the inclusion criteria described in Table 1. 10.1371/journal.pone.0287470.t001 Table 1 EPARIS inclusion and exclusion criteria. Inclusion Exclusion An ICU admission > 48 hours Life expectancy at discharge < 6 months No cognitive impairment that prevents participation Unable or unwilling to provide consent to participate for the study duration ≥ 18 years Unlikely to remain contactable for study duration Sufficient English Willing to provide GP information 3.6 Initial approach and consent Eligible patients will be contacted by clinical staff and invited to attend the clinic 1 to 3 months after their ICU discharge, as summarised in Fig 1. If a patient agrees to attend the clinic, the staff member will inform them about the study. If the patient expresses interest, verbal permission will be sought to allocate the patient’s appointment time with a view to conducting full consent to participate upon attending their appointment. 10.1371/journal.pone.0287470.g001 Fig 1 SPIRIT schedule. Upon attending the clinic, potential participants will be provided written and verbal information regarding the study and invited to ask any questions they have before being invited to participate. Potential participants will not be aware if they have been allocated to the control or intervention arm at this stage, but staff and investigator concealment will not be possible beyond this point due to the psychiatrist being present/absent in the clinic. A written patient information and consent form will be provided. People who agree to participate will complete the written consent form before baseline data collection. Participants will also give permission for research staff to access data from their clinical records and will complete a series of questionnaires as described above. Eligible, fully informed, and consenting patients will then be entered into the study (see Fig 2). 10.1371/journal.pone.0287470.g002 Fig 2 Recruitment flowchart. 3.7 Allocation and concealment Patients who provisionally agree to participate will be allocated to attend appointments when either only business-as-usual cares are available, or when the intervention also is available. We will use block randomisation in blocks of 4 or 6, in a 1:1 ratio, with a computer-generated list by the study statistician (AB) and provided in enclosed envelopes to conceal allocation until verbal consent is provided. An appointment time will then be provided, but allocation to treatment or control will remain concealed to the participant at this stage. This will be an open label RCT as will not be possible to conceal whether participants are in the intervention or control arm due to the nature of the intervention. Patients who choose not to participate will be offered appointment times as per business-as-usual and will not be part of the study. To monitor recruitment, a re-identifiable screening and recruitment log will be kept that will document patients eligible for approach, and subsequent contact. If a participant that has been allocated to receive the early psychiatric intervention chooses to withdraw consent, they will receive the standard cares provided by the clinic without the intervention, and any collected data will be withdrawn from the study. 3.8 Data collection The surveys described in Table 2 below have been selected to provide information on the patient’s background (premorbid risk/protective factors and baseline level of function), PICS measures (psychological, physical, and cognitive function) and Post appointment assessments (acceptability of the appointment, and subsequent health service use patterns). The battery of questions conducted at the appointment and at 6 months were both tested with a control sample, finding that completion takes 13 to 20 minutes. Data will only be accessible to members of the research team. 10.1371/journal.pone.0287470.t002 Table 2 Surveys conducted during the study. Survey Structure Description Routinely Collected Collected for Study Collected at 6-month follow-up Background Information Patient Reported Experience Measure (PREM) 11 item self-reported survey Used to collect information about the participant’s experience during their hospital admission. X Life Events Checklist (LEC-5) [16] 16 item self-reported survey Designed to screen for potentially traumatic events in a respondent’s lifetime. X X Posttraumatic Adjustment Screen (PAS) 10 item self-reported survey Designed to identify individuals at risk of developing PTSD/depression following a traumatic injury. X General Self Efficacy Scale [17] 10 item self-reported Survey Designed to assess optimistic self-beliefs to cope with a variety of difficult demands in life. X X Employment Information Questionnaire 7 item self-reported survey Explores changes to employment and income since their admission. X X PICS Measures Hospital Anxiety and Depression Scale (HADS) [18] 14 item self-reported survey in 2 subscales Measures symptoms of anxiety and depression X X PTSD Checklist for DSM-5 (PCL-5) [19] 20 item self-reported survey Assesses the 20 DSM-5 symptoms of PTSD. X X EQ5D-5L [20] 5 item self-reported survey Non-disease specific instrument for measuring health-related quality of life. X X Montreal Cognitive Assessment (MOCA-BLIND) [21] 10 item clinician administered test Rapid screening instrument for mild cognitive dysfunction. X Post Appointment Assessments Post Appointment Questionnaire 7 item self-reported survey Questions related to the perceived acceptability of their appointment X Health Services Use 12 item self-reported survey Explores access and utilisation of various health services in the preceding month. X 3.9 Clinic interventions 3.9.1 Treatment as usual At their appointment, all patients will complete standardised tools related to physical and mental wellbeing and participate in an interview (See Table 2) followed by the opportunity to provide feedback to the service about their hospital and clinic experience. The standard interview process is unstructured and guided by the patient, but generally covers the topics summarised in Table 3. 10.1371/journal.pone.0287470.t003 Table 3 Content of treatment-as-usual clinical interview. History The electronic medical record and discharge summary will be reviewed. Events surrounding the patient’s initial presentation are used to begin the conversation about admission. ICU events such as issues and interventions encountered are discussed. Staff are guided by the patient, and respectful when a patient chooses not to revisit their admission in detail Systems Assessment A review of body systems (eg. Cardiovascular, musculoskeletal, including mental health) is conducted, then the patient self-assesses their quality of life and functional ability pre and post ICU. Further assessment and referral to specialist services is discussed as appropriate. Psycho-social Social history encompassing pre and post ICU admission is explored, including relationships, employment, housing, and social interactions. Staff review services that may be able to alleviate identified stressors. The patient’s recollection of their admission is explored, mindful that some patient recollections will vary. Staff acknowledge patient feelings and experiences by explaining the prevalence and causes (eg. hallucinations and delusions) and consider referral for counselling services. 3.9.2 Early psychiatric assessment and referral (EPARIS) intervention EPARIS consists of an assessment phase, personalised treatment recommendations, and referrals to relevant services. 3.9.2.1 Assessment. Participants randomised to the intervention group will be given an appointment on a day and time when the psychiatrist is in attendance. Participants will see the psychiatrist in addition to completing the treatment-as-usual process described above. Prior to assessment, the psychiatrist will review clinical notes pertaining to premorbid history, and their ICU admission. In addition, the psychiatrist will review the baseline questionnaires, ICU notes and other relevant clinical information. The psychiatrist will discuss these with the participant and explore how this interrelates with their premorbid history, and their ICU experience. The psychiatrist will conduct a comprehensive psychiatric review, including comorbid disorders, substance use, suicidal ideation, psychosocial stressors, social/emotional supports. Diagnoses of any mental illnesses present will be made based on DSM-V criteria. Psychoeducation will be provided on any new mental illness present, detailing how this interrelates with their critical illness recovery, and general lifestyle advice will be provided. Initial treatment for any new mental illness commonly seen in post-ICU populations will be provided in accordance with local psychiatric guidelines. 3.9.2.2 Psychological treatments. Where indicated, education will be provided on appropriate psychological treatments. A letter will be sent to the patient’s GP to make referral for the agreed-on therapy. 3.9.2.3 Pharmacological treatments. The risks and benefits of pharmacological treatment will be discussed. If commenced, a letter will be sent to the patient’s GP to follow-up response and tolerability. Time taken for the intervention will vary between patients and will be documented, but up to one hour will be allowed for each patient. 3.9.2.4 Mental illness not related to ICU presentation. Where a patient has a pre-existing mental illness which is already being adequately managed, no further intervention will be provided. If new mental illness is identified or suspected, but unrelated to their ICU admission, contact details for relevant services will be provided and the psychiatrist will notify the patient’s GP. 3.9.2.5 Intervention follow-up. The Psychiatrist will follow-up all patients where an intervention is initiated 4 to 6 weeks after their appointment. If there has been at least a partial clinical response, a letter will be sent to the participant’s GP recommending ongoing monitoring. If there has been no response or a non-urgent deterioration, the letter will suggest referral for ongoing psychiatric review. 3.9.2.6 Imminent risks. If the participant appears to require inpatient psychiatric treatment, or there is concern of an imminent risk (such as suicidal ideation with intent and plan), or an urgent clinical deterioration, the participant will be directed to the local Emergency Department for review. If the imminent risk is identified during the intervention follow-up, the participant will be encouraged to attend their local hospital for urgent review. 3.10 Follow-up at 6 months Six months after clinic presentation, research staff will contact all participants to offer a follow-up appointment either in the clinic or by phone and conduct the follow-up survey as described below. If participants do not respond to the first contact attempt, research staff will attempt contact again one week later. Participants will complete a combination of some repeated measures from baseline, and some new measures as described in Table 2 above. 3.11 Fidelity of intervention The intervention will be administered by a single psychiatrist (DF) who will meet regularly with content experts (OM and TV) to discuss scenarios arising from the study, and how best to maintain intervention fidelity in each scenario. For situations not adequately accounted for in the protocol, a decision will be made by this group and documented as a precedent for future scenarios. This will be published with the results of the study in a deidentified format. 4. Statistical plan Analysis of this study aims to: Evaluate the feasibility and acceptability of the intervention to the patient population Estimate the effect size of any treatment effects to inform power calculations of future studies evaluating whether the intervention is beneficial 4.1 Outcome measures We will not use a primary outcome as this is a pilot study and hence the results are primarily to inform a larger design rather than confirming any hypothesis. This pilot, will also not use p-values or test a null hypothesis, but will provide relevant confidence intervals. 4.1.1 Feasibility and acceptability outcomes Responses to the Post Appointment Questionnaire will be assumed to be additive and averaged to produce an outcome measure of acceptability. Differences between groups will be assessed using an analysis of covariance (ANCOVA) model with the baseline questionnaire as an independent variable. A clinically significant finding in favour of the control arm will indicate a lack of acceptability for the EPARIS intervention, whereas no difference, or a difference in favour of the EPARIS arm will indicate acceptability. Resource requirements to administer the intervention will be evaluated by reporting the mean duration of the EPARIS assessment and approximate cost per patient to provide this service as a measure of feasibility. Principal costs are likely to be human resources, but other considerations such as space and materials will also be described. It is anticipated that a process that allows 4 to 8 patients to complete the EPARIS intervention within a 4-hour clinic session would constitute a feasible process. As with acceptability, differences in resource requirements will be compared between the control and intervention groups. 4.1.2 Treatment outcomes Symptom scores for Anxiety, Depression, PTSD, and Physical functioning will be completed at the clinic appointment and repeated at 6 months. Anxiety and depression will be measured with the Hospital Anxiety and Depression Scale (HADS), PTSD symptoms with the PTSD Checklist for DSM-5 (PCL-5), and physical function with the EuroQOL survey (5 domains, 5 levels) EQ-5D-5L. Changes in treatment measures between baseline and 6 months will be compared between intervention and control groups to identify any clinically significant differences using ANCOVA regression with patients results at baseline fitted as a covariate. The model residuals will be checked to look for outliers and bimodality. Leave-one-out sensitivity analyses will be used to look for patients that strongly influence the results. To maintain a patient outcome focus, effect size will be estimated using Minimally Clinically Important Difference. Minimally Clinically Important Differences (MCID) of outcome variables are summarised in Table 4. The HADS MCID has been validated in a population of acute respiratory failure survivors, and showed comparable estimates across studies, follow-up and country [22]. The U.S. Department of Veterans Affairs advises that when using the PCL-5 to monitor progress of PTSD during treatment, a change of 5–10 points is reliable, while a change of >10 points is considered clinically meaningful [23]. A review of MCID for EQ-5D found heterogeneity in the literature, with thresholds between 0.03–0.52 being reported [24]. A threshold of 0.5 was selected for this study to ensure only meaningful change would be reported. 10.1371/journal.pone.0287470.t004 Table 4 MCID for secondary outcomes. PICS Feature Measure MCID Anxiety/Depression HADS ≥ 2.5 points(22) PTSD PCL-5 ≥ 10 points(23) Physical Function EQ-5D-5L ≥ 0.5 points(24) 4.3 Sample characteristics The demographics and results of the Baseline Outcome Measures Bundle will be described using proportions and associated 95% confidence intervals and visually compared between intervention and control groups to check the integrity of the randomisation. The overall characteristics of the sample will be described using summary statistics. This will help inform the generalisability of our results. The number of patients approached and consented will be tabulated, together with the number who dropped out or died. If 40% of more of patients drop-out, we will use a logistic regression model to identify potential predictors of drop-out using the variables collected at baseline. The amount of wave and item-missing data will be tabulated by treatment group. In a sensitivity analysis, we will impute item missing data using multiple imputation. There are no planned subgroup analyses. Data will be exported to R (version 4.2.0 or higher) for analysis. Initial results will be created using a scrambled treatment group with the real analysis being created once the investigators agree that the proposed statistical analysis, tables, and graphs are complete and appropriate [25]. 4.4 Data management and security All data will be treated in confidence and only made accessible to members of the research team on an as needs basis. All paper records will be stored in a locked filing cabinet, and any electronic databases will be stored on password protected computers. For dissemination of results, participants will only be referred to in the coded form e.g. “Participant A”, “Participant B” etc. All records will be destroyed (permanently deleted or shredded as appropriate) after 15 years, as per ‘Good Clinical Practice’ (GCP) guidelines. Electronically collected data will be directly entered into REDCap, hosted on a Queensland Health server. Hard copy responses will be manually entered into REDCap by a member of the research team. Once recruitment is complete, Data will be cleaned and uploaded to statistical software package R for analysis. Findings will be published in an academic journal and presented in scientific meetings. Deidentified data will be made publicly available for verification via the Open Science Framework. 5. Discussion While the healthcare burden associated with PICS is clear, and an improved way to prevent, detect and treat the syndrome is needed, current literature is yet to identify the best approach to post-ICU follow-up and care. Most studies advocate for some form of multidisciplinary approach which is sensitive to the complex nature of the patient population, but more evidence is needed to support clinicians in identifying which patients to follow-up, in what setting, and what services to provide. EPARIS will explore whether an early psychiatric review is an acceptable contribution to follow-up, and if the findings are suggestive of a possible clinical benefit. It will inform the design of larger clinical studies seeking to confirm whether the intervention improves patient outcomes. The clinic involved in this study is one of few post-ICU clinics currently operating in Australia. However, there has been growing interest in post-ICU clinics in Australia, with new clinics being planned. As such, the findings of this study provide an opportunity to inform post-ICU care both locally and nationally. The strengths of EPARIS are the prospective, longitudinal design with a control population and its use of validated post-ICU outcome measures. 6. Limitations As a pilot study with a small sample, this study is not powered to be able to identify clinical benefit, and while the participating clinic does accept referrals from other ICUs, the findings may not be generalisable to other settings given the heterogeneous nature of ICU populations. These limitations could be addressed by a subsequent multisite study adequately powered to evaluate the efficacy of the treatment on improving patient outcomes. The design and sample size for such a study would be greatly informed by the findings of this pilot study. Some aspects of the feasibility and acceptability of the intervention would be better explored in a subsequent or nested qualitative study to compliment EPARIS, but a quantitative approach has been selected for this pilot study to estimate effect size and assist the research team in planning subsequent larger studies. Further, feasibility and acceptability to other stakeholders such as family members and general practitioners should be explored in subsequent studies. 7. Implications for practice Improving post-ICU outcomes for patients with features of PICS has proven challenging. A multidisciplinary approach to post-ICU follow-up is commonly advocated for, with many health services providing this through a nurse-led post-ICU clinic. With evidence for post-ICU interventions currently being mixed and limited, the best approach remains unclear. This study will provide the first evidence as to whether there is a role for an early psychiatric review in the post-ICU follow-up process and provide a framework for future studies that wish to replicate this intervention in larger, multisite studies. This will help ICUs in planning and implementing post-ICU care pathways and referral processes. 8. Conclusion This protocol provides a pragmatic evaluation of the acceptability of introducing early psychiatric assessment into an existing post-ICU follow-up process, and if considered acceptable will inform future research into the efficacy and generalisability of the intervention. 9. Impacts This protocol provides a framework for a practical psychiatric intervention that can be applied to a post-ICU population and will evaluate whether that intervention will be acceptable to patients. The findings will inform larger multisite studies in demonstrating whether the intervention is effective and generalisable. Supporting information S1 Checklist Spirit guidelines checklist. (DOCX) Click here for additional data file. S1 Appendix Initial survey documents. (DOC) Click here for additional data file. S2 Appendix Follow-up survey documents. (DOC) Click here for additional data file. S1 File (DOCX) Click here for additional data file. 10.1371/journal.pone.0287470.r001 Decision Letter 0 Wang Tao (Alison) Academic Editor © 2023 Tao (Alison) Wang 2023 Tao (Alison) Wang https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The PLOS ONE style templates can be found at  https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and  https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.  3. We note that the original protocol that you have uploaded as a Supporting Information file contains an institutional logo. As this logo is likely copyrighted, we ask that you please remove it from this file and upload an updated version upon resubmission. Additional Editor Comments: 1. Please further detail the methods of this study, including the methods of randomization, concealment, blinding. 2. please add one section to elaborate how to maintain the intervention fidelity of this study. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ********** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ********** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes ********** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: No ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a protocol paper for a pilot trial. Keeping up with the goal of the pilot trial the paper describes what the feasibility and acceptability of the pilot RCT type paper should target. My suggestion to only change is that author must either remove the ANCOVA analysis description or must state what is the purpose of that analysis. As a pilot RCT this must not target for establishing or testing any statistical anything. The other revision I suggest is the writing style. For example, almost all sections consist of too many small paragraphs each consisting of 2-4 sentences. Also, provide section numbers for ease of readability and references. Reviewer #2: This paper will contribute to a pragmatic evaluation of the acceptability of introducing early psychiatric assessment into an existing post-ICU follow-up process, and if considered acceptable, will inform future research into the efficacy and generalisability of the intervention. However, some changes are advised in order to improve the transparency for the reader: 1. -Was the sample size calculated upon previous studies? It remains unclear whether appropriate power calculations were made prior to recruiting patients. Please take this up in your methods section or in the discussion. 2. can you provide further details regarding how to recruit participants and research team members? 3. Page 10: No cognitive impairment that prevents participation: please be concise, what scale are you talking about here? It would be good to name this scale and add the appropriate reference of this scale. 4. What will be the primary outcomes and the secondary outcomes for this pilot RCT, and how to measure these outcomes? Please provide more details about the outcome measurements. 5. Please provide information about the roles of research team members. For example, who will be responsible for the intervention delivery? Who will be responsible for the data collection? 6. as stated in Page 17:” Estimate the effect size of any treatment effects to inform power calculations of future studies evaluating whether the intervention is beneficial”, how to calculate the effect size of any treatment effects? Are you going to use cohen’s d or Hedges's g? 7. as stated in Page 17 “The amount of wave and item-missing data will be tabulated by treatment group. We will impute item missing data using multiple imputation.” Please justify why multiple imputation will be used to deal with the missing data, instead of another commonly used method- last observation carried forward (LOCF). 8. please provide the information of “Data management”. Who can access all the collected data? And where are you going to store and dispose of the research data hard copies? ********** 10.1371/journal.pone.0287470.r002 Author response to Decision Letter 0 Submission Version1 23 Jan 2023 The authors would like to thank the reviewers for their comments and feedback. We have reviewed the reviewers' comments and suggestions and made a series of changes to the manuscript in light of these which we feel strengthen and clarify the paper. In addition, the authors have decided to remove the surveys from supporting documents due to concerns publishing these may contradict the licensing for some of the underlying clinical tools being used. All tools used in the surveys are still described and cited. Thank you again for taking the time to review this manuscript, and we hope that the changes summarized below have addressed your comments. Warm Regards, A/Prof. Dylan Flaws Reviewer #1: This is a protocol paper for a pilot trial. Keeping up with the goal of the pilot trial the paper describes what the feasibility and acceptability of the pilot RCT type paper should target. My suggestion to only change is that author must either remove the ANCOVA analysis description or must state what is the purpose of that analysis. As a pilot RCT this must not target for establishing or testing any statistical anything. We acknowledge the reviewer’s concerns, as while Statistical analysis can be used in pilot studies and be appropriate, problems can arise when people create p-values and start testing hypotheses. We have clarified both in the abstract, and in section 4.1 – Outcome Measures that we won’t test hypotheses in this study, but we still want to fit appropriate statistical models to get an idea of the size of the effect and best inform the effect size for the larger sample size calculation. The other revision I suggest is the writing style. For example, almost all sections consist of too many small paragraphs each consisting of 2-4 sentences. Also, provide section numbers for ease of readability and references. The manuscript has been revised to improve readability with better paragraphing and section numbers. Reviewer #2: This paper will contribute to a pragmatic evaluation of the acceptability of introducing early psychiatric assessment into an existing post-ICU follow-up process, and if considered acceptable, will inform future research into the efficacy and generalisability of the intervention. However, some changes are advised in order to improve the transparency for the reader: 1. -Was the sample size calculated upon previous studies? It remains unclear whether appropriate power calculations were made prior to recruiting patients. Please take this up in your methods section or in the discussion. This is a convenience sample based on the availability of the psychiatrist to administer the intervention for the purposes of this study for 12 months. This has now been clarified in Section 3.4 – Participants and Sample Size 2. can you provide further details regarding how to recruit participants and research team members? This is now described in more detail in section 3.4 – Study Team, Participants and Sample Size 3. Page 10: No cognitive impairment that prevents participation: please be concise, what scale are you talking about here? It would be good to name this scale and add the appropriate reference of this scale. This has been reworded as “and able to provide informed consent” 4. What will be the primary outcomes and the secondary outcomes for this pilot RCT, and how to measure these outcomes? Please provide more details about the outcome measurements. The authors have intentionally avoided describing a “primary outcome measure” due to this being a pilot RCT. However, section 4.1 “Outcome Measure” has been reworded to try and clarify which outcome measures are being collected, and with which measurement tools. For further clarity, these have now been subdivided into “4.1.1 - Feasibility and acceptability outcomes”, and “4.1.2 – Treatment outcomes”. 5. Please provide information about the roles of research team members. For example, who will be responsible for the intervention delivery? Who will be responsible for the data collection? This is now better described in section 3.4 – Study Team, Participants and Sample Size. 6. as stated in Page 17:” Estimate the effect size of any treatment effects to inform power calculations of future studies evaluating whether the intervention is beneficial”, how to calculate the effect size of any treatment effects? Are you going to use cohen’s d or Hedges's g? The purpose of this pilot is to inform subsequent studies that will inform patient care. As such, our intention is to keep all measures focused on patient outcome. For this reason, the investagors have elected for MCID rather than Cohen’s d or Hedge’s g as a measure of effect size. Section 4.1.2 clarifies the rationale for this choice and refers the reader to Table 4 for the MCID of each outcome variable. 7. as stated in Page 17 “The amount of wave and item-missing data will be tabulated by treatment group. We will impute item missing data using multiple imputation.” Please justify why multiple imputation will be used to deal with the missing data, instead of another commonly used method- last observation carried forward (LOCF). Section 4.3 The authors elected for multiple imputation as LOCF relies on a strong assumption of no change and makes no use of potentially valuable information about the participants and/or time. Simulation studies have shown that it does not perform as well as multiple imputation for dealing with missing data (see for example DOI: 10.1002/sim.2099 and DOI: 10.1080/10543400903242795 and https://pubmed.ncbi.nlm.nih.gov/15889392/). 8. please provide the information of “Data management”. Who can access all the collected data? And where are you going to store and dispose of the research data hard copies? Section 4.4 – Data Management and Security now describes how physical and electronic data will be managed during the study, and how findings and deidentified data will be made available after study completion. Attachment Submitted filename: Response to Reviewers 120123.docx Click here for additional data file. 10.1371/journal.pone.0287470.r003 Decision Letter 1 D'Agostino Armando Academic Editor © 2023 Armando D'Agostino 2023 Armando D'Agostino https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 23 Mar 2023 PONE-D-22-25386R1A Protocol for a Pilot Randomised Controlled Trial of an Early Psychiatric Assessment, Referral, and Intervention Study (EPARIS) for Intensive Care PatientsPLOS ONE Dear Dr. Flaws, Thank you for submitting your revised manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a new revised version to address the points raised during this round of reviews. Due to unavailability of previous reviewers, your manuscript was sent to two new reviewers who expressed a favourable opinion, but require further minor amendments and specifications before publication. Please submit your revised manuscript by May 07 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Armando D'Agostino Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #3: Yes Reviewer #4: Yes ********** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #3: Yes Reviewer #4: Yes ********** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #3: Yes Reviewer #4: Yes ********** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #3: Yes Reviewer #4: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #3: Yes Reviewer #4: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #3: I am late to this party. I wonder if the chosen acceptability outcome will really reflect acceptability. The analysis will, of course, be carried on people who accepted to participate in the study. Among those who refused, some may have issues of acceptance of a psychiatric intervention. I guess the authors will have the opportunity to discuss this in their final paper. A qualitative approach might provide a deeper understanding of the acceptability and the overall experience of meeting a psychiatrist. Reviewer #4: Thank you for giving me the opportunity to review this protocol manuscript. The authors propose an interesting intervention that if feasible, could greatly impact the well-being of ICU patients. I was however surprised that the authors went for a quantitative approach for this pilot study. With such a small expected sample size and given the objectives, focus groups or interviews with patients and healthcare providers might have been more pertinent. At the very least, I would recommend to carefully document any comments from patients, psychiatrist, and other healthcare provider to strengthen the evaluation of the feasibility and acceptability of the psychiatric intervention. This being said, I appreciate how the authors remain humble and transparent regarding sample size, statistical power, and analyses. For instance, the sample size and participation rate estimation are very well described: “The feasible recruitment window is 12 months, with an estimated maximum possible sample size of 80. Assuming a 50% recruitment percentage, it is estimated that data will be collected from a sample of approximately 30 to 40 patients attending the Redcliffe ICU follow-up clinic over 12 months, with 15 to 20 allocated to the control and intervention arms respectively.” However, they do not mention any expectation regarding dropout between appointment and 6-months post-appointment time. I would advise to give an approximation of the expected dropout when describing the expected sample size. I would advise to also measure the LEC-5 at 6-months post appointment to ensure that no new adverse life event could explain a big change at follow-up. The authors mention how and when the psychiatrist will refer to the patients’ GP, and all in all it seems that a lot is put on the hands of the GPs. Thus, the authors might want to also include the GPs’ perspective when evaluating feasibility and acceptability of the intervention. Also, the “Health Service Use” variable results at follow-up will depend quite substantially on the reactivity of the patient’s GP. Could the authors please provide a reference for the MCID they plan to use? And ideally mention whether and how those thresholds have been validated. Other minor comments: - I would advise the authors to avoid abbreviations in the Abstract or clearly state their meaning the first time they are mentioned in the abstract. - Please provide the full name of the EQ5D-5L somewhere. - In Table 3, the term “Systems” is not clear. - “Participants will also give permission for research staff to access data from their clinical records and will complete a series of questionnaires as described below.” I think the authors mean “above” ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #3: Yes: Michael Saraga Reviewer #4: Yes: Valerie Carrard ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0287470.r004 Author response to Decision Letter 1 Submission Version2 5 Apr 2023 Thank you for the opportunity to revise this manuscript, and for the feedback from the reviewers. We acknowledge the limitations noted by both reviewers of a quantitative approach evaluating the acceptability of the intervention, and this will be reflected in the way the findings are interpreted and reported. We have made a small amendment to the acceptability question to provide the participant to specifically comment on whether they would recommend adding a psychiatric review to current clinic cares. The free text question at the bottom of the post-appointment questionnaire may provide some insights, but the authors feel a dedicated qualitative study is likely to be required following this study. Similarly, the need to look to other important stakeholders such as GPs is also a very important point, and one the authors have discussed thoroughly. We looked at how we could modify the current study to capture this information but are concerned that it would not produce data of a sufficient quality to answer the question. As such, propose that a subsequent dedicated study will be required to explore the feasibility and acceptability of the intervention from the GP perspective, perhaps combined with the aforementioned qualitative study. We now discuss this in the limitations section. We have attempted to address the other points raised by the reviewers, including clarifying the expected dropout rates and adding LEC-5 to the follow-up survey. Thank you again for taking the time to review this protocol paper and constructive feedback. Attachment Submitted filename: Response to Reviewers 040423.docx Click here for additional data file. 10.1371/journal.pone.0287470.r005 Decision Letter 2 D'Agostino Armando Academic Editor © 2023 Armando D'Agostino 2023 Armando D'Agostino https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version2 30 May 2023 PONE-D-22-25386R2A Protocol for a Pilot Randomised Controlled Trial of an Early Psychiatric Assessment, Referral, and Intervention Study (EPARIS) for Intensive Care PatientsPLOS ONE Dear Dr. Flaws, Thank you for submitting your revised manuscript to PLOS ONE. We invite you to submit a new version of the manuscript that addresses the two minor points raised during this round of the review process. Please submit your revised manuscript by Jul 14 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Armando D'Agostino Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #4: Yes ********** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #4: Yes ********** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #4: Yes ********** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #4: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #4: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #4: I thank the authors for their answer to my comments and the revisions undertaken. I found that they addressed satisfactorily my concerns, except for two minor points: 1. I now see the references for the MCIDs and I would still encourage the author to mention their validation in the text. For instance, by stating that the HADS’ MCID was validated in a survivors of acute respiratory failure sample using distribution-based methods and that it showed comparable estimates across studies, follow-up, and country. 2. Mentioning a potential qualitative follow-up investigation is a good think. I would additionally indicate why a quantitative exploration is an important first step. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #4: Yes: Valerie Carrard ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0287470.r006 Author response to Decision Letter 2 Submission Version3 1 Jun 2023 To whom it may concern, We hope the attached manuscript has addressed the comments and provided a more detailed justification for the MCIDs used in this study, as well as the rationale for a quantitative pilot study prior to a subsequent qualitative or nested study. Reviewer #4: I thank the authors for their answer to my comments and the revisions undertaken. I found that they addressed satisfactorily my concerns, except for two minor points: 1. I now see the references for the MCIDs and I would still encourage the author to mention their validation in the text. For instance, by stating that the HADS’ MCID was validated in a survivors of acute respiratory failure sample using distribution-based methods and that it showed comparable estimates across studies, follow-up, and country. Thank you, we have now elaborated in section 4.1.2 how the MCID values listed in table 4 were validated. 2. Mentioning a potential qualitative follow-up investigation is a good think. I would additionally indicate why a quantitative exploration is an important first step. We have elaborated in section 6 that a quantitative pilot has been selected in the first instance to inform subsequent larger studies, with subsequent or nested qualitative studies intended. Thank you for taking the time to review this manuscript, and please let us know if you have any further questions. Warm Regards, A/Prof. Dylan Flaws Attachment Submitted filename: Response to Reviewers 010623.docx Click here for additional data file. 10.1371/journal.pone.0287470.r007 Decision Letter 3 D'Agostino Armando Academic Editor © 2023 Armando D'Agostino 2023 Armando D'Agostino https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version3 6 Jun 2023 A Protocol for a Pilot Randomised Controlled Trial of an Early Psychiatric Assessment, Referral, and Intervention Study (EPARIS) for Intensive Care Patients PONE-D-22-25386R3 Dear Dr. Flaws, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. 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If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Armando D'Agostino Academic Editor PLOS ONE ==== Refs References 1 Zimmerman JE , Kramer AA , Knaus WA . Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Critical care. 2013;17 (2 ):R81. doi: 10.1186/cc12695 23622086 2 Needham DM , Davidson J , Cohen H , Hopkins RO , Weinert C , Wunsch H , et al . 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