Phenobarbital as an Adjuvant to benzodiazepine administration when compared to Single-agent benzodiazepine Treatment (usual care) for Alcohol Withdrawal Syndrome in the Intensive Care Unit (PASTA): a study protocol for a feasibility trial that embeds screening, enrolment and randomization within the electronic medical records

Phenobarbital as an Adjuvant to benzodiazepine administration when compared to Single-agent benzodiazepine Treatment (usual care) for Alcohol Withdrawal Syndrome in the Intensive Care Unit (PASTA): a study protocol for a feasibility trial that embeds screening, enrolment and randomization within the electronic medical records | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phenobarbital as an Adjuvant to benzodiazepine administration when compared to Single-agent benzodiazepine Treatment (usual care) for Alcohol Withdrawal Syndrome in the Intensive Care Unit (PASTA): a study protocol for a feasibility trial that embeds screening, enrolment and randomization within the electronic medical records Haustine Patt Panganiban, Samuel G. Ricciardone, Tess Evans, Melissa J. Ankravs, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7521474/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Abrupt cessation of alcohol consumption following hospital admission can induce alcohol withdrawal syndrome. This syndrome is challenging to manage and is associated with considerable morbidity and mortality. Current management of alcohol withdrawal syndrome in Australia is generally titrated benzodiazepine administration. In some regions, phenobarbital is preferred but evidence to support its superiority is weak. Methods: We will conduct a single centre, three-arm, open-label, parallel group, randomized clinical trial. Our primary objective is to determine the feasibility of embedding a randomized clinical trial within an electronic medical record to compare phenobarbital to single-agent benzodiazepine for patients with alcohol withdrawal. We will screen and randomize 45 patients using the Epic electronic medical record system. Patients will receive either low- or standard-dose intravenous phenobarbital (4 or 8 milligrams per kilogram), or usual care (benzodiazepine regimen). The primary outcome is feasibility, determined by useability, screening rates, enrolment rates, and compliance. Secondary outcomes include alcohol withdrawal scale scores, dose of benzodiazepine administered, health utilisation, adjuvant drug treatments, and patient outcomes. Discussion: There are limited high quality data evaluating the use of phenobarbital administration for alcohol withdrawal syndrome. Additionally, there is limited data evaluating the embedding of screening, randomization, and administration of a sedative drug within the electronic medical record. Our feasibility trial will establish whether this is possible within our health care system. In this protocol paper we detail how we will embed this trial within the electronic medical record Epic. Trial registration The study (RMH2024.320 v2 06/01/2025) is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12625000320459. Registered 17 April 2025, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12625000320459 . Trial Sponsor: The Royal Melbourne Hospital. Alcohol Withdrawal Syndrome Benzodiazepines Clinical Decision Support Systems Critical illness Electronic Medical Records Phenobarbital Randomized Controlled Trial Embedded Research. Figures Figure 1 Figure 2 BACKGROUND Alcohol is the most used and misused drug globally ( 1 ). In Australia, approximately 30% of the population aged greater than 14 years of age use alcohol in a way that puts their health at risk, with more than 80,000 alcohol-related hospitalisations annually ( 2 ). Hospital admission results in immediate cessation of alcohol consumption for individuals with an alcohol use disorder, which risks precipitating the alcohol withdrawal syndrome ( 3 ). Alcohol withdrawal syndrome causes symptoms that are distressing for patients, their families and health care workers. The symptoms include tremors, irritability, insomnia, diaphoresis, tachycardia, and fever ( 4 ). Twenty percent of those with alcohol withdrawal syndrome develop severe symptoms. Features of severe alcohol withdrawal include delirium tremens and withdrawal seizures ( 4 ); severe alcohol withdrawal markedly increases the risk of death ( 3 ). It is, therefore, critical that severe alcohol withdrawal syndrome is prevented and/or treated urgently ( 3 ). Treatment of alcohol withdrawal In Australia, benzodiazepines remain the default drug class for the prevention and treatment of alcohol withdrawal syndrome ( 5 ). Benzodiazepines reduce withdrawal severity, incidence of delirium and frequency of seizures ( 5 ). However, in some cases of severe alcohol withdrawal syndrome, even extremely large doses of the benzodiazepine diazepam (e.g. \(\:\ge\:\) 120 mg/day) may not achieve adequate clinical response ( 6 ). Patients with severe alcohol withdrawal syndrome can also exhibit tolerance to benzodiazepines, and cumulative doses of benzodiazepines risk respiratory depression, falls, and extended delirium ( 7 – 9 ). Phenobarbital is a barbiturate drug that is inexpensive and has a long half-life. The clinical introduction of barbiturates began in 1904 and caused great change in the management of psychiatric and neurological disorders at the time ( 10 ). Some studies have proposed that phenobarbital may be superior to benzodiazepines for the treatment of alcohol withdrawal syndrome ( 11 – 14 ). There is variation in the treatment of alcohol withdrawal but in some regions phenobarbital is the preferred drug however, there is no high-quality evidence that phenobarbital is superior to a benzodiazepine regimen ( 11 – 13 , 15 ). Umar and colleagues conducted a systematic review and meta-analysis of all studies that evaluated the use of phenobarbital when compared to other strategies in patients admitted to an intensive care unit (ICU) for alcohol withdrawal syndrome ( 11 ). Of nine studies identified by their systematic review, one was a retrospective case series (11 participants) and eight were retrospective observational studies (31 to 135 participants). The pooled mean differences in duration of hospital admission with phenobarbital compared to control was − 2.6 days (95% CI, -4.9 to -0.7). Regarding duration of ICU admission, the pooled mean difference was − 1.17 days (95% CI, -1.17, 0.09, n = 6 studies, n = 624 participants) in patients who received phenobarbital compared to control. While the difference in risk of intubation was not statistically significant between groups [relative risk, 0.52 (95% CI, 0.25 to 1.08), n = 6 studies, n = 624 participants], the point estimate suggested that intubation was less common with phenobarbital. A recently published study described the implementation of a phenobarbital monotherapy order set for alcohol withdrawal syndrome in a single-centre setting ( 16 ). A total of 254 patients were included in the retrospective analysis, including 154 before and 100 after the phenobarbital order set was implemented. Prior to order set implementation, 33.8% of patients received a median (IQR) of 3.7 (1.9–10.5) mg/kg of phenobarbital cumulative, following implementation, 71.0% received a median (IQR) 12.6 (9.7–16.1) mg/kg ( 16 ). A significant improvement in clinical outcomes was reported following phenobarbital order set implementation. Alcohol withdrawal treatment duration and time to hospital discharge were both significantly reduced following order set implementation by 30.1 hours (p < 0.001) and 2.2 days (p = 0.004), respectively ( 16 ). Between groups, alcohol withdrawal scale scores were similar in the first 24 hours but were significantly lower after order set implementation on subsequent days of treatment ( 16 ). Safety outcomes, including prolonged mechanical restraints, new intubation, and in-hospital mortality did not differ between groups. There is no randomized clinical trial conducted in an ICU to evaluate the effects of phenobarbital for alcohol withdrawal. An experienced group attempted to assess the feasibility of conducting an allocation-concealed, blinded, randomized controlled trial comparing symptom-triggered benzodiazepine therapy with either a single dose of adjuvant intravenous phenobarbital (7.5 milligrams per kilogram ideal body weight), or a single dose of matching intravenous placebo for patients with alcohol withdrawal syndrome ( 17 ). This feasibility trial (Phenobarbital for Severe Acute Alcohol Withdrawal Syndrome [PHENOMANAL] NCT03586089) was terminated due to a difficulty in recruiting patients (personal communication). This may be because in North America the use of phenobarbital is widespread. However, in Australia, phenobarbital use is not yet established. Accordingly, it may be possible for us to systematically test the repurposing of this medication for alcohol withdrawal syndrome. Embedding critical care trials within electronic medical records trials Electronic medical records offer the potential to significantly increase the efficiency of conducting clinical trials ( 18 , 19 ). Using electronic medical records can enhance screening, recruitment, treatment ordering, monitoring, and data collection, to improve feasibility, and reduce trial expense ( 20 , 21 ). Despite its potential, few electronic medical record-embedded clinical trials have been conducted in the ICU ( 22 , 23 ). Our group has embedded trial activities within the electronic medical record ( 20 ). While we have utilised the electronic medical records for screening, randomization and encouraging compliance with allocated treatment, we have never used his approach to evaluate the effect of a sedative drug. This is relevant as it is conceivable that clinicians may be less compliant following electronic medical record guidance in recommending the use of a sedative drug, particularly one with which they are unfamiliar. Furthermore, in prior protocols we have used a simple randomization schedule within the electronic medical record. This trial will evaluate if more sophisticated approaches to randomization can be implemented. There is a recent report describing the implementation of a phenobarbital order set within an electronic medical records system (Epic Systems Corporation) for all patients admitted to a community hospital with alcohol withdraw ( 16 ). This retrospective audit reported the phenobarbital order set was frequently used and when compared to historical controls reduced time to hospital discharge ( 16 ). In summary, it is unknown whether we can conduct a randomized clinical trial to evaluate the use of a sedative drug, such as intravenous phenobarbital, to treat alcohol withdrawal and embed all research processes within an electronic medical record. METHODS Study Objectives Our primary aim is to determine the feasibility of embedding this intervention within an electronic medical record platform. Feasibility will be assessed by useability, screening, randomization, and compliance with treatment allocation. The criteria and thresholds are described in greater detail below (see outcomes measures). Our secondary aims are to, between groups, provide point estimates and 95% confidence intervals of: 1. The effect on alcohol withdrawal scale scores over time. 2. The dose of diazepam administered. 3. The effect on health utilization. 4. The effect on patient outcomes - (delirium/coma free days), seizures, respiratory depression, need for tracheal intubation, and death. Screening Screening will be performed automatically within the electronic medical record using a Clinical Decision Support System called “ Our Practice Advisories ”. The Our Practice Advisories were built to include local rules and logic that contain the study inclusion criteria. Once a patient meets all inclusion criteria the Our Practice Advisory will trigger but should not interruptive the physician’s workflow. The screened patient will be counted using a real-time electronic medical records reporting called “ Reporting Workbench ” and a real-time messaging tool called “ In-Basket ”. Study Participants Forty-five participants will be included in this trial. All patients admitted to the Intensive Care Unit will be screened using the eligibility criteria detailed in Table 1. Table 1) Eligibility Criteria Inclusion Criteria 18 years old Admitted to ICU Treatment ordered for alcohol withdrawal syndrome, defined as an order for >20mg of diazepam (or equipotent benzodiazepine) within a 6-hour period or >40mg of diazepam within a 24-hour period Exclusion Criteria > 75 years old Pregnant or breast feeding Documented liver cirrhosis or severe liver disease (indicated by an INR > 5.0) A cause other than alcohol withdrawal is thought to be more likely for delirium Admission with polypharmacy overdose and substantial co-ingestion of a CNS depressant drugs (opioids, benzodiazepines, quetiapine, toxic alcohol ingestion, or gamma-hydroxy-butyrate) is documented Prescribed phenobarbital prior to admission Known allergy or hypersensitivity syndrome to phenobarbital Clinician deems is highly likely to discharge against medical advice or die in the next 24 hours Treatment limitations precluding endotracheal intubation Acute Kidney Injury (Stage 3) Current treatment with drug known to interact with phenobarbital, i.e., ticagrelor, prasugrel, warfarin, enteral/parenteral calcineurin inhibitor, or HIV-protease inhibitor. History of porphyria History of myasthenia gravis Allergy or rash with other antiepileptics Previous participation in this trial Phenobarbital contraindicated for patient due to local product information Inability to obtain intravenous access Eligibility Assessment Once a patient meets the eligibility criteria, the Our Practice Advisory alert will notify the physician of the study, and the eligibility criteria will be displayed for review. The physician will confirm patient eligibility using the steps outlined in supplemental material 1. Consent and ethical approval Given all patients included in this study will have been admitted to the ICU with underlying diagnosis and treatment and have alcohol withdrawal syndrome and have received at least 20 mg of diazepam, they will lack capacity to provide informed consent prior to participation. Treatment of alcohol withdrawal is an emergency and is already provided to non-consenting patients when it is deemed to be in the patient’s best interest. Accordingly, it is not possible to identify and obtain consent from the medical treatment decision maker. Trial participants will continue to receive usual care or usual care and phenobarbital – which is the preferred drug at many international centres. Participants in this trial will be included based on Section 53 of the Medical Treatment Planning and Decisions Act (Victoria) - “Medical treatment and medical research procedures in an emergency”. The administration of intravenous phenobarbital in the setting of acute alcohol withdrawal syndrome is necessary, as a matter of urgency to prevent serious damage to the person’s health, and limit suffering, pain or distress. A waiver of consent is consistent with the Australian National Health and Medical Research Council (NHMRC) Statement on Ethical conduct in Human Research (chapter 2.3) (24). The protocol and consent process were approved by the Royal Melbourne Hospital Human Research Ethics Committee (HREC114383). The protocol is registered with Australian New Zealand Clinical Trials Registry (ACTRN12625000320459). Enrolment, randomization, and allocation concealment Once the physician confirms eligibility, enrolment occurs in the electronic medical records. This will be performed by creating an action extension record attached to the Our Practice Advisory that triggers silently within the system to prevent interruption (see supplemental material 1). To determine group allocation we previously used a simple randomization at the patient level within the electronic medical records (23). This randomization process utilises a flip coin process, but in smaller trials this can result in unbalanced participant distribution between groups. This is a limitation of randomization within the software and is noted by the developer as a future system development (Epic Systems Corporation, Wisconsin, USA). For this trial, we will link the REDCap stratified randomization module to Epic (25,26). Enrolled patients will be randomized to groups using a 1:1:1 ratio allocation. The Our Practice Advisories will alert the physician that a patient is enrolled and provide a REDCap link to randomize (see supplemental material 1). If the physician cancels the advisory, the patient remains suitable for screening and the alert will reappear until the participant is assessed for eligibility. An instructional video on how to perform the randomization will be available via hyperlink within the Our Practice Advisories to guide the physician. The study team will monitor the REDCap randomization dashboard regularly to ensure consistent participant arm allocation between REDCap and the electronic medical records. In the event of randomization errors in which the physician did not enter the allocated arm correctly in the electronic medical records, the participants will be included in the intention-to-treat analysis but excluded in the per-protocol analysis (see scenario examples in supplemental material 1). The randomization sequence was created using the random function in Excel by a researcher independent of this trial and uploaded into REDCap. This sequence will be concealed from all physicians and will be restricted by setting user privileges in the REDCap project. The detailed REDCap project configuration is available in the supplemental material 1. Compliance with treatment allocation The physician will transcribe the treatment arm allocation from REDCap to the electronic medical record alert (see supplemental material 1). Once the treatment arm option is selected, the system will assign a “Smart Data Element ” that stores a number that signifies arm allocation at the patient record level. This system element is not visible to end-users and will only be visible to certified technical users with restricted access. Physicians will also be alerted when they are prescribing a drug included in the drug group being investigated and includes a study “ Order Set” (see supplemental material 1). Compliance within the treatment allocation will be achieved by incorporating a well-defined system of rules and logic within the electronic medical records study Order Set . This will ensure that only the allocated treatment for a specific participant will be presented to the physician when ordering. The physician will have the capacity to override the alert and provide an override reason within the alert. The study team will monitor override reasons through a message sent to the “ InBasket ” (see supplemental material 1). Randomized participants will be automatically enrolled within the electronic medical records into a study record and will send a real-time notification message via InBasket to the study team (see supplemental material 1). This study record will be used to monitor participant progress within the study. This will also be accompanied by a series of cross-arm Our Practice Advisories to prevent treatment deviation (see supplemental material 1). Design & Intervention This feasibility study protocol is reported according to the SPIRIT 2025 statement (27). We will conduct a single centre, three-arm, open-label, parallel group, randomized controlled trial. This trial will take place in a mixed medical-surgical-trauma ICU in Australia (28). Eligible participants will be randomized to one of three arms; the overall study design is depicted in Fig 1. The schedule of assessments is shown in the recommended SPIRIT Table (Table 2). Low dose phenobarbital (4 milligrams per kilogram ideal body weight), infused over 30 minutes in addition to usual care; Standard dose phenobarbital (8 milligrams per kilogram ideal body weight) over 30 minutes in addition to usual care; or Usual care. If allocated to phenobarbital arms, patients may also receive additional lower doses of the study drug once 30 minutes have elapsed from the initial load. Up to a maximum of two additional doses (2 milligrams per kilogram ideal body weight) may be given in a 48-hour period after randomization. Table 2) Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Table Summary TRIAL PERIOD Enrolment Post-randomization Close-out TIMEPOINT Pre-eligibility Eligibility Up to 48-hours post-enrollment >48-hours post-enrollment Data Analysis ENROLLMENT: Eligibility screen X Eligibility assessment X Randomization X INTERVENTIONS Low/Standard Dose Phenobarbital Administration X Usual Care X X X ASSESSMENTS: Demographic Information X Feasibility (Primary Outcome) X X X X Secondary Outcomes X X X X Adverse Events X X X X Rationale for dosing For this trial we will use intravenous phenobarbital. Studies conducted outside of a critical care environment have used enteral or intramuscular dosing (29,30). However, intravenous administration of drugs is generally preferred in the emergency and critical care settings due to more predictable pharmacokinetics and onset of action. Existing literature describes using intravenous phenobarbital for the treatment of alcohol withdrawal syndrome in either a weight-based or a fixed dose regimen. A retrospective cohort study included 179 adult patients admitted to a tertiary academic hospital with alcohol withdrawal syndrome and reported no difference in phenobarbital-related adverse drug events between 6 milligrams per kilogram and 10 milligrams per kilogram ideal body weight (31). Of these 179 patients, the majority (~56%) received their initial phenobarbital load in the emergency department, a third (~32%) received initial phenobarbital in the ICU, and the remainder were treated in other inpatient wards (31). A prospective blinded randomized trial of patients presenting to the emergency department with alcohol withdrawal syndrome compared intravenous phenobarbital to intravenous lorazepam (32). Patients received 260 milligrams of intravenous phenobarbital initially. Subsequent doses of 130 milligrams were given at the discretion of the treating physician. Of the 25 patients who received phenobarbital. the mean number of doses was 2.9 (range 1 to 6) for a mean dose of 509 milligrams (range 260 to 910). A single centre retrospective study of 87 patients compared patients after a protocol change from a ‘low-intermittent’ phenobarbital dosing regimen to a ‘front loaded’ phenobarbital. During the initial period all patients with a high alcohol withdrawal syndrome score despite three intravenous doses of 8 milligrams of lorazepam (total) received a fixed dose of 260 milligrams followed by 130 milligrams intravenous push every 15 minutes as needed. After the protocol change, patients received a weight-based regimen 10 milligrams per kilogram actual body weight. The patients receiving the weight-based dosing (subsequent period) were significantly less likely to be mechanically ventilated and had a shorter duration of admission (33). In our intervention arms we will test two weight-based dosing regimens. The doses chosen are slightly less than administered in the studies above. We have reduced doses because our clinicians are less familiar with using phenobarbital. We will also use ideal body weight rather than actual body weight (34). In the lower- and standard-dose groups, patients will receive 4 and 8 milligrams per kilogram ideal body weight of phenobarbital respectively. Usual care At our institution, usual care for the management of alcohol withdrawal syndrome is guided by a hospital protocol. This policy recommends enteral administration of 20 milligrams of diazepam every 2 hours when needed (i.e., PRN) based on withdrawal symptoms, with repeated dosing determined by alcohol withdrawal scale score. This policy reflects the standard for treatment for alcohol withdrawal Australia-wide, with the Australian Government classifying diazepam as a ‘gold standard’ with an ‘A’ strength of recommendation, and a ‘Ia’ level of evidence but individual clinicians can modified prescriptions to lesser dose or the intravenous route (35). Prescribing of diazepam can occur within the electronic medical records using an alcohol withdrawal syndrome order set. Oxazepam is considered for patients with relative contraindications to long-acting benzodiazepines, such as severe alcoholic hepatitis. Oxazepam 15 mg is approximately equipotent to 5 mg diazepam. Patient flow will occur as outlined in Figure 2 below. Electronic medical records embedded trial design The embedding process was designed with multiple key stakeholders from the ICU and electronic medical record team as detailed in supplemental material 1. We established proof-of-concept of embedding all aspects of a trial evaluating electrolyte administration (23) using the Epic electronic medical records system. Multiple iterations were performed to arrive at an acceptable design concept for this trial. Validation and co-design sessions were conducted before the implementation with pharmacists, physicians, and a physician informatician to collect feedback and incorporate it into the design. The final design was tested using multiple cycles following the electronic medical record standard test case scenarios. The design underwent governance and change control procedures to ensure system compliance. A training plan was delivered to ensure that the end-user is informed of the new functionality. During the implementation phase, the electronic medical record build records monitoring, enhancement, and maintenance will be conducted to ensure compliance with local hospital and precinct-wide system policy. Outcome measures Primary outcomes Feasibility will be determined by: 1. Useability. 2. Screening rates. 3. Enrolment rates. 4. Compliance with treatment allocation. Usability will be determined by conducting physician perceived electronic medical records usability survey using the System Usability Scale 10 item questionnaire (see table 3) (36). The System Usability Scale ranges from 0 to 100, with greater scores indicating better usability. Feasibility of screening will be determined as the electronic medical records identifying two patients per month who meet all eligibility criteria. Feasibility of enrolment and randomization will be defined as 70% of eligible patients being randomized (eligible patients determined by manual screening and in basket message alerts) and completion of the trial within 2.5 years. The thresholds for feasibility of compliance with treatment allocation is that 80% of patients allocated to phenobarbital receive it and < 10% of patients assigned usual care receive phenobarbital. Secondary outcomes Cumulative alcohol withdrawal scale scores from study days 1-7. Alcohol withdrawal scale scores are reported in Epic by nurses and entered at least once per admission. Quantity of diazepam administered will be extracted from the medical records. Diazepam (or equivalent) dosing will be extracted from Epic and reported as days received, dose per day and total dose. Health utilization include number of code grey events (code grey events – these are a hospital-wide response due to aggression or threatened/actual violence, episodes of harm to staff due to aggression or violence, and violence, duration of intensive care admission, duration of hospital admission, days of antibiotic therapy, use of mechanical restraints, need for additional staff on discharge to ward to manage behaviour (so-called ‘Nurse Special’)), and adjuvant drug treatments (including, clonidine, dexmedetomidine, olanzapine, quetiapine, haloperidol, and droperidol) (37). Code grey events will be reported as actual number and mean per patient for seven days after randomization. Occupational aggression and violence will be extracted from the medical records. Duration of intensive care admission from randomization (reported as days free of ICU at day 7). Duration of hospital admission from randomization (reported as days free of ICU at day 28). Days of antibiotic therapy for seven days after randomization reported as binary (Y/N) and days received. Code grey events will be reported as actual number and mean per patient for seven days after randomization. Use of mechanical restraints for seven days after randomization and reported as binary (Y/N) and days received. Use of Nurse Special on discharge to ward and reported as binary (Y/N), Other adjuvant drug treatments in ICU (clonidine, dexmedetomidine, olanzapine, quetiapine, haloperidol, droperidol) for seven days after randomization will be reported as received (Y/N) The effect on patient outcomes: delirium/coma free days, seizures, respiratory depression, need for tracheal intubation, mortality).Delirium and coma free days will be recorded using the process used previously (38). A patient will be regarded as delirium/coma free for that calendar day if: They are alive and discharged from the ICU or They are alive in the ICU with (all of the following): 1. The Richmond Agitation-Sedation Scale (RASS) score being -2 to 0 all day at all time points; 2. No Confusion Assessment Method for the ICU (CAM-ICU) positive outcome recorded at any time point; and 3. No documentation of agitation during the calendar day For unintubated patients, frequency of intubation post randomization and for seven days after randomization will be reported as yes/no. Ventilator days will be reported as median (range) Time to extubation Frequency of seizures will be reported (for seven days after randomization) and reported as number of patients having one seizure and total number of seizures. Incident neuroimaging (CT or MRI) in ICU and for seven days after randomization Respiratory depression, counted as hypoxia (SpO2 95% in the context of respiratory rate 50 mm Hg) Sedation scores will be recorded using the Richmond Agitation Sedation Score. RASS scores are reported in Epic by nurses and reported at least once per nursing shift. Highest PaCO2 for calendar day will be recorded when available Falls during hospitalization for first 7 days (documented using Riskman) Data collection As an embedded trial, eligibility screening, enrolment, randomization, and patient demographics will be collected in real time during hospital admission using the Epic reporting tool. This will serve as an operational data set for monitoring participant accruals and progress. A study database will be created using REDCap case report forms (see supplemental material 1) hosted at The Royal Melbourne Hospital (25,26). Data that requires narrative interpretation will be collected manually from the electronic medical records and entered into case report forms by the delegated study team members. Data verification All data will be kept securely for at least 15 years and stored as per Royal Melbourne Hospital research policy. Access will be password-controlled and limited to members of the study team. An ICU Research Coordinator independent of this trial will perform source data verification. Source data verification will be conducted for 100% of the primary outcome (feasibility) and 100% of serious adverse events. Trial oversight and monitoring The Trial Safety Committee includes intensive care physicians Adam Deane and Tess Evans and senior ICU pharmacist Melissa Ankravs. The Data Safety Monitoring Committee includes intensive care physician Matthew Maiden and addiction medicine physician Nazila Jamshidi. The Trial Safety Committee will meet monthly to review all adverse events, recruitment, and compliance with the interventions. The Trial Safety Committee may decide to stop the trial if it is clearly not feasible despite attempts to resolve issues. Every three months the Data Safety Monitoring Committee will be provided a summary of all serious adverse events, adverse events, recruitment rates and compliance with the interventions. The Data Safety Monitoring Committee will use their own discretion to recommend stopping the trial due to adverse/serious adverse events. Patients with alcohol withdrawal syndrome who are admitted to the ICU are at high-risk for adverse events. However, the drugs used as part of usual care, benzodiazepines, and the intervention, phenobarbital, have known adverse effects associated with their use. It is recognised that the patient population in the ICU will experience aberrations in laboratory values, signs, and symptoms due to the severity of the underlying disease and the impact of standard treatments (39). These will not necessarily constitute adverse events or serious adverse events unless they are considered related to study treatment, or in the principal investigator’s clinical judgement are not recognised events consistent with the participants underlying critical illness and/or chronic diseases and expected clinical course. In Australian ICU trials, the reporting of adverse events for medicinal products is restricted to events that are considered related to study treatment (possibly, probably, or definitely). For the purposes of this open-label trial, Serious Adverse Events will only be reported if they occur in participants receiving phenobarbital. Serious Adverse Events be defined as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), anaphylaxis (angioedema), tracheal intubation, cardiac arrest or pre-arrest, and death post randomization and prior to ICU discharge. Any of these events that considered to be identified as probably or definitely related to phenobarbital will be reported to the data safety monitoring committee within 48 hours. Because events such as tracheal intubation and cardiac arrest can occur in the usual care group (i.e., diazepam as single agent drug), these will be collated and reported with adverse events. For the purposes of this trial an adverse event will be considered new hypotension (mean arterial pressure 50% of vasoactive drug infusion) during infusion of phenobarbital for 30 minutes after infusion ceased, or ‘mild’ skin reaction (rash, hives, itch). Any adverse event thought to be study treatment related will be evaluated by a trial physician. Adverse events will be collated and reported to the Trial Safety Committee and Data Safety Monitoring Committee at three monthly intervals. Withdrawals In the circumstance that the treatment physician believes usual care is clearly preferable over the allocated phenobarbital regimen, the treatment physician can override the treatment allocation. This will be recorded as a protocol violation with data retained for intention to treat analysis. In the circumstance that the medical treatment decision maker (MTDM) refuses retention of data, all patient data will be removed from database and the patient will be considered removed from the intention to treat analysis, if this occurs the participant will not be replaced. Sample size Our feasibility trial will include 45 participants. It is reasoned that a sample size of 45 participants will ensure assessment of our feasibility metrics (useability, screening and enrolment rates, and compliance) and that the multidisciplinary team members gain experience with administration of phenobarbital for alcohol withdrawal. Statistical analysis Consistent with pilot and feasibility trial recommendations, the statistical focus will be descriptive statistics (means, proportions, medians) and differences between the groups and their associated confidence intervals or quantile ranges, rather than repeated P value testing (40). Pilot studies may usefully help assess minimum clinically important differences even if confidence intervals reported are numerically less than 95% (such as 85% or 75%) (37). Due to this study relying on prescribers correctly transcribing randomization schedules from REDCap into the electronic medical records, our primary analysis will be a per-protocol analysis. We will also conduct an intention to treat analysis for all patients who were eligible and randomized. If a patient is randomized in error and were ineligible on the eligibility criteria, they will not be included in the intention to treat analysis. Dissemination Trial results will be disseminated by a final report and sent to participants upon request. Any protocol amendments will be noted in the publication of the results. Further dissemination will include local institute and wider conference presentations, and publication in peer-reviewed journal articles. Discussion Alcohol is the most used and misused drug globally, and alcohol use disorders represent a considerable burden to healthcare systems ( 1 ). Alcohol-use disorders include a spectrum from excessive use, abuse, dependence, to addiction. Patients with alcohol-use disorders are not only at risk of withdrawal symptoms, but these patients have a higher rate of complications, longer duration of ICU and hospital admission, and increased mortality in comparison to patients who do not abuse alcohol ( 1 ). Managing patients with alcohol-use disorders who present to the hospital or ICU can be extremely complicated, as a hospital admission usually results in immediate abstinence from drinking alcohol and can trigger alcohol withdrawal syndrome. While the symptoms vary in intensity, approximately one in five patients can develop seizures, and patients in the ICU who are reliant on life support and who develop delirium due to alcohol withdrawal syndrome may risk harming themselves by accidental removal of catheters or tubes that are providing this life support. An additional complexity with alcohol withdrawal in the critically ill is that alcohol withdrawal is commonly an intercurrent issue and often not the primary diagnosis at admission – and that symptoms of withdrawal (autonomic hyperactivity and delirium) may be masked by another primary diagnosis, co-morbidity, or current ICU treatment. The current mainstay of treatment for alcohol withdrawal are benzodiazepines ( 41 ). This class of drug is known to ameliorate patient agitation, reduce the incidence of alcohol withdrawal seizures, and prevent alcohol withdrawal delirium ( 42 ). However, for many patients, lesser doses of benzodiazepines provide inadequate symptom control, such that larger doses of benzodiazepines are administered. Benzodiazepine drugs in large doses can exacerbate the patient’s acute confusion state (known as delirium), and weaken respiratory effort, leading to mechanical ventilation and prolonged ICU admission ( 8 , 9 , 43 ). Other pharmacological adjuncts that have been reported to be useful in the management of alcohol withdrawal syndrome include carbamazepine, valproic acid, sodium oxybate, baclofen, gabapentin, and topiramate, but none of these drugs will be tested in this trial ( 44 ). In North America, many centres use phenobarbital for the treatment for alcohol withdrawal, either administered alone or as a benzodiazepine sparing agent, and it is increasingly being recommended as an alternative agent in guidelines, albeit on quite sparse randomized literature. ( 12 , 32 , 45 – 47 ). This study will determine whether it is feasible to conduct a trial administering phenobarbital in addition to usual care. Strengths of our trial include novel data reporting in an ICU population, and the embedding of all aspects of the trial within the electronic medical records with stratified randomization. One-directional communication from the electronic medical record to REDCap to perform real-time randomization. The use of the Epic electronic medical record and alerts to support real-time screening and randomization minimises human error and saves time for clinical staff, allowing resource allocation of staff to more complex tasks. Limitations of our trial include the open label design and small sample population being studied; however, this was deemed necessary given difficulties with patient recruitment elsewhere (PHENOMANAL) and clinical unfamiliarity with phenobarbital in Australia ( 17 ). Trial Status The recruitment began on 8 July 2026. The trial will be stopped if recruitment is not completed by 7 January 2028. Declarations Ethics approval and consent to participate : The protocol has been approved by the Royal Melbourne Hospital Research Ethics Committee (RMH2024.320 HREC114383). Participants will be included under emergency treatment with an opt-out process for retention of data. The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12625000320459). Consent for publication : All authors consent to the publication of the protocol manuscript. No restrictions have been placed on the publication of future data resulting from the trial. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests : The authors declare that they have no competing interests. Funding : There is no funding to declare. The trial sponsor had no involvement in the study design, collection, analysis, and interpretation of the data, nor the decision to submit the report for publication. Authors' contributions: HP, SR, TE, MA, TF, NC, AA, CM, JP, ES, MS, TI, and AD (all authors) contributed significantly to the study conception and design; and critically reviewed the manuscript for important scientific content. HP, SR, TE, and AD drafted the manuscript. All authors reviewed the final manuscript and agree to be accountable for the accuracy and integrity of the work. Acknowledgements : Not applicable. References Mehta AJ. Alcoholism and critical illness: A review. World J Crit Care Med. 2016;5(1):27. Australian Institute of Health and Welfare. Alcohol, tobacco & other drugs in Australia [Internet]. AIHW; 2024 July [cited 2024 Aug 30]. (Alcohol). Available from: https://www.aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-types/alcohol Kattimani S, Bharadwaj B. 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Available from: https://pilotfeasibilitystudies.biomedcentral.com/articles/10.1186/s40814-019-0423-8 Perry EC. Inpatient Management of Acute Alcohol Withdrawal Syndrome. CNS Drugs. 2014 May;28(5):401–10. Mainerova B, Prasko J, Latalova K, Axmann K, Cerna M, Horacek R, et al. Alcohol withdrawal delirium - diagnosis, course and treatment. Biomed Pap. 2015 Mar 9;159(1):044–52. Johnson MT, Yamanaka TT, Fraidenburg DR, Kane SP. Benzodiazepine misadventure in acute alcohol withdrawal: the transition from delirium tremens to ICU delirium. J Anesth. 2013 Feb;27(1):135–6. Mirijello A, D’Angelo C, Ferrulli A, Vassallo G, Antonelli M, Caputo F, et al. Identification and Management of Alcohol Withdrawal Syndrome. Drugs. 2015 Mar;75(4):353–65. Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F, et al. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-blind Placebo-controlled Study. J Emerg Med. 2013 Mar;44(3):592-598.e2. Young GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987 Aug;16(8):847–50. Punia K, Scott W, Manuja K, Campbell K, Balodis IM, MacKillop J. SAEM GRACE : Phenobarbital for alcohol withdrawal management in the emergency department: A systematic review of direct evidence. Acad Emerg Med. 2024 May;31(5):481–92. Table Table 3 is available in the Supplementary Files section. Supplementary Files Table3.docx PASTA2024.320SPIRIT2025editablechecklist.docx PASTASupplementalMaterialCLEAN21.08.2025.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 23 Feb, 2026 Reviewers agreed at journal 21 Feb, 2026 Reviewers invited by journal 01 Oct, 2025 Editor assigned by journal 09 Sep, 2025 First submitted to journal 07 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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09:13:32","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":181400,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/1a589aea0eece87d09be770c.html"},{"id":93573930,"identity":"5ccaa502-297a-44bc-aec1-87231398b223","added_by":"auto","created_at":"2025-10-15 09:13:32","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106091,"visible":true,"origin":"","legend":"\u003cp\u003eSimplified Overview of Study Design\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/3fd1be8eefc27cebe3e0cf83.jpeg"},{"id":93573931,"identity":"a2c41dcd-3773-49bb-89d2-2ff65173ffc6","added_by":"auto","created_at":"2025-10-15 09:13:32","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120498,"visible":true,"origin":"","legend":"\u003cp\u003ePatient Flow Diagram\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/fe0cd151fc1b5a8b577b6d4e.jpeg"},{"id":93576626,"identity":"3a4281df-0737-4e5f-aefa-19637fbe9289","added_by":"auto","created_at":"2025-10-15 09:37:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1366366,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/1393957d-37f7-4bed-a164-ce46e2552ffa.pdf"},{"id":93573929,"identity":"fb418fcc-c3c9-4220-9c76-8c0b17e861d7","added_by":"auto","created_at":"2025-10-15 09:13:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18608,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/c296ed126f431ff574817644.docx"},{"id":93575043,"identity":"7df87fa8-3e40-44b9-b620-98bc929f9f36","added_by":"auto","created_at":"2025-10-15 09:21:32","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":35018,"visible":true,"origin":"","legend":"","description":"","filename":"PASTA2024.320SPIRIT2025editablechecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/ead789e83decab19c9b5760a.docx"},{"id":93573944,"identity":"d1e415e4-9993-40c0-bd7b-88f706a201e0","added_by":"auto","created_at":"2025-10-15 09:13:32","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1171906,"visible":true,"origin":"","legend":"","description":"","filename":"PASTASupplementalMaterialCLEAN21.08.2025.docx","url":"https://assets-eu.researchsquare.com/files/rs-7521474/v1/951072cfb023bccb5ffb27ae.docx"}],"financialInterests":"","formattedTitle":"Phenobarbital as an Adjuvant to benzodiazepine administration when compared to Single-agent benzodiazepine Treatment (usual care) for Alcohol Withdrawal Syndrome in the Intensive Care Unit (PASTA): a study protocol for a feasibility trial that embeds screening, enrolment and randomization within the electronic medical records","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eAlcohol is the most used and misused drug globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In Australia, approximately 30% of the population aged greater than 14 years of age use alcohol in a way that puts their health at risk, with more than 80,000 alcohol-related hospitalisations annually (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHospital admission results in immediate cessation of alcohol consumption for individuals with an alcohol use disorder, which risks precipitating the alcohol withdrawal syndrome (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Alcohol withdrawal syndrome causes symptoms that are distressing for patients, their families and health care workers. The symptoms include tremors, irritability, insomnia, diaphoresis, tachycardia, and fever (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Twenty percent of those with alcohol withdrawal syndrome develop severe symptoms. Features of severe alcohol withdrawal include delirium tremens and withdrawal seizures (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e); severe alcohol withdrawal markedly increases the risk of death (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It is, therefore, critical that severe alcohol withdrawal syndrome is prevented and/or treated urgently (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eTreatment of alcohol withdrawal\u003c/h3\u003e\n\u003cp\u003eIn Australia, benzodiazepines remain the default drug class for the prevention and treatment of alcohol withdrawal syndrome (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Benzodiazepines reduce withdrawal severity, incidence of delirium and frequency of seizures (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, in some cases of severe alcohol withdrawal syndrome, even extremely large doses of the benzodiazepine diazepam (e.g. \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\ge\\:\\)\u003c/span\u003e\u003c/span\u003e120 mg/day) may not achieve adequate clinical response (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Patients with severe alcohol withdrawal syndrome can also exhibit tolerance to benzodiazepines, and cumulative doses of benzodiazepines risk respiratory depression, falls, and extended delirium (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePhenobarbital is a barbiturate drug that is inexpensive and has a long half-life. The clinical introduction of barbiturates began in 1904 and caused great change in the management of psychiatric and neurological disorders at the time (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Some studies have proposed that phenobarbital may be superior to benzodiazepines for the treatment of alcohol withdrawal syndrome (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). There is variation in the treatment of alcohol withdrawal but in some regions phenobarbital is the preferred drug however, there is no high-quality evidence that phenobarbital is superior to a benzodiazepine regimen (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Umar and colleagues conducted a systematic review and meta-analysis of all studies that evaluated the use of phenobarbital when compared to other strategies in patients admitted to an intensive care unit (ICU) for alcohol withdrawal syndrome (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Of nine studies identified by their systematic review, one was a retrospective case series (11 participants) and eight were retrospective observational studies (31 to 135 participants). The pooled mean differences in duration of hospital admission with phenobarbital compared to control was \u0026minus;\u0026thinsp;2.6 days (95% CI, -4.9 to -0.7). Regarding duration of ICU admission, the pooled mean difference was \u0026minus;\u0026thinsp;1.17 days (95% CI, -1.17, 0.09, n\u0026thinsp;=\u0026thinsp;6 studies, n\u0026thinsp;=\u0026thinsp;624 participants) in patients who received phenobarbital compared to control. While the difference in risk of intubation was not statistically significant between groups [relative risk, 0.52 (95% CI, 0.25 to 1.08), n\u0026thinsp;=\u0026thinsp;6 studies, n\u0026thinsp;=\u0026thinsp;624 participants], the point estimate suggested that intubation was less common with phenobarbital.\u003c/p\u003e\u003cp\u003eA recently published study described the implementation of a phenobarbital monotherapy order set for alcohol withdrawal syndrome in a single-centre setting (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). A total of 254 patients were included in the retrospective analysis, including 154 before and 100 after the phenobarbital order set was implemented. Prior to order set implementation, 33.8% of patients received a median (IQR) of 3.7 (1.9\u0026ndash;10.5) mg/kg of phenobarbital cumulative, following implementation, 71.0% received a median (IQR) 12.6 (9.7\u0026ndash;16.1) mg/kg (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). A significant improvement in clinical outcomes was reported following phenobarbital order set implementation. Alcohol withdrawal treatment duration and time to hospital discharge were both significantly reduced following order set implementation by 30.1 hours (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 2.2 days (p\u0026thinsp;=\u0026thinsp;0.004), respectively (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Between groups, alcohol withdrawal scale scores were similar in the first 24 hours but were significantly lower after order set implementation on subsequent days of treatment (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Safety outcomes, including prolonged mechanical restraints, new intubation, and in-hospital mortality did not differ between groups.\u003c/p\u003e\u003cp\u003eThere is no randomized clinical trial conducted in an ICU to evaluate the effects of phenobarbital for alcohol withdrawal. An experienced group attempted to assess the feasibility of conducting an allocation-concealed, blinded, randomized controlled trial comparing symptom-triggered benzodiazepine therapy with either a single dose of adjuvant intravenous phenobarbital (7.5 milligrams per kilogram ideal body weight), or a single dose of matching intravenous placebo for patients with alcohol withdrawal syndrome (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This feasibility trial (Phenobarbital for Severe Acute Alcohol Withdrawal Syndrome [PHENOMANAL] NCT03586089) was terminated due to a difficulty in recruiting patients (personal communication). This may be because in North America the use of phenobarbital is widespread. However, in Australia, phenobarbital use is not yet established. Accordingly, it may be possible for us to systematically test the repurposing of this medication for alcohol withdrawal syndrome.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eEmbedding critical care trials within electronic medical records trials\u003c/h2\u003e\u003cp\u003eElectronic medical records offer the potential to significantly increase the efficiency of conducting clinical trials (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Using electronic medical records can enhance screening, recruitment, treatment ordering, monitoring, and data collection, to improve feasibility, and reduce trial expense (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Despite its potential, few electronic medical record-embedded clinical trials have been conducted in the ICU (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur group has embedded trial activities within the electronic medical record (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). While we have utilised the electronic medical records for screening, randomization and encouraging compliance with allocated treatment, we have never used his approach to evaluate the effect of a sedative drug. This is relevant as it is conceivable that clinicians may be less compliant following electronic medical record guidance in recommending the use of a sedative drug, particularly one with which they are unfamiliar. Furthermore, in prior protocols we have used a simple randomization schedule within the electronic medical record. This trial will evaluate if more sophisticated approaches to randomization can be implemented.\u003c/p\u003e\u003cp\u003eThere is a recent report describing the implementation of a phenobarbital order set within an electronic medical records system (Epic Systems Corporation) for all patients admitted to a community hospital with alcohol withdraw (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). This retrospective audit reported the phenobarbital order set was frequently used and when compared to historical controls reduced time to hospital discharge (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn summary, it is unknown whether we can conduct a randomized clinical trial to evaluate the use of a sedative drug, such as intravenous phenobarbital, to treat alcohol withdrawal and embed all research processes within an electronic medical record.\u003c/p\u003e\u003c/div\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Objectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur primary aim is to determine the feasibility of embedding this intervention within an electronic medical record platform. Feasibility will be assessed by useability, screening, randomization, and compliance with treatment allocation. The criteria and thresholds are described in greater detail below (see outcomes measures).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur secondary aims are to, between groups, provide point estimates and 95% confidence intervals of:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. The effect on alcohol withdrawal scale scores over time.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. The dose of diazepam administered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. The effect on health utilization.\u003c/p\u003e\n\u003cp\u003e4. The effect on patient outcomes - (delirium/coma free days), seizures, respiratory depression, need for tracheal intubation, and death.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScreening\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eScreening will be performed automatically within the electronic medical record using a Clinical Decision Support System called \u0026ldquo;\u003cem\u003eOur Practice Advisories\u003c/em\u003e\u0026rdquo;. The \u003cem\u003eOur Practice Advisories\u003c/em\u003e were built to include local rules and logic that contain the study inclusion criteria. Once a patient meets all inclusion criteria the \u003cem\u003eOur Practice Advisory\u0026nbsp;\u003c/em\u003ewill trigger but should not interruptive the physician\u0026rsquo;s workflow. The screened patient will be counted using a real-time electronic medical records reporting called \u0026ldquo;\u003cem\u003eReporting Workbench\u003c/em\u003e\u0026rdquo; and a real-time messaging tool called \u0026ldquo;\u003cem\u003eIn-Basket\u003c/em\u003e\u0026rdquo;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Participants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty-five participants will be included in this trial. All patients admitted to the Intensive Care Unit will be screened using the eligibility criteria detailed in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1)\u0026nbsp;\u003c/strong\u003eEligibility Criteria\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cimg width=\"11\" height=\"19\" src=\"https://myfiles.space/user_files/58895_8739fc6c57c1c19a/58895_custom_files/img1760515899.png\" alt=\"image\"\u003e18 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eAdmitted to ICU\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eTreatment ordered for alcohol withdrawal syndrome, defined as an order for \u0026gt;20mg of diazepam (or equipotent benzodiazepine) within a 6-hour period or \u0026gt;40mg of diazepam within a 24-hour period\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003e\u0026gt; 75 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003ePregnant or breast feeding\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eDocumented liver cirrhosis or severe liver disease (indicated by an INR \u0026gt; 5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eA cause other than alcohol withdrawal is thought to be more likely for delirium\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eAdmission with polypharmacy overdose and substantial co-ingestion of a CNS depressant drugs (opioids, benzodiazepines, quetiapine, toxic alcohol ingestion, or gamma-hydroxy-butyrate) is documented\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003ePrescribed phenobarbital prior to admission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eKnown allergy or hypersensitivity syndrome to phenobarbital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eClinician deems is highly likely to discharge against medical advice or die in the next 24 hours\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eTreatment limitations precluding endotracheal intubation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eAcute Kidney Injury (Stage 3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eCurrent treatment with drug known to interact with phenobarbital, i.e., ticagrelor, prasugrel, warfarin, enteral/parenteral calcineurin inhibitor, or HIV-protease inhibitor.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eHistory of porphyria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eHistory of myasthenia gravis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eAllergy or rash with other antiepileptics\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003ePrevious participation in this trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003ePhenobarbital contraindicated for patient due to local product information\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 553px;\"\u003e\n \u003cp\u003eInability to obtain intravenous access\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnce a patient meets the eligibility criteria, the \u003cem\u003eOur Practice Advisory\u003c/em\u003e alert will notify the physician of the study, and the eligibility criteria will be displayed for review. The physician will confirm patient eligibility using the steps outlined in supplemental material 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent and ethical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven all patients included in this study will have been admitted to the ICU with underlying diagnosis and treatment and have alcohol withdrawal syndrome and have received at least 20 mg of diazepam, they will lack capacity to provide informed consent prior to participation. Treatment of alcohol withdrawal is an emergency and is already provided to non-consenting patients when it is deemed to be in the patient\u0026rsquo;s best interest. Accordingly, it is not possible to identify and obtain consent from the medical treatment decision maker. Trial participants will continue to receive usual care or usual care and phenobarbital \u0026ndash; which is the preferred drug at many international centres. Participants in this trial will be included based on Section 53 of the Medical Treatment Planning and Decisions Act (Victoria) - \u0026ldquo;Medical treatment and medical research procedures in an emergency\u0026rdquo;. The administration of intravenous phenobarbital in the setting of acute alcohol withdrawal syndrome is necessary, as a matter of urgency to prevent serious damage to the person\u0026rsquo;s health, and limit suffering, pain or distress. A waiver of consent is consistent with the Australian National Health and Medical Research Council (NHMRC) Statement on Ethical conduct in Human Research (chapter 2.3) (24). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe protocol and consent process were approved by the Royal Melbourne Hospital Human Research Ethics Committee (HREC114383). The protocol is registered with Australian New Zealand Clinical Trials Registry (ACTRN12625000320459).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEnrolment, randomization, and allocation concealment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnce the physician confirms eligibility, enrolment occurs in the electronic medical records. This will be performed by creating an action extension record attached to the\u003cem\u003e\u0026nbsp;Our Practice Advisory\u003c/em\u003e that triggers silently within the system to prevent interruption (see supplemental material 1).\u003c/p\u003e\n\u003cp\u003eTo determine group allocation we previously used a simple randomization at the patient level within the electronic medical records (23). This randomization process utilises a flip coin process, but in smaller trials this can result in unbalanced participant distribution between groups. This is a limitation of randomization within the software and is noted by the developer as a future system development (Epic Systems Corporation, Wisconsin, USA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor this trial, we will link the REDCap stratified randomization module to Epic (25,26). Enrolled patients will be randomized to groups using a 1:1:1 ratio allocation. The \u003cem\u003eOur Practice Advisories\u003c/em\u003e will alert the physician that a patient is enrolled and provide a REDCap link to randomize (see supplemental material 1). If the physician cancels the advisory, the patient remains suitable for screening and the alert will reappear until the participant is assessed for eligibility. An instructional video on how to perform the randomization will be available via hyperlink within the \u003cem\u003eOur Practice Advisories\u003c/em\u003e to guide the physician. The study team will monitor the REDCap randomization dashboard regularly to ensure consistent participant arm allocation between REDCap and the electronic medical records. In the event of randomization errors in which the physician did not enter the allocated arm correctly in the electronic medical records, the participants will be included in the intention-to-treat analysis but excluded in the per-protocol analysis (see scenario examples in supplemental material 1). The randomization sequence was created using the random function in Excel by a researcher independent of this trial and uploaded into REDCap. This sequence will be concealed from all physicians and will be restricted by setting user privileges in the REDCap project. The detailed REDCap project configuration is available in the supplemental material 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with treatment allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe physician will transcribe the treatment arm allocation from REDCap to the electronic medical record alert (see supplemental material 1). Once the treatment arm option is selected, the system will assign a \u003cem\u003e\u0026ldquo;Smart Data Element\u003c/em\u003e\u0026rdquo; that stores a number that signifies arm allocation at the patient record level. This system element is not visible to end-users and will only be visible to certified technical users with restricted access. Physicians will also be alerted when they are prescribing a drug included in the drug group being investigated and includes a study \u0026ldquo;\u003cem\u003eOrder Set\u0026rdquo;\u0026nbsp;\u003c/em\u003e(see supplemental material 1). Compliance within the treatment allocation will be achieved by incorporating a well-defined system of rules and logic within the electronic medical records study \u003cem\u003eOrder Set\u003c/em\u003e. This will ensure that only the allocated treatment for a specific participant will be presented to the physician when ordering. The physician will have the capacity to override the alert and provide an override reason within the alert. The study team will monitor override reasons through a message sent to the \u0026ldquo;\u003cem\u003eInBasket\u003c/em\u003e\u0026rdquo; (see supplemental material 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRandomized participants will be automatically enrolled within the electronic medical records into a study record and will send a real-time notification message via \u003cem\u003eInBasket\u003c/em\u003e to the study team (see supplemental material 1). This study record will be used to monitor participant progress within the study. \u0026nbsp; This will also be accompanied by a series of cross-arm \u003cem\u003eOur Practice Advisories\u003c/em\u003e to prevent treatment deviation (see supplemental material 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign \u0026amp; Intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis feasibility study protocol is reported according to the SPIRIT 2025 statement (27).\u003c/p\u003e\n\u003cp\u003eWe will conduct a single centre, three-arm, open-label, parallel group, randomized controlled trial. This trial will take place in a mixed medical-surgical-trauma ICU in Australia (28). Eligible participants will be randomized to one of three arms; the overall study design is depicted in Fig 1. The schedule of assessments is shown in the recommended SPIRIT Table (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eLow dose phenobarbital (4 milligrams per kilogram ideal body weight), infused over 30 minutes in addition to usual care;\u003c/li\u003e\n \u003cli\u003eStandard dose phenobarbital (8 milligrams per kilogram ideal body weight) over 30 minutes in addition to usual care; or\u003c/li\u003e\n \u003cli\u003eUsual care.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIf allocated to phenobarbital arms, patients may also receive additional lower doses of the study drug once 30 minutes have elapsed from the initial load. Up to a maximum of two additional doses (2 milligrams per kilogram ideal body weight) may be given in a 48-hour period after randomization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2)\u003c/strong\u003e Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Table Summary\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"644\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 484px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTRIAL PERIOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnrolment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 238px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-randomization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClose-out\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTIMEPOINT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePre-eligibility\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eEligibility\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eUp to 48-hours post-enrollment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026gt;48-hours post-enrollment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eData Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eENROLLMENT:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEligibility screen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEligibility assessment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eINTERVENTIONS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eLow/Standard Dose Phenobarbital Administration\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eUsual Care\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eASSESSMENTS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic Information\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFeasibility (Primary Outcome)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eRationale for dosing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor this trial we will use intravenous phenobarbital. Studies conducted outside of a critical care environment have used enteral or intramuscular dosing (29,30). However, intravenous administration of drugs is generally preferred in the emergency and critical care settings due to more predictable pharmacokinetics and onset of action.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExisting literature describes using intravenous phenobarbital for the treatment of alcohol withdrawal syndrome in either a weight-based or a fixed dose regimen. A retrospective cohort study included 179 adult patients admitted to a tertiary academic hospital with alcohol withdrawal syndrome and reported no difference in phenobarbital-related adverse drug events between 6 milligrams per kilogram and 10 milligrams per kilogram ideal body weight (31). Of these 179 patients, the majority (~56%) received their initial phenobarbital load in the emergency department, a third (~32%) received initial phenobarbital in the ICU, and the remainder were treated in other inpatient wards (31). A prospective blinded randomized trial of patients presenting to the emergency department with alcohol withdrawal syndrome compared intravenous phenobarbital to intravenous lorazepam (32). Patients received 260 milligrams of intravenous phenobarbital initially. Subsequent doses of 130 milligrams were given at the discretion of the treating physician. Of the 25 patients who received phenobarbital. the mean number of doses was 2.9 (range 1 to 6) for a mean dose of 509 milligrams (range 260 to 910). A single centre retrospective study of 87 patients compared patients after a protocol change from a \u0026lsquo;low-intermittent\u0026rsquo; phenobarbital dosing regimen to a \u0026lsquo;front loaded\u0026rsquo; phenobarbital. During the initial period all patients with a high alcohol withdrawal syndrome score despite three intravenous doses of 8 milligrams of lorazepam (total) received a fixed dose of 260 milligrams followed by 130 milligrams intravenous push every 15 minutes as needed. After the protocol change, patients received a weight-based regimen 10 milligrams per kilogram actual body weight. The patients receiving the weight-based dosing (subsequent period) were significantly less likely to be mechanically ventilated and had a shorter duration of admission (33).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our intervention arms we will test two weight-based dosing regimens. The doses chosen are slightly less than administered in the studies above. We have reduced doses because our clinicians are less familiar with using phenobarbital. We will also use ideal body weight rather than actual body weight (34). \u0026nbsp;In the lower- and standard-dose groups, patients will receive 4 and 8 milligrams per kilogram ideal body weight of phenobarbital respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUsual care\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt our institution, usual care for the management of alcohol withdrawal syndrome is guided by a hospital protocol. This policy recommends enteral administration of 20 milligrams of diazepam every 2 hours when needed (i.e., PRN) based on withdrawal symptoms, with repeated dosing determined by alcohol withdrawal scale score. This policy reflects the standard for treatment for alcohol withdrawal Australia-wide, with the Australian Government classifying diazepam as a \u0026lsquo;gold standard\u0026rsquo; with an \u0026lsquo;A\u0026rsquo; strength of recommendation, and a \u0026lsquo;Ia\u0026rsquo; level of evidence but individual clinicians can modified prescriptions to lesser dose or the intravenous route (35). Prescribing of diazepam can occur within the electronic medical records using an alcohol withdrawal syndrome order set. Oxazepam is considered for patients with relative contraindications to long-acting benzodiazepines, such as severe alcoholic hepatitis. Oxazepam 15 mg is approximately equipotent to 5 mg diazepam.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient flow will occur as outlined in Figure 2 below.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eElectronic medical records embedded trial design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe embedding process was designed with multiple key stakeholders from the ICU and electronic medical record team as detailed in supplemental material 1. We established proof-of-concept of embedding all aspects of a trial evaluating electrolyte administration (23) using the Epic electronic medical records system. Multiple iterations were performed to arrive at an acceptable design concept for this trial. Validation and co-design sessions were conducted before the implementation with pharmacists, physicians, and a physician informatician to collect feedback and incorporate it into the design. The final design was tested using multiple cycles following the electronic medical record standard test case scenarios. The design underwent governance and change control procedures to ensure system compliance. A training plan was delivered to ensure that the end-user is informed of the new functionality. During the implementation phase, the electronic medical record build records monitoring, enhancement, and maintenance will be conducted to ensure compliance with local hospital and precinct-wide system policy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFeasibility will be determined by: 1. Useability. 2. Screening rates. 3. Enrolment rates. 4. Compliance with treatment allocation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUsability will be determined by conducting physician perceived electronic medical records usability survey using the System Usability Scale 10 item questionnaire (see table 3) (36). The System Usability Scale ranges from 0 to 100, with greater scores indicating better usability. Feasibility of screening will be determined as the electronic medical records identifying two patients per month who meet all eligibility criteria. Feasibility of enrolment and randomization will be defined as 70% of eligible patients being randomized (eligible patients determined by manual screening and in basket message alerts) and completion of the trial within 2.5 years. The thresholds for feasibility of compliance with treatment allocation is that 80% of patients allocated to phenobarbital receive it and \u0026lt; 10% of patients assigned usual care receive phenobarbital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eCumulative alcohol withdrawal scale scores from study days 1-7. Alcohol withdrawal scale scores are reported in Epic by nurses and entered at least once per admission.\u003c/li\u003e\n \u003cli\u003eQuantity of diazepam administered will be extracted from the medical records. \u0026nbsp;Diazepam (or equivalent) dosing will be extracted from Epic and reported as days received, dose per day and total dose.\u003c/li\u003e\n \u003cli\u003eHealth utilization include number of code grey events (code grey events \u0026ndash; these are a hospital-wide response due to aggression or threatened/actual violence, episodes of harm to staff due to aggression or violence, and violence, duration of intensive care admission, duration of hospital admission, days of antibiotic therapy, use of mechanical restraints, need for additional staff on discharge to ward to manage behaviour (so-called \u0026lsquo;Nurse Special\u0026rsquo;)), and adjuvant drug treatments (including, clonidine, dexmedetomidine, olanzapine, quetiapine, haloperidol, and droperidol) (37). Code grey events will be reported as actual number and mean per patient for seven days after randomization. Occupational aggression and violence will be extracted from the medical records. Duration of intensive care admission from randomization (reported as days free of ICU at day 7). Duration of hospital admission from randomization (reported as days free of ICU at day 28). Days of antibiotic therapy for seven days after randomization reported as binary (Y/N) and days received. Code grey events will be reported as actual number and mean per patient for seven days after randomization. Use of mechanical restraints for seven days after randomization and reported as binary (Y/N) and days received. Use of Nurse Special on discharge to ward and reported as binary (Y/N), Other adjuvant drug treatments in ICU (clonidine, dexmedetomidine, olanzapine, quetiapine, haloperidol, droperidol) for seven days after randomization will be reported as received (Y/N)\u003c/li\u003e\n \u003cli\u003eThe effect on patient outcomes: delirium/coma free days, seizures, respiratory depression, need for tracheal intubation, mortality).Delirium and coma free days will be recorded using the process used previously (38). A patient will be regarded as delirium/coma free for that calendar day if: They are alive and discharged from the ICU \u003cstrong\u003e\u003cu\u003eor\u0026nbsp;\u003c/u\u003e\u003c/strong\u003eThey are alive in the ICU with (all of the following): 1. The Richmond Agitation-Sedation Scale (RASS) score being -2 to 0 all day at all time points; 2. No Confusion Assessment Method for the ICU (CAM-ICU) positive outcome recorded at any time point; and 3. No documentation of agitation during the calendar day\u003c/li\u003e\n \u003cli\u003eFor unintubated patients, frequency of intubation post randomization and for seven days after randomization will be reported as yes/no.\u003c/li\u003e\n \u003cli\u003eVentilator days will be reported as median (range)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTime to extubation\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFrequency of seizures will be reported (for seven days after randomization) and reported as number of patients having one seizure and total number of seizures.\u003c/li\u003e\n \u003cli\u003eIncident neuroimaging (CT or MRI) in ICU and for seven days after randomization\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRespiratory depression, counted as hypoxia (SpO2 \u0026lt; 92% on room air when previously \u0026gt;95% in the context of respiratory rate \u0026lt;10) or new hypercapnia (PaCO2 \u0026gt; 50 mm Hg)\u003c/li\u003e\n \u003cli\u003eSedation scores will be recorded using the Richmond Agitation Sedation Score. RASS scores are reported in Epic by nurses and reported at least once per nursing shift.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHighest PaCO2 for calendar day will be recorded when available\u003c/li\u003e\n \u003cli\u003eFalls during hospitalization for first 7 days (documented using Riskman)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs an embedded trial, eligibility screening, enrolment, randomization, and patient demographics will be collected in real time during hospital admission using the Epic reporting tool. This will serve as an operational data set for monitoring participant accruals and progress.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA study database will be created using REDCap case report forms (see supplemental material 1) hosted at The Royal Melbourne Hospital (25,26). Data that requires narrative interpretation will be collected manually from the electronic medical records and entered into case report forms by the delegated study team members.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData verification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data will be kept securely for at least 15 years and stored as per Royal Melbourne Hospital research policy. Access will be password-controlled and limited to members of the study team. An ICU Research Coordinator independent of this trial will perform source data verification. Source data verification will be conducted for 100% of the primary outcome (feasibility) and 100% of serious adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial oversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Trial Safety Committee includes intensive care physicians Adam Deane and Tess Evans and senior ICU pharmacist Melissa Ankravs. The Data Safety Monitoring Committee includes intensive care physician Matthew Maiden and addiction medicine physician Nazila Jamshidi.\u003c/p\u003e\n\u003cp\u003eThe Trial Safety Committee will meet monthly to review all adverse events, recruitment, and compliance with the interventions. The Trial Safety Committee may decide to stop the trial if it is clearly not feasible despite attempts to resolve issues. Every three months the Data Safety Monitoring Committee will be provided a summary of all serious adverse events, adverse events, recruitment rates and compliance with the interventions. The Data Safety Monitoring Committee will use their own discretion to recommend stopping the trial due to adverse/serious adverse events.\u003c/p\u003e\n\u003cp\u003ePatients with alcohol withdrawal syndrome who are admitted to the ICU are at high-risk for adverse events. However, the drugs used as part of usual care, benzodiazepines, and the intervention, phenobarbital, have known adverse effects associated with their use. It is recognised that the patient population in the ICU will experience aberrations in laboratory values, signs, and symptoms due to the severity of the underlying disease and the impact of standard treatments (39). These will not necessarily constitute adverse events or serious adverse events unless they are considered related to study treatment, or in the principal investigator\u0026rsquo;s clinical judgement are not recognised events consistent with the participants underlying critical illness and/or chronic diseases and expected clinical course. In Australian ICU trials, the reporting of adverse events for medicinal products is restricted to events that are considered related to study treatment (possibly, probably, or definitely).\u003c/p\u003e\n\u003cp\u003eFor the purposes of this open-label trial, Serious Adverse Events will only be reported if they occur in participants receiving phenobarbital. Serious Adverse Events be defined as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), anaphylaxis (angioedema), tracheal intubation, cardiac arrest or pre-arrest, and death post randomization and prior to ICU discharge. Any of these events that considered to be identified as probably or definitely related to phenobarbital will be reported to the data safety monitoring committee within 48 hours. Because events such as tracheal intubation and cardiac arrest can occur in the usual care group (i.e., diazepam as single agent drug), these will be collated and reported with adverse events.\u003c/p\u003e\n\u003cp\u003eFor the purposes of this trial an adverse event will be considered new hypotension (mean arterial pressure \u0026lt; 60 mmHg or an increase of \u0026gt; 50% of vasoactive drug infusion) during infusion of phenobarbital for 30 minutes after infusion ceased, or \u0026lsquo;mild\u0026rsquo; skin reaction (rash, hives, itch). Any adverse event thought to be study treatment related will be evaluated by a trial physician. Adverse events will be collated and reported to the Trial Safety Committee and Data Safety Monitoring Committee at three monthly intervals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWithdrawals\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the circumstance that the treatment physician believes usual care is clearly preferable over the allocated phenobarbital regimen, the treatment physician can override the treatment allocation. This will be recorded as a protocol violation with data retained for intention to treat analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the circumstance that the medical treatment decision maker (MTDM) refuses retention of data, all patient data will be removed from database and the patient will be considered removed from the intention to treat analysis, if this occurs the participant will not be replaced.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur feasibility trial will include 45 participants. It is reasoned that a sample size of 45 participants will ensure assessment of our feasibility metrics (useability, screening and enrolment rates, and compliance) and that the multidisciplinary team members gain experience with administration of phenobarbital for alcohol withdrawal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsistent with pilot and feasibility trial recommendations, the statistical focus will be descriptive statistics (means, proportions, medians) and differences between the groups and their associated confidence intervals or quantile ranges, rather than repeated P value testing (40). Pilot studies may usefully help assess minimum clinically important differences even if confidence intervals reported are numerically less than 95% (such as 85% or 75%) (37). Due to this study relying on prescribers correctly transcribing randomization schedules from REDCap into the electronic medical records, our primary analysis will be a per-protocol analysis. We will also conduct an intention to treat analysis for all patients who were eligible and randomized. If a patient is randomized in error and were ineligible on the eligibility criteria, they will not be included in the intention to treat analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial results will be disseminated by a final report and sent to participants upon request. Any protocol amendments will be noted in the publication of the results. Further dissemination will include local institute and wider conference presentations, and publication in peer-reviewed journal articles.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlcohol is the most used and misused drug globally, and alcohol use disorders represent a considerable burden to healthcare systems (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Alcohol-use disorders include a spectrum from excessive use, abuse, dependence, to addiction. Patients with alcohol-use disorders are not only at risk of withdrawal symptoms, but these patients have a higher rate of complications, longer duration of ICU and hospital admission, and increased mortality in comparison to patients who do not abuse alcohol (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eManaging patients with alcohol-use disorders who present to the hospital or ICU can be extremely complicated, as a hospital admission usually results in immediate abstinence from drinking alcohol and can trigger alcohol withdrawal syndrome. While the symptoms vary in intensity, approximately one in five patients can develop seizures, and patients in the ICU who are reliant on life support and who develop delirium due to alcohol withdrawal syndrome may risk harming themselves by accidental removal of catheters or tubes that are providing this life support. An additional complexity with alcohol withdrawal in the critically ill is that alcohol withdrawal is commonly an intercurrent issue and often not the primary diagnosis at admission \u0026ndash; and that symptoms of withdrawal (autonomic hyperactivity and delirium) may be masked by another primary diagnosis, co-morbidity, or current ICU treatment.\u003c/p\u003e\u003cp\u003eThe current mainstay of treatment for alcohol withdrawal are benzodiazepines (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). This class of drug is known to ameliorate patient agitation, reduce the incidence of alcohol withdrawal seizures, and prevent alcohol withdrawal delirium (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). However, for many patients, lesser doses of benzodiazepines provide inadequate symptom control, such that larger doses of benzodiazepines are administered. Benzodiazepine drugs in large doses can exacerbate the patient\u0026rsquo;s acute confusion state (known as delirium), and weaken respiratory effort, leading to mechanical ventilation and prolonged ICU admission (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Other pharmacological adjuncts that have been reported to be useful in the management of alcohol withdrawal syndrome include carbamazepine, valproic acid, sodium oxybate, baclofen, gabapentin, and topiramate, but none of these drugs will be tested in this trial (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e In North America, many centres use phenobarbital for the treatment for alcohol withdrawal, either administered alone or as a benzodiazepine sparing agent, and it is increasingly being recommended as an alternative agent in guidelines, albeit on quite sparse randomized literature. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). This study will determine whether it is feasible to conduct a trial administering phenobarbital in addition to usual care.\u003c/p\u003e\u003cp\u003eStrengths of our trial include novel data reporting in an ICU population, and the embedding of all aspects of the trial within the electronic medical records with stratified randomization. One-directional communication from the electronic medical record to REDCap to perform real-time randomization. The use of the Epic electronic medical record and alerts to support real-time screening and randomization minimises human error and saves time for clinical staff, allowing resource allocation of staff to more complex tasks. Limitations of our trial include the open label design and small sample population being studied; however, this was deemed necessary given difficulties with patient recruitment elsewhere (PHENOMANAL) and clinical unfamiliarity with phenobarbital in Australia (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\u003ch2\u003eTrial Status\u003c/h2\u003e\u003cp\u003eThe recruitment began on 8 July 2026. The trial will be stopped if recruitment is not completed by 7 January 2028.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: The protocol has been approved by the Royal Melbourne Hospital Research Ethics Committee (RMH2024.320 HREC114383). Participants will be included under emergency treatment with an opt-out process for retention of data. The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12625000320459).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: All authors consent to the publication of the protocol manuscript. No restrictions have been placed on the publication of future data resulting from the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u0026nbsp;There is no funding to declare. The trial sponsor had no involvement in the study design, collection, analysis, and interpretation of the data, nor the decision to submit the report for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eHP, SR, TE, MA, TF, NC, AA, CM, JP, ES, MS, TI, and AD (all authors) contributed significantly to the study conception and design; and critically reviewed the manuscript for important scientific content. HP, SR, TE, and AD drafted the manuscript. All authors reviewed the final manuscript and agree to be accountable for the accuracy and integrity of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMehta AJ. Alcoholism and critical illness: A review. World J Crit Care Med. 2016;5(1):27. \u003c/li\u003e\n\u003cli\u003eAustralian Institute of Health and Welfare. Alcohol, tobacco \u0026amp; other drugs in Australia [Internet]. AIHW; 2024 July [cited 2024 Aug 30]. (Alcohol). Available from: https://www.aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-types/alcohol\u003c/li\u003e\n\u003cli\u003eKattimani S, Bharadwaj B. Clinical management of alcohol withdrawal: A systematic review. Ind Psychiatry J. 2013 July;22(2):100\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eMaldonado JR, Sher Y, Das S, Hills-Evans K, Frenklach A, Lolak S, et al. Prospective Validation Study of the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) in Medically Ill Inpatients: A New Scale for the Prediction of Complicated Alcohol Withdrawal Syndrome. Alcohol Alcohol Oxf Oxfs. 2015 Sept;50(5):509\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eMayo-Smith MF. Pharmacological Management of Alcohol Withdrawal: A Meta-analysis and Evidence-Based Practice Guideline. JAMA. 1997 July 9;278(2):144. \u003c/li\u003e\n\u003cli\u003eLanglois H, Cormier M, Villeneuve E, Hoffman RS, Longo C, Gosselin S. Benzodiazepine resistant alcohol withdrawal: What is the clinician\u0026rsquo;s preferred definition? CJEM. 2020 Mar;22(2):165\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eL\u0026ouml;scher W, Rogawski MA. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. 2012 Dec;53 Suppl 8:12\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eZaal IJ, Devlin JW, Hazelbag M, Klein Klouwenberg PMC, Van Der Kooi AW, Ong DSY, et al. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med. 2015 Dec;41(12):2130\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eShafiekhani M, Mirjalili M, Vazin A. Psychotropic drug therapy in patients in the intensive care unit - usage, adverse effects, and drug interactions: a review. Ther Clin Risk Manag. 2018;14:1799\u0026ndash;812. \u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez-Mu\u0026ntilde;oz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat. 2005 Dec;1(4):329\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eUmar Z, Haseeb Ul Rasool M, Muhammad S, Yousaf S, Nassar M, Ilyas U, et al. Phenobarbital and Alcohol Withdrawal Syndrome: A Systematic Review and Meta-Analysis. Cureus. 2023 Jan;15(1):e33695. \u003c/li\u003e\n\u003cli\u003eHammond DA, Rowe JM, Wong A, Wiley TL, Lee KC, Kane-Gill SL. Patient Outcomes Associated With Phenobarbital Use With or Without Benzodiazepines for Alcohol Withdrawal Syndrome: A Systematic Review. Hosp Pharm. 2017 Oct;52(9):607\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eMalone D, Costin BN, MacElroy D, Al‐Hegelan M, Thompson J, Bronshteyn Y. Phenobarbital versus benzodiazepines in alcohol withdrawal syndrome. Neuropsychopharmacol Rep. 2023 Dec;43(4):532\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eLaw TM, Roper SL, McKinney A, Starnes C, Rains J, Yune JM, et al. Evaluation of Symptom-Triggered Benzodiazepines Versus Phenobarbital for Alcohol Withdrawal Syndrome in Trauma-Surgical Intensive Care Patients. Ann Pharmacother. 2025 May 28;10600280251340164. \u003c/li\u003e\n\u003cli\u003eErfle BA, Steel TL, Law AC, Kaufman DA, Hills-Dunlap K, Afshar M, et al. Pharmacological Interventions for Alcohol Withdrawal Syndrome Among Hospitalized Adults: A Multicenter Cohort Study. J Gen Intern Med. 2025 Aug 28; \u003c/li\u003e\n\u003cli\u003eWolpaw BJ, Oren H, Quinnan-Hostein L, Bradley KA, Johnson NJ, Hallgren KA, et al. Hospital-Wide Implementation, Clinical Outcomes, and Safety of Phenobarbital for Alcohol Withdrawal. JAMA Netw Open. 2025 Aug 1;8(8):e2528694. \u003c/li\u003e\n\u003cli\u003eFilewod N, Hwang S, Turner CJ, Rizvi L, Gray S, Klaiman M, et al. Phenobarbital for the management of severe acute alcohol withdrawal (the PHENOMANAL trial): a pilot randomized controlled trial. Pilot Feasibility Stud. 2022 Jan 22;8(1):14. \u003c/li\u003e\n\u003cli\u003eMacnair A, Love SB, Murray ML, Gilbert DC, Parmar MKB, Denwood T, et al. Accessing routinely collected health data to improve clinical trials: recent experience of access. Trials. 2021 Dec;22(1):340. \u003c/li\u003e\n\u003cli\u003eMc Cord KA, Ewald H, Ladanie A, Briel M, Speich B, Bucher HC, et al. Current use and costs of electronic health records for clinical trial research: a descriptive study. CMAJ Open. 2019 Jan;7(1):E23\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003ePanganiban HP, Nguyen CD, Abdelhamid YA, Ankravs M, Karahalios E, Macisaac C, et al. Feasibility of Embedding a Randomised Clinical Trial (RCT) into an Electronic Medical Record (EMR) for Patients Admitted to an Intensive Care Unit (ICU). Stud Health Technol Inform. 2024 Jan 25;310:1420\u0026ndash;1. \u003c/li\u003e\n\u003cli\u003eAppleyard SE, Gilbert DC. Innovative Solutions for Clinical Trial Follow-up: Adding Value from Nationally Held UK Data. Clin Oncol. 2017 Dec;29(12):789\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eQian ET, Casey JD, Wright A, Wang L, Shotwell MS, Siemann JK, et al. Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial. JAMA. 2023 Oct 24;330(16):1557. \u003c/li\u003e\n\u003cli\u003eNguyen CD, Panganiban HP, Fazio T, Karahalios A, Ankravs MJ, MacIsaac CM, et al. A Randomized Noninferiority Trial to Compare Enteral to Parenteral Phosphate Replacement on Biochemistry, Waste, and Environmental Impact and Healthcare Cost in Critically Ill Patients With Mild to Moderate Hypophosphatemia. Crit Care Med. 2024 July 1;52(7):1054\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eNational Statement on Ethical Conduct in Human Research 2023. 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Beta‐hydroxy‐beta‐methylbutyrate supplementation and functional outcomes in multitrauma patients: A pilot randomized controlled trial. J Parenter Enter Nutr. 2023 Nov;47(8):983\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eBrooks L, Reinert JP. Phenobarbital Dosing for the Treatment of Alcohol Withdrawal Syndrome: A Review of the Literature. J Pharm Technol. 2024 Aug;40(4):186\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eViswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol. 1978;18(2\u0026ndash;3):100\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eStallworth S, Stilley K, Viriyakitja W, Powers S, Parish A, Erkanli A, et al. Evaluation of phenobarbital dosing strategies for hospitalized patients with alcohol withdrawal syndrome. Gen Hosp Psychiatry. 2023;85:155\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eHendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. Am J Emerg Med. 2011 May;29(4):382\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eShah P, Stegner-Smith KL, Rachid M, Hanif T, Dodd KW. Front-Loaded Versus Low-Intermittent Phenobarbital Dosing for Benzodiazepine-Resistant Severe Alcohol Withdrawal Syndrome. J Med Toxicol Off J Am Coll Med Toxicol. 2022 July;18(3):198\u0026ndash;204. \u003c/li\u003e\n\u003cli\u003eNafiu OO, Mills K, Tremper KK. Some Cautionary Tales About Ideal Body Weight Dosing of Anesthetic Medications: It Is Not All That Ideal! Anesth Analg. 2018 Aug;127(2):586\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eHaber P. Guidelines for the Treatment of Alcohol Problems. Canberra: Dept. of Health and Ageing; 2009. \u003c/li\u003e\n\u003cli\u003eBrooke J. SUS: a retrospective. J Usability Stud. 2013 Feb;8(2):29\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eNorthcott MH, Johnston G, Presneill JJ, Fazio TN, Adamson N, Ankravs MJ, et al. Aggression, violence and threatening behaviour during critical illness. Crit Care Resusc. 2023 June;25(2):65\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eAnkravs MJ, Udy A, Bellomo R, Presneill JJ, Adams L, Abdelhamid YA, et al. Olanzapine versus quetiapine in critically ill patients with hyperactive delirium: Protocol for a multicentre, cluster-randomised, double-crossover, pragmatic clinical trial (CALM-ICU). Crit Care Resusc. 2024 Dec;26(4):249\u0026ndash;54. \u003c/li\u003e\n\u003cli\u003eTyler PD, Du H, Feng M, Bai R, Xu Z, Horowitz GL, et al. Assessment of Intensive Care Unit Laboratory Values That Differ From Reference Ranges and Association With Patient Mortality and Length of Stay. JAMA Netw Open. 2018 Nov 9;1(7):e184521. \u003c/li\u003e\n\u003cli\u003eThabane L, Lancaster G. A guide to the reporting of protocols of pilot and feasibility trials. Pilot Feasibility Stud [Internet]. 2019 Dec [cited 2025 July 18];5(1). Available from: https://pilotfeasibilitystudies.biomedcentral.com/articles/10.1186/s40814-019-0423-8\u003c/li\u003e\n\u003cli\u003ePerry EC. Inpatient Management of Acute Alcohol Withdrawal Syndrome. CNS Drugs. 2014 May;28(5):401\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eMainerova B, Prasko J, Latalova K, Axmann K, Cerna M, Horacek R, et al. Alcohol withdrawal delirium - diagnosis, course and treatment. Biomed Pap. 2015 Mar 9;159(1):044\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eJohnson MT, Yamanaka TT, Fraidenburg DR, Kane SP. Benzodiazepine misadventure in acute alcohol withdrawal: the transition from delirium tremens to ICU delirium. J Anesth. 2013 Feb;27(1):135\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eMirijello A, D\u0026rsquo;Angelo C, Ferrulli A, Vassallo G, Antonelli M, Caputo F, et al. Identification and Management of Alcohol Withdrawal Syndrome. Drugs. 2015 Mar;75(4):353\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eRosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F, et al. Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-blind Placebo-controlled Study. J Emerg Med. 2013 Mar;44(3):592-598.e2. \u003c/li\u003e\n\u003cli\u003eYoung GP, Rores C, Murphy C, Dailey RH. Intravenous phenobarbital for alcohol withdrawal and convulsions. Ann Emerg Med. 1987 Aug;16(8):847\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003ePunia K, Scott W, Manuja K, Campbell K, Balodis IM, MacKillop J. SAEM GRACE : Phenobarbital for alcohol withdrawal management in the emergency department: A systematic review of direct evidence. Acad Emerg Med. 2024 May;31(5):481\u0026ndash;92. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alcohol Withdrawal Syndrome, Benzodiazepines, Clinical Decision Support Systems, Critical illness, Electronic Medical Records, Phenobarbital, Randomized Controlled Trial, Embedded Research.","lastPublishedDoi":"10.21203/rs.3.rs-7521474/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7521474/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAbrupt cessation of alcohol consumption following hospital admission can induce alcohol withdrawal syndrome. This syndrome is challenging to manage and is associated with considerable morbidity and mortality. Current management of alcohol withdrawal syndrome in Australia is generally titrated benzodiazepine administration. In some regions, phenobarbital is preferred but evidence to support its superiority is weak.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eWe will conduct a single centre, three-arm, open-label, parallel group, randomized clinical trial. Our primary objective is to determine the feasibility of embedding a randomized clinical trial within an electronic medical record to compare phenobarbital to single-agent benzodiazepine for patients with alcohol withdrawal. We will screen and randomize 45 patients using the Epic electronic medical record system. Patients will receive either low- or standard-dose intravenous phenobarbital (4 or 8 milligrams per kilogram), or usual care (benzodiazepine regimen). The primary outcome is feasibility, determined by useability, screening rates, enrolment rates, and compliance. Secondary outcomes include alcohol withdrawal scale scores, dose of benzodiazepine administered, health utilisation, adjuvant drug treatments, and patient outcomes.\u003c/p\u003e\u003ch2\u003eDiscussion:\u003c/h2\u003e\u003cp\u003eThere are limited high quality data evaluating the use of phenobarbital administration for alcohol withdrawal syndrome. Additionally, there is limited data evaluating the embedding of screening, randomization, and administration of a sedative drug within the electronic medical record. Our feasibility trial will establish whether this is possible within our health care system. In this protocol paper we detail how we will embed this trial within the electronic medical record Epic.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003eThe study (RMH2024.320 v2 06/01/2025) is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12625000320459. Registered 17 April 2025, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12625000320459\u003c/span\u003e\u003cspan address=\"https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12625000320459\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Trial Sponsor: The Royal Melbourne Hospital.\u003c/p\u003e","manuscriptTitle":"Phenobarbital as an Adjuvant to benzodiazepine administration when compared to Single-agent benzodiazepine Treatment (usual care) for Alcohol Withdrawal Syndrome in the Intensive Care Unit (PASTA): a study protocol for a feasibility trial that embeds screening, enrolment and randomization within the electronic medical records","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 09:13:27","doi":"10.21203/rs.3.rs-7521474/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2026-02-23T18:13:05+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-02-22T00:21:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-01T18:32:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-09T06:01:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pilot and Feasibility Studies","date":"2025-09-07T18:10:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pilot-and-feasibility-studies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pafs","sideBox":"Learn more about [Pilot and Feasibility Studies](http://pilotfeasibilitystudies.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/PAFS/default.aspx","title":"Pilot and Feasibility Studies","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e3c949c-b630-4f0f-8c19-b93ad4da43b1","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T22:14:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-15 09:13:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7521474","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7521474","identity":"rs-7521474","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}