Alcohol Withdrawal, Alcohol Abstinence, Alcohol Use Disorder
Conditions
Keywords
Alcohol Withdrawal
Brief summary
Alcohol withdrawal syndrome is a highly morbid condition affecting a substantial percentage of patients hospitalized who have alcohol use disorders, estimated at 5-6% of all hospitalized patients. Standard treatment paradigms for alcohol withdrawal syndrome have common and serious side effects, and do not fully address this condition's underlying pathophysiology. This study will examine the feasibility and safety of administering intravenous acetate, an alcohol metabolite and alternative brain fuel, as an adjunctive treatment for alcohol withdrawal in hospitalized patients that will to set the stage for future investigations of its efficacy as an adjunctive treatment in the hospital setting.
Detailed description
Alcohol withdrawal syndrome manifests in up to 30% of hospitalized patients with severe alcohol use disorders (AUD), and is a potentially life-threatening, highly morbid condition. Standard medications to treat alcohol withdrawal (e.g. benzodiazepines) can induce respiratory depression and prolong hospitalization, while medications used as adjuncts (e.g. dexmedetomidine) are also sedating and necessitate intensive monitoring. Therefore, alternative treatments targeting novel pathways in alcohol withdrawal are needed to address this treatment gap and improve patient care. Although alcohol withdrawal symptoms arise from counterregulatory neuroadaptations in γ-aminobutyric acid (GABA) and glutamate signaling, homeostatic alterations in the brain's fuel preference and sudden changes in its fuel supply have also been implicated that are not addressed by current treatment paradigms. Longstanding AUD diminishes the brain's ability to metabolize glucose, enhancing its metabolic preference for the alcohol metabolite acetate. Acetate is converted to acetyl-CoA, which is used for fuel and neurotransmitter production. When a person with AUD is hospitalized, stopping alcohol consumption, acetate supply ceases at a time when the brain has a reduced preference for glucose, potentially driving withdrawal symptoms. Investigations in patients with alcohol withdrawal that administered alternative energy substrates via oral ketogenic diet (which also generates acetyl-CoA) reported symptom improvement; however, prominent gastrointestinal symptoms in acute, severe alcohol withdrawal limit their use in this setting. Notably, we have shown that intravenous (IV) acetate administration to participants with AUD was feasible and safe and had a demonstrable physiological effect on cerebral blood flow (CBF), measured by magnetic resonance arterial spin labeling, including increased CBF to thalami, cerebellum, and cortex, which was not observed in healthy controls. Since metabolism and blood flow are tightly linked in the brain, our results support metabolic adaptations in AUD, paving the way for future investigations of acetate's efficacy as an adjunctive treatment in alcohol withdrawal that will be refined in this R34 proposal. We will conduct a single- center, placebo-controlled randomized clinical trial (RCT) of IV acetate in patients hospitalized at a large academic university hospital who are receiving inpatient standard of care treatment for alcohol withdrawal syndrome. Aim 1 will optimize screening, recruitment, informed consent, and enrollment strategies. Aim 2 will establish processes to ensure protocol fidelity, safety, and patient retention, to include collection of outcome variables reflecting patient symptoms and medication administration for alcohol withdrawal, and healthcare resource utilization. Aim 3 will use qualitative methods to incorporate the experiences and perceptions of patients hospitalized with alcohol withdrawal to improve study design and magnify the impact of the research. Results of this study will inform the final protocol and procedures for a future multi-center RCT focused on determining efficacy of adjunctive acetate treatment in patients admitted for alcohol withdrawal syndrome.
Interventions
DRUGSodium Acetate
Sodium acetate (82mg/mEq) will be mixed in solution with sterile water to create a 150 mEq/L (same as 150 mM) isotonic solution. Patients randomized to active drug will initially receive 300 mM (mEq) acetate in 2L fluid over a two-hour period. The study drug will be administered as an initial 6 mg/kg/min bolus (\~250mL volume) over 10 min, followed by a 3 mg/kg/min infusion (1750ml volume) over 110 min to complete 2L total. After the two hours are completed, patients will continue to receive the acetate solution infusion at a reduced rate of 50 mL/hour (or 615 mg acetate/ hour) until alcohol withdrawal orders are discontinued, or up to 72 hours, whichever comes first.
DRUGPlacebo
The placebo solution will be 0.9% saline, administered as a bolus/infusion in a manner identical to what would be administered for acetate.
Sponsors
University of Colorado, Denver
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Active treatment for alcohol withdrawal (e.g. use of protocolized order set in an inpatient setting) * Inpatient admission ordered * Adult \> 21 years old
Exclusion criteria
* End-stage renal disease or likely need for renal replacement therapy in the next 12 hours * Heart failure with reduced ejection fraction (\<30%) * Receipt of \>2L crystalloids prior to randomization * Advanced liver disease (Child's C or D) * Uncontrolled mental health condition * \>24 hours since ED arrival * Pregnant or incarcerated * Unable to consent and/or no proxy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Consent Rate for Study Participation per Week | Assessed weekly during the study recruitment period, pre-consent | Number and percentage of patients meeting all study eligibility criteria who provide informed consent for study participation among all eligible patients identified during each week of recruitment. |
| Proportion of Randomized Participants Receiving Greater Than or Equal to 2 L of Assigned Study Infusion | After consent and randomization, immediately before study infusion, through completion or discontinuation of the study infusion, up to 72 hours. | Number and percentage of randomized participants who receive at least 2 L of their assigned study infusion (study drug or placebo), as a measure of study protocol fidelity. |
| Proportion of Randomized Participants Withdrawn from Study for Safety Concerns | After consent, immediately before study infusion, through completion, withdraw or discontinuation of the study infusion during the index hospitalization, up to 72 hours. | Number and percentage of randomized participants for whom study participation or study intervention is discontinued because of a safety concern. |
| Alcohol Withdrawal Medications Administered, per Patient | After consent and randomization, through hospital discharge from the index hospitalization or study completion at 18 months, what occurs first. | Alcohol withdrawal medication utilization will be characterized descriptively for each participant by the total dose administered and total number of treatment days. Medications will be summarized by prespecified treatment category: (1) GABAergic medications, including benzodiazepines and phenobarbital, and (2) adjunctive medications, including dexmedetomidine and ketamine. Individual medications and medication classes will be reported separately, as applicable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Screening Volume | Pre-consent. Assessed weekly during the study recruitment period | Number of emergency department patients with an alcohol withdrawal pathway or order set initiated per week. Screening opportunities will also be characterized according to day of the week and time of day when the pathway or order set is initiated. |
| Eligibility Rate | Pre-consent. Assessed weekly during the study recruitment period | Number and percentage of screened patients meeting all inclusion criteria and no exclusion criteria and therefore eligible to be approached for informed consent. |
| Characteristics of Patients Who Do and Do Not Consent | Pre-consent through completion of the consent/enrollment attempt during the index hospitalization | Characteristics of eligible patients who do and do not consent to study participation will be summarized descriptively, including age, gender, race, ethnicity, English versus Spanish language, comorbid conditions, availability of a proxy, and whether consent was provided by a proxy. |
| Time to Informed Consent | Pre-consent. From emergency department arrival through documentation of informed consent | Time from documented emergency department arrival to documentation of informed consent, determined using electronic medical record date and time stamps. |
| Study Drug Receipt, per Patient | After consent and randomization. Assessed through completion or discontinuation of the study infusion, for up to 72 hours. | Receipt of the assigned study intervention (either drug or placebo) will be characterized by total study drug dose received, total infusion volume received, total duration of infusion, and time between randomization and initiation of the study drug infusion. |
| Reasons for Study Withdrawal | After randomization through study completion, withdrawal, or hospital discharge, for up to 72 hours. | Reasons for study withdrawal will be characterized, with particular assessment of withdrawal related to acid-base and/or electrolyte abnormalities, and respiratory-related instability. |
| Thiamine Dosing | At baseline, after hospital arrival, through hospital discharge or study conclusion, for up to 18 months, whichever occurs first. | Total thiamine administration will be characterized descriptively based on the total dose received per randomized participant. |
| Modified Minnesota Detoxification Scale (mMINDS) Scores Over Time | At baseline, after hospital arrival, through hospital discharge or study conclusion, for up to 18 months, whichever occurs first. | Serial mMINDS scores recorded by nurses will be used to characterize the severity and trajectory of alcohol withdrawal symptoms during the course of the hospitalization. |
| Requirement for Mechanical Ventilation | At baseline, after hospital arrival, through hospital discharge or study conclusion, for up to 18 months, whichever occurs first. | Determined by wheter the patient required mechanical ventilation or not, for any reason. |
| In-hospital Mortality | After consent and randomization, through discharge from the index hospitalization or study consluion, for up to 18 months, whichever occurs first. | Number and percentage of participants who die during the index hospitalization and number and percentage who are discharged against medical advice. Each outcome will be reported separately. |
| Upgrade in Level of Care | After consent and randomization, thourgh the patient's hospital admission period or study conclusion, for up to 18 months, whichever occurs first. | Level of care will be recorded by whether or not the patient required transfer to higher level of care, for example if the patient was on a medical ward but was transferred to an Intensive Care Unit. |
| Duration and Intensity of Alcohol Withdrawal Monitoring | After hospital arrival through hospital discharge, or study conclusion, for up to 18 months, whichever occurs first. | Alcohol withdrawal monitoring will be characterized by the total duration that the alcohol withdrawal order set remains active and the total number of nursing alcohol withdrawal assessments, including mMINDS assessments, completed for each participant. |
Countries
United States
Contacts
CONTACTJeffrey McKeehan, AC-AGNP
CONTACTEllen Burnham, MD
PRINCIPAL_INVESTIGATOREllen Burnham, MD
University of Colorado, Department of Pulmonary, Allergy and Critical Care Medicine
Outcome results
None listed