Intravenous Acetate as an Adjunctive Treatment for Alcohol Withdrawal in Hospitalized Patients

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.

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