Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations

Abstract

Provision of adequate sedation is a fundamental part of caring for critically ill patients. Propofol, dexmedetomidine, and benzodiazepines are the most commonly administered sedative medications for adult patients in the intensive care unit (ICU). These agents are limited by adverse effects, need for a monitored environment for safe administration, and lack of universal effectiveness. Increased interest has recently been expressed about repurposing older pharmacologic agents for patient comfort in the ICU. Valproate, enteral clonidine, and phenobarbital are three agents with increasing evidence supporting their use. Potential benefits associated with their utilization are cost minimization and safe administration after transition out of the ICU. This literature review describes the historical context, pharmacologic characteristics, supportive data, and practical considerations associated with the administration of these agents for comfort in critically ill adult patients.

The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo‐controlled trial

“…Our impression is that many of the patients who had to be excluded had in fact delirium. Even though no evidence exists regarding the need for dose adjustments based on renal dysfunction, such adjustment seems reasonable based on the renal elimination …”

COVID-19: ICU delirium management during SARS-CoV-2 pandemic—pharmacological considerations

“…Early recommendations for hydroxychloroquine therapy, empiric community-acquired pneumonia coverage with azithromycin for atypical bacterial coinfections, and the possibility of COVID-related cardiomyopathies all increase the risk of cardiac decompensation [4], with the addition of antipsychotics only serving to amplify the risk of QTc prolongation and worsen morbidity. In an attempt to avoid the preventable adverse events associated with antipsychotics, a recommendation endorsing agents like ketamine, valproic acid, or clonidine may be more appropriate options when implementing intravenous sedative-sparing strategies [3,5].…”

Beyond Opioids for Pain Management in Adult Critically Ill Patients

“…a-2 agonists are best known for their sedative and antihypertensive effects but may also possess opioid-sparing effects and reduce opioid-induced hyperalgesia. [27][28][29][30] Clonidine and dexmedetomidine may provide analgesia by reducing sympathetic outflow from the central nervous system (CNS), specifically the locus ceruleus and substantia gelatinosa. 27 Dexmedetomidine has approximately 7 times the affinity for the a-2 receptor compared to clonidine.…”

“…Clonidine is available as a tablet, epidural injection, and transdermal patch in the United States. 27 The transdermal patch is not recommended in the ICU due to its prolonged onset and unpredictable absorption. Clonidine tablets may be given orally or sublingually.…”

“…Approximately 50% of clonidine is renally eliminated as unchanged drug, but no recommendations exist for adjustment in the setting of renal dysfunction. 27…”