Posted on February 13, 2015 in: Innovative Practice
by Blake Bonkowski, Pharm.D., and Jennie Heidmann, Pharm.D., PGY1 pharmacy residents, Spectrum Health
Alcohol withdrawal is a neurologic disorder that has a continuum of worsening symptoms caused by the effects of chronic alcohol use on the central nervous system (CNS). Continuous use of alcohol leads to a down regulation of the inhibitory γ-aminobutyric acid (GABA) receptor and up regulation of the excitatory N-methyl-D-aspartate (NMDA) receptor in the CNS. This increased excitation and loss of inhibition results in the tremor, hyperactivity, insomnia, nausea, hallucinations, agitation, anxiety and seizures seen in patients with alcohol withdrawal syndrome (AWS).
In 2012, about 17 million, or 7.2 percent, of Americans ages 18 and older had an alcohol use disorder (AUD). In the intensive care unit (ICU), this number increases to approximately 10-33 percent of patients having an AUD, putting these patients at an increased risk for AWS, intubation and death.
Benzodiazepines (BZD) are the drug of choice for AWS. However, they are not without side effects and can lead to increased sedation and respiratory depression, which may ultimately result in the need for mechanical ventilation. Dexmedetomidine (DEX) is an α-2 receptor agonist that might be helpful in AWS because it may control the adrenergic symptoms seen in AWS, while not requiring the patient to be intubated. There is limited data for the use of DEX in patients with AWS and none of the studies are prospective. Two recent trials, one prospective and the other retrospective, were conducted to evaluate the efficacy of DEX as an adjunctive to standard therapy in ICU patients with AWS.
The first study by Vanderweide and colleagues was a retrospective cohort study that evaluated the impact of early DEX use in 20 critically ill patients with AWS compared with 22 control patients who received the standard alcohol withdrawal protocol (AWP) utilizing BZD. After the point of maximal decrease of BZD requirements, the primary endpoint was cumulative 12-hour BZD requirement change (post minus pre). The mean 12-hour change in BZD requirement was significantly different with a mean cumulative decrease of 20 mg in the DEX group and 8.3 mg in the control group (p = 0.0455). There were no significant differences in length of ICU stay or duration of intubation. The study demonstrated that early initiation of DEX may be associated with reducing BZD dose requirements, especially in the initial 12-hour period after initiation. Although this study demonstrated a significant decrease in BZD requirements after early DEX initiation, there were no significant changes in any of the clinical endpoints and some even showed trends in favor of the control group. This study itself does not lead to recommendation of DEX in severe AWS, but it does generate hypotheses for larger studies.
The second study consisting of 24 patients with severe AWS conducted by Mueller and colleagues, was a prospective, randomized, double-blind, placebo-controlled trial. The study evaluated the effect of adding either high-dose (1.2 mcg/kg/min) or low-dose (0.4 mcg/kg/min) DEX to the standard AWP on BZD requirements in critically ill patients with AWS compared to a control group receiving only the standard AWP. The primary endpoint included change in total lorazepam requirements over the first 24 hours after starting the study medication compared with the 24 hours before starting the study drug. The median 24-hour change in pre-post lorazepam requirements was not significantly different for either the high-dose or low-dose DEX groups compared to the standard AWS protocol group (p = 0.1 and 0.066, respectively). However, when the two DEX groups were combined and compared to the standard AWS protocol group, a significant difference was seen (p = 0.037). Neither the high-dose nor the low-dose DEX groups showed a significant decrease in median ICU and hospital length of stay. This study demonstrated that when DEX is added to the standard AWP, a short-term reduction in BZD use was seen.
These studies show that the adjunct use of DEX to standard AWP resulted in a short-term reduction in BZD use in patients with severe AWS. However, since the reduction in BZD use did not correlate to a decrease in ICU or hospital stay, DEX use should not be recommended in these patients. Both these studies were small and larger randomized, controlled trials are needed.
References available upon request from MPA office.