Dexmedetomidine is centrally-acting highly-selective a2-receptor agonist that is approved by the Food and Drug Administration (FDA) for sedation in the ICU for less than 24 hours in 19991. As dexmedetomidine is more selective towards the 2A subtype of the receptor, it causes more sedation and analgesia than the other commonly used a2-receptor agonist clonidine5. However, as it does not act on the GABA-receptors, it does not carry the risk of respiratory depression as much as other sedatives.
Recently dexmedetomidine is being used for managing delirium and sedative-hypnotic withdrawal, such as alcohol-withdrawal, in addition to sedation1. Several case reports have described its use beyond the 24 hour recommended period without any major document adverse reactions. Thus the question arises, why is it only approved for 24 hours in the first place?
Dexmedetomidine has a distribution half life of only 6 minutes and an elimination half life of 2 hours. It is mostly bound to plasma proteins such as albumin and a1glycoprotein, metabolized via the cytochrome P450 system and glucoronidation in the liver and excreted by the kidneys6.
Similar to clonidine, high-dose dexmedetomidine can cause initial transient hypertension due to action on peripheral a2b-receptors. This is followed by hypotension due to action on central a2a-receptors. Two concerns with prolonged (>24 hours) sedation with dexmedetomidine are severe hypotension and bradycardia during infusion and the theoretical concern of rebound hypertension after abrupt withdrawal, as seen with clonidine. This was evaluated by Venn et al in 2003 in a prospective observation trial of medical intensive care patients who received dexmedetomidine infusions for >48 hours. These patients did not experience any significant hemodynamic withdrawal changes when dexmedetomidine was discontinued8. Shehabi and colleagues found similar results in 20 critically ill patients receiving an infusion of dexmedetomidine for a mean 71.5 hours1. When these patients received the infusion without a loading dose, mean systolic blood pressure decreased by 16% and heart rate decreased by 21% in the first 4 hours. After an abrupt discontinuation of dexmedetomidine, mean systolic blood pressure increased by a mere 7% and heart rate by 11% only within 24 hours.
Besides the concerns with bradycardia and hypotension during infusion and the theoretical concerns with increased sympathetic response during withdrawal, there are other adverse reactions that the FDA warns about during a prolonged (24 hours) exposure to dexmedetomidine4. The FDA states that if used for >24 hours, dexmedetomidine can cause tolerance and tachyphylaxis. The FDA also states that prolonged exposure can cause a dose-related increase in adverse events such as acute respiratory distress syndrome (ARDS), respiratory failure and agitation. The limited studies so far have not shown any of these events to be associated with prolonged use of dexmedetomidine.
A 2011 retrospective review of 127 trauma patients by Devabhaktuni and colleagues does show, however, increased adverse events with high-dose and standard-dose dexemedetomidine compared to propofol when used for >24 hours for sedation in critically ill trauma patients2. These adverse events include hypotension, longer length of stay and increased use of concomitant medications for analgesia, sedation and antipsychotis. Perhaps hypovolemic hypotension in trauma patients makes them less ideal candidates for sedation with dexmedetomidine compared to other medical or surgical patients previously studied.
When the FDA approved dexmedetomidine, there were no studies evaluating its safety after 24 hours of infusion5. However, with the slowly growing evidence of safely infusing dexmedetomidine for prolonged times, approval is being explored with the FDA for use for >24 hours7.
References:
- Shehabi, Y. et al, Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects, Intensive Care Med, 2004 (30)2188-2196
- Devabhakthuni, S. et al, Evaluation of Dexmedetomidine: Safety and Clinical Outcomes in Critically Ill Trauma Patients, Journal of Trauma, Injury, Infection and Critical Care, 2011
- Venn, R.M., Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care, Critical Care, 2000 (4)302-308
- Product information. Precedex (Dexmedetomidine). Lake Forest, IL: Hospira; 2011
- Bhatia, P. et al, Dexmedetomidine: A New Agent in Anaesthesia & Critical Care Practice, Journal of Anaesthesiology, Critical Care and Pain Management, 2002
- Lam, S. W., Alexander, E., Dexmedetomidine Use in Critical Care, Advanced Critical Care, 2008 (19)2, 113-120
- Short, J., Use of Dexmedetomidine for Primary Sedation in a General Intensive Care Unit, Critical Care Nurse, 2010 (30), 29-38
- Venn M, Newman J, Grounds M. A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med. 2003;29(2):201–207
