Dexmedetomidine (DEX) (Precedex) is a relatively new option for sedation in critically ill patients. The agent is a parenteral, centrally acting [alpha]₂-receptor agonist approved by the Food and Drug Administration (FDA) in 1999 for short-term (<24 hours) sedation in initially intubated and mechanically ventilated patients. Despite the agent being available for the past 8 years, clinicians are still discovering new roles for this unique sedative. Published studies have evaluated DEX as a general anesthetic, as a postoperative sedative/analgesic, and as short-term and long-term sedatives. Some case reports have supported its role in the prevention and treatment of alcohol withdrawal syndrome and in the management of delirium in the intensive care unit (ICU). This article focuses on its emerging roles in the ICU.

Numerous studies have shown that DEX produces sedation and analgesic effects without any respiratory depression, a unique characteristic of this medication. The lack of respiratory depression makes this agent a potential consideration for patients being weaned from mechanical ventilation or for some nonintubated patients.

Mechanism of Action

Dexmedetomidine is a distinct sedative that does not work by the [gamma]-aminobutyric acid (GABA)-mimetic system, a mechanism common with other sedatives (eg, benzodiazepines and propofol). Unlike other sedatives, this mechanism of action allows DEX to be free from respiratory suppressive effects.1 In a retrospective analysis of a multicenter, randomized, double-blind, placebo-controlled study of 33 postsurgical patients after extubation, Venn et al2 found that no differences existed in respiratory rates, arterial partial carbon dioxide tension, or oxygen saturation in the DEX group compared with placebo. Furthermore, the DEX group showed significantly higher arterial oxygenation to fractional inspired oxygen (Pao₂:Fio₂) ratio throughout the 6-hour study period. In this trial, the Pao₂:Fio₂ ratio was not a primary outcome measurement, and the authors acknowledge that it may represent a type 1 error. In addition, a clear surrogate relationship between the Pao₂:Fio₂ ratio and patient outcomes has not been documented in the literature.

Unlike other commonly used sedatives, DEX is advertised for its provision of analgesia in addition to sedative and anxiolytic effects. The analgesic actions of DEX have been examined and are not well understood. However, the sedative effects of DEX are mediated through postsynaptic [alpha]₂-adrenoreceptor, which increases conductance through potassium channels.1 As a sedative, its mechanism of action is similar to that of clonidine, another central [alpha]₂-agonist. Dexmedetomidine has an 8-fold increase in the specificity for the [alpha]₂-receptor subunit with an [alpha]₂/[alpha]₁ binding affinity ratio of 1620:1.3 The [alpha]_2a-adrenoreceptor subtype is reported to be the predominant subtype in the brain, with involvement in various physiologic functions including sedative, antinociceptive, sympatholytic, hypothermic, and behavioral actions.4

Pharmacokinetics

Dexmedetomidine exhibits a linear relationship between dose and plasma concentration; therefore, increasing the dose should result in proportional increases in effects. The relatively short distribution half-life (t_1/2) of about 6 minutes results in rapid onset, and an elimination t_1/2 of approximately 2 hours facilitates clearance of the drug in a matter of hours.5 Dexmedetomidine is markedly protein bound (94%) to serum albumin and [alpha]₁-glycoprotein. It is extensively metabolized through oxidative metabolism via cytochrome P450 and direct glucuronidation in the liver, with its metabolites excreted by the kidneys. The pharmacokinetics of DEX is heavily affected by severe liver abnormalities. Patients with severe hepatic failure on administration of DEX showed significantly increased elimination t_1/2 (7.5 vs 2.6 hours) and decreased clearance (0.32 vs 0.64 L/h/kg).1 No official dose reduction is available for patients with varying degrees of hepatic dysfunction, but the manufacturer does warn that lower doses may be warranted.

Dosing

The recommended dosing for DEX consists of a loading infusion of 1.0 mcg/kg over 10 minutes, followed by a continuous infusion of 0.2-0.7 mcg/kg/h.6This agent is prescribed in mcg/kg/h and not in mcg/kg/min. Confusing these infusion rates can result in a 60-fold overdose. Dexmedetomidine displays a biphasic dose-dependent blood pressure (BP) response. High doses (typically associated with loading infusions) could produce a transient hypertensive response by the activation of the peripheral [alpha]_2b-receptors, which could cause vasoconstriction. Similar to clonidine, hypotension may also ensue by decreased sympathetic outflow because of the dominant vasodilatory effects of the central [alpha]_2a-receptor.3 Because of the unforeseeable hemodynamic effects of the loading dose, many clinicians avoid giving the recommended loading infusion. In a recent survey of 10 institutions, only 33% of the clinicians documented the use of a loading dose before initiating a continuous infusion.7 Although avoiding the loading dose may prevent erratic hemodynamic effects, it may potentially prolong the onset of action and time to steady state for DEX.

Although DEX has FDA approval for short-term sedation (<24 hours), its use beyond 24 hours has been evaluated in 2 descriptive studies.8,9 Initial concerns related to prolonged sedation with DEX centered around the potential of rebound hypertension after withdrawal, similar to what is experienced upon withdrawal of clonidine. Venn et al8 evaluated this in a prospective observational trial of 12 medical intensive care patients in whom infusions of DEX were allowed for up to 7 days. Of 12 patients, 3 required DEX infusions for more than 48 hours, with no significant hemodynamic effects upon withdrawal of medication. Another observational trial of 20 medical-surgical intensive care patients with median duration of DEX infusion of 71.5 hours (35-168 hours) demonstrated nonclinically significant changes in heart rate (HR) and BP upon abrupt discontinuation of DEX.9 All patients received 0.4 mcg/kg/h of DEX, without a loading dose, and titrated to doses between 0.2 and 0.7 mcg/kg/h. The primary outcome was hemodynamic effects for 24 hours upon discontinuation of DEX. The authors observed a 16% reduction in systolic blood pressure and 21% reduction in HR in the first 4 hours after DEX infusion, with minimal subsequent changes during the remainder of the infusion. After abrupt discontinuation of DEX, there was an increase in systolic blood pressure and HR of 7% and 11%, respectively. Based on these limited results, it seems DEX is safe for use beyond 24 hours from a hemodynamic perspective. Other adverse effects of DEX infusion beyond 24 hours, including adrenocortical suppression, have not been evaluated in humans.

Adverse Reaction

Results from 401 patients in a phase III trial demonstrated that the most common adverse effects associated with DEX were hypotension (30%), hypertension (12%), nausea (11%), bradycardia (9%), and dry mouth (3%).1 With the exception of hypertension, these adverse effects were more common in patients treated with DEX than with placebo. In contrast, another phase III trial of 353 patients revealed an increased incidence of hypertension in patients treated with DEX (22%) when compared with placebo (12%).1

Dexmedetomidine has a dose-dependent bradycardic effect, mediated by a decrease in sympathetic tone and enhanced vagal activity.10 Severe bradycardia leading to cardiac arrest has been reported in the literature, but the case reports have multiple confounding factors that might have contributed to the cardiac arrest.11

Clinical Trials

In studies used to evaluate the agent for FDA approval, treatment was started within 1 hour of arrival to the ICU and continued for at least 6 hours after extubation, for a total of no more than 24 hours. Additional sedatives, including propofol and midazolam, and analgesics were added as required. The primary outcome measure was the need for rescue sedatives. In a study of 401 patients, 60% of the patients on DEX did not require rescue propofol, whereas 60% of the patients in the placebo arm did require propofol rescue.12 In another study of 353 patients, 61% of DEX and 44% of the placebo patients did not require rescue midazolam.13 In addition, the number of DEX-treated patients agitated with a Ramsay score of 1 was significantly reduced compared with placebo. The need for rescue morphine was also significantly reduced among DEX-treated patients in both trials.

Results of a number of prospective randomized controlled trials have also been published comparing DEX with propofol in surgical populations.14-17Table 1 summarizes the trial design and major findings of these studies. Most of the trials demonstrated a decrease in analgesic requirements for the patients who were treated with DEX. Conversely, Corbett et al,14 in a trial of 89 patients undergoing elective coronary artery bypass graft surgery, found that the requirements for rescue midazolam and morphine were similar between DEX and propofol. In addition, MacLaren and colleagues,18 in a retrospective study in intensive care patients who were already sustained on either propofol or lorazepam and fentanyl when DEX was started found that there was no difference in analgesic requirements. All these comparison trials also demonstrated that patients treated with DEX had similar decreases in BP levels as propofol but had significantly lower HRs. Time to extubation withdrawal was evaluated in 3 trials, with no significant difference reported between the groups. In conclusion, in the surgical population, it seems that DEX is capable of successfully sedating patients to adequate levels, but no additional benefits in mechanical ventilation weaning over propofol were observed. In addition, the concerns with propofol and its hypotensive effects should be extended to DEX as well.

Table 1: Comparison Trials Between Dexmedetomidine and Propofol for Sedation in the Intensive Care Unit

Table 1: Comparison Trials Between Dexmedetomidine and Propofol for Sedation in the Intensive Care Unit (Continued)

Nonsedative Use of DEX in the ICU

Delirium

Delirium in the critically ill patient is associated with significant increases in morbidity and mortality.19 The use of benzodiazepines, namely, lorazepam, has been associated with delirium in acutely ill patients.20 It has been postulated that sedatives that work through GABA receptor interaction may play a role in the pathophysiology of delirium in the ICU. Furthermore, some suggest that reducing the use of drugs that exert their action via the GABA pathway may help reduce the incidence of delirium. As such, Pandharipande et al21 showed that cardiac surgical patients who were randomized to receive DEX at sterna closure were less likely to develop delirium than patients sedated with propofol or benzodiazepines (8% vs 50%). The "maximizing efficacy of targeted sedation and reducing neurological dysfunction" trial was recently published.22 This trial involved 101 patients who were randomized to either lorazepam or DEX and assessed for the incidence of delirium and other clinical outcomes. Overall, patients treated with DEX had significantly more coma- or delirium-free days (7.0 vs 3.0; P = .01).22 However, no statistically significant difference was reported in delirium-free days (9.0 vs 7.0; P = .09), which signifies that the beneficial effects of DEX are mostly associated with the prevention of excessive sedation. In addition, no differences were reported in mechanical ventilation-free days or 28-day mortality. The specifics of the trial cannot be discerned until the study is published and available. A number of hypothesis-generating arguments for a potential role of DEX in delirious ICU patients are available; however, this role must be further elucidated with future clinical trials.

Shivering

Postoperative shivering is caused by disarray in thermoregulation and could result in significant increases in myocardial oxygen consumption. An [alpha]₂-receptor agonist such as DEX is thought to potentially reduce postanesthetic shivering by inhibiting central thermoregulation control and vasoconstriction. In a study of 10 healthy individuals, DEX significantly reduced the shivering threshold compared with placebo.23 Because of the small number of patients evaluated, the use of DEX for this purpose necessitates further investigation.

Withdrawal

Patients having a history of alcohol/drug abuse are frequently admitted to the ICU. Furthermore, patients who have been in the ICU on prolonged sedation or analgesia may also develop acute withdrawal symptoms upon discontinuation of these medications. The use of an [alpha]₂-adrenergic agonist has long been recognized as a potential agent for the treatment of substance withdrawal. Clonidine has previously been evaluated in the attenuation of alcohol withdrawal symptoms in 45 postoperative patients.24 Clonidine has also been used in alcohol withdrawal. Because DEX and clonidine share a similar mechanism of action, it is conceivable that DEX may also be a useful agent for the treatment of substance withdrawal. As such, the use of DEX for the management of withdrawal symptoms has been reported; however, these data are mostly limited to case reports.25

Administration and Monitoring

Dexmedetomidine is supplied in a single 2-mL clear glass vial at a concentration of 100 mcg/mL. It must be diluted to a final concentration of 4 mcg/mL, and the product should be stored at room temperature. Compatibility information for coadministration with blood, serum, or plasma has not been evaluated.

Dexmedetomidine should be administered using a controlled infusion device in a setting with continuous monitoring capabilities. Frequent assessment with a valid sedation assessment tool should be done and dosing of the drug titrated to maintain a targeted sedation score. Patients with hepatic dysfunction may require a lower dose of DEX than healthy subjects to achieve a similar response, given the extensive hepatic metabolism of DEX. A rapid bolus of DEX should be avoided given its potential for both hypotensive and hypertensive effects. Given the hemodynamic effects of DEX, caution should be exercised when administering to patients with advanced heart block or ventricular dysfunction. Volume status should also be assessed when initiating DEX, because hypovolemic patients are most likely to experience the hypotensive/bradycardic effects. The sedative, bradycardic, and hypotensive effects of DEX are most likely additive when administered with other medications. As such, caution should be exercised when coadministering with other sedatives, analgesics, vasodilators, or other negative chronotropic medications.

Dexmedetomidine is currently approved in the United States for short-term use (<24 hours), although certain clinical trials have demonstrated that its use beyond 24 hours may be safe. Theoretically, the concern exists for withdrawal symptoms with DEX similar to those reported with other [alpha]₂-adrenergic agonists. Based on limited information, the abrupt discontinuation of DEX beyond 24 hours has not been associated with rebound hypertensive effects.

Place in Therapy

Dexmedetomidine represents a viable option for short-term sedation in postoperative intensive care patients. Data from 12 medical intensive care patients seem to suggest that DEX at recommended doses does not provide adequate sedation.8 Based on these data, more experience and clinical evidence are needed before the use of DEX can be recommended for either the medical or neurological patient population. Several placebo-controlled trials have demonstrated considerable reductions in other sedatives and analgesics when DEX is also administered. Comparison trials between DEX and propofol did not demonstrate considerable clinical advantage.

Dexmedetomidine is considerably more expensive than other sedatives, with even more significant cost associated when used beyond the recommended dosing range (Table 2). This financial impact on the healthcare system has led to significant scrutiny in the use of this agent in the ICU. A retrospective analysis of postoperative management of cardiothoracic surgical patients in 250 hospitals found significantly lower overall hospital charges for those who received DEX compared to patients who received standard sedation therapy.26 Their results suggest that the use of DEX in the real world after cardiothoracic surgery may have a potential economic benefit. However, the proposed economic benefit was confounded by the fact that the 2 groups of patients were not equally matched, with patients in the DEX group being younger and having less comorbidities. Until more trials are performed with DEX to prove a definite clinical benefit over other sedatives, it is difficult to recommend the routine use of DEX in all surgical patients, given the considerable cost increase. Dexmedetomidine appears to be most suitable for use in hemodynamically stable patients refractory to other sedatives. Its use may also be warranted in patients who have failed weaning from the ventilator because of anxiety issues and in patients for whom other sedatives have proven to be excessively respiratory depressive.

Table 2: Drug Acquisition Cost for Commonly Used Sedative Agents in the Intensive Care Unita

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