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What is the role of dexmedetomidine in sedation of critically ill patients?

Background
The use of sedative agents in critical care settings is often essential to maintain patient safety and comfort.¹ The Society of Critical Care Medicine (SCCM) published comprehensive practice guidelines for the use of sedatives and analgesics in critically ill patients in 2002. According to the guideline midazolam and propofol are the agents of choice for sedation lasting less than 24 hours. For sedation lasting greater than 24 hours, lorazepam via intermittent or continuous infusion is the sedative agent of choice.^1-5 The guideline briefly mentions dexmedetomidine, however, states that the role of this agent in the sedation of critically ill remains to be determined.¹

Numerous guidelines and protocols have been developed for the monitoring and use of sedatives in critically ill patients. The most comprehensive protocols include daily sedative interruptions (for patient assessment) in addition to the use of sedation rating scales, such as the Richmond Agitation-Sedation Scale (RASS) in order to titrate sedation to a specified endpoint. The RASS score ranges from -5 (unarousable) to +4 (combative).⁶ A common target level of sedation in intensive care unit (ICU) patients is for the patient to be calm and in a slightly sleepy, easily arousable state.^1,3,4 Despite the implementation of these protocols, sedative use is still not without risk.^1,2 Recent attention has been placed on the incidence of delirium in critically ill patients.⁶ Delirium is defined as a syndrome of fluctuating mental status with reduced attention and impaired cognitive function that may or may not be accompanied by agitation.^1,5 It is estimated that as many as 80% of patients in the ICU experience delirium.¹ Recent studies have found that delirium is associated with prolonged hospital stays, increased cognitive impairment at hospital discharge, and increased mortality.^5,7 Oversedation of patients impairs the ability to accurately screen for delirium.³ Furthermore, benzodiazepine agents used for sedation (particularly lorazepam) have been implicated in the development of delirium.^3,4,7 Benzodiazepines produce their sedative, hypnotic, and anxiolytic properties via activation of gamma-aminobutyric acid (GABA) receptors in the central nervous system.^1,3 It is purported that patients are predisposed to delirium due to the release of neurotransmitters such as dopamine, serotonin, norepinephrine, and glutamate following GABA receptor activation by benzodiazepines.³ These findings suggest the need for alternative sedative agents in the critically ill.

Dexmedetomidine (Precedex) is a short-acting alpha-2 agonist that has sedative, analgesic, and anxiolytic properties and was approved for short-term (less than 24 hours) sedation of critically ill patients in 1999.^1-4,7,8 Sedation is produced via decreased sympathetic output; however, the patient remains easily aroused. Benefits of dexmedetomidine include lack of respiratory depression, lower incidence of delirium, reduced need for concurrent analgesic and sedatives, and the ability to maintain the patient in an easily rousable state.^1-4,7 Adverse effects include hypertension followed by hypotension, bradycardia, nausea, vomiting, tachycardia, and anemia.^1,2,8 Caution should be used in patients with intravascular volume depletion, high sympathetic tone or low cardiac output as they are at greater risk of experiencing these adverse events.^1,8 Finally, although the acquisition cost of dexmedetomidine is greater than traditional sedative agents, this cost may be offset by decreased ICU and hospital length of stay.

Literature Review

In 2004, Pandharipande and colleagues conducted a study to determine if adequate sedation with dexmedetomidine would decrease the duration of delirium or coma in mechanically intubated patients compared to sedation with lorazepam (MENDS trial).⁹ A total of 106 adults were randomized to receive treatment with dexmedetomidine at initial infusion of 0.15 mcg/kg/hr (n=54) or lorazepam at initial rate of 1 mg/hr (n=52). Study drug was administered until extubation or for a maximum of 120 hours. The primary outcome measure was days alive without delirium or coma and percentage of time spent within sedation goal as determined by the patient’s medical team using RASS. Secondary outcomes included length of stay with ventilation in the ICU and hospital, neuropsychological testing after ICU discharge, and 28- and 365-day mortality.

The researchers found that sedation with dexmedetomidine resulted in more days alive without delirium or coma (median days 7.0 vs. 3.0, p= 0.01) versus treatment with lorazepam.⁹ Patients receiving dexmedetomidine also spent more time within goal range of sedation (median percentage of days 80% vs. 67%, p=0.04) compared to those receiving lorazepam. No difference was found in the patient ability to complete the post-ICU neuropsychological test (42% vs. 31%, p=0.61) or 28-day mortality between the dexmedetomidine vs. lorazepam group (17% vs. 27%, p=0.18). Patients receiving dexmedetomidine had a greater incidence of bradycardia during treatment as compared to patients receiving lorazepam (9% vs. 2%, p=0.04). The 12-month time to death was 363 days in dexmedetomidine group versus 188 days in the lorazepam group (p=0.48). Overall, patients who received dexmedetomidine experienced fewer days of delirium and spent more time within target sedation range than patients who received traditional sedation with lorazepam. One limitation of the MENDS trial was that it was limited to 2 study centers; however, this allowed for prolonged patient follow-up.

A recently published study by Riker and colleagues was completed shortly after the MENDS study and strived to compare the safety and efficacy of prolonged sedation with dexmedetomidine compared to midazolam in mechanically ventilated patients.¹⁰ The study was a prospective, double-blind, randomized controlled trial in which patients were randomized 2:1 to receive dexmedetomidine at 0.8 mcg/kg/hr (n=244) or lorazepam at 0.06 mg/kg/hr (n=122) for up to 30 days; the dose was titrated as clinically indicated. Blinded loading doses of dexmedetomidine (1 mcg/kg) or lorazepam (0.05 mg/kg) were administered at the investigators’ discretion. Patients were also allowed to receive open-label bolus doses of midazolam and fentanyl for undersedation and analgesia, respectively. The primary outcome measure was percentage of time spent within target sedation range of RASS -2 to +1 (light sedation to restless). Secondary outcomes included prevalence and duration of delirium and use of open-label midazolam and fentanyl.

The investigators found no difference in the amount of time spent within target RASS range when comparing dexmedetomidine to midazolam (77.3% vs. 75.1%, 95% confidence interval [CI] -3.2% to 7.5%, p=0.18).¹⁰ In fact, significantly more patients in the dexmedetomidine (153/244 [63%]) group received open-label midazolam for undersedation versus the midazolam group (60/122 [49%], p=0.02) There was a decreased incidence of delirium in dexmedetomidine group vs. midazolam (132/244 [54%] vs. 93/122 [76.6%], 95% CI 4.6 to 5.9, p=0.01) as well as decreased mean time to extubation (3.7 days, 95% CI 3.1 to 4.0 vs. 5.6 days, 95% CI, 4.6 to 5.9, p=0.01). Length of stay in the ICU did not differ significantly between groups.

Patients receiving dexmedetomidine had a greater incidence of bradycardia (42.2% vs. 18.9%, p<0.001) and hyperglycemia (56.6% vs. 42.6%, p=0.02) as compared to patients receiving midazolam.¹⁰ Overall, patients who received sedation with dexmedetomidine spent fewer days intubated and had lower incidence of delirium as compared midazolam recipients. Limitations of this study would be that it did not follow the SCCM recommendations for long-term sedative agent (i.e. lorazepam). Midazolam is limited to short-term use since it produces unpredictable awakening and time to extubation following prolonged infusions. This is believed to be due to accumulation of active metabolites in critically ill patients.^1,8 Although a large number of patients in the dexmedetomidine group received open label midazolam, the incidence of delirium was still significantly less when compared to the midazolam group.

Conclusion
Delirium due to traditional benzodiazepine sedation in critically ill patients is associated with increased morbidity and mortality. Dexmedetomidine has consistently shown decreased rates of delirium in this patient population as well as the ability to produce comparable sedation. From this data dexmedetomidine appears to be a viable sedative agent for use in critically ill patients.

References

1. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30(1):119-141.
2. Fuchs EM, Von Rueden K. Sedation management in the mechanically vented critically ill patient. AACN. 2008;19(4):421-432.
3. Delvin JW. The pharmacology of oversedation in mechanically ventilated adults. Curr Opin Crit Care. 2008;14:403-407.
4. Fraser GL, Riker RR. Sedation and analgesia in the critically ill adult. Curr Opin Anaesthesiol. 2007.20;119-123.
5. Shapiro MB, West MA, Nathens AB, et al. Guidelines for sedation analgesia during mechanical ventilation general overview. J Trauma. 2007;63:945-950.
6. Sessler CN, Gosnell M, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344.
7. Wunsch H, Kress JP. A new era for sedation in ICU patients [editorial]. JAMA. 2009;301(5):542-544.
8. Lui LL, Gropper MA. Postoperative analgesia and sedation in the adult intensive care unit. Drugs. 2003;63(8):755-767.
9. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007; 298(22):2644-2653.
10. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs. midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489-499.