Critical Care
Role of Dexmedetomidine for the Prevention and Treatment of Delirium in Intensive Care Unit Patients Yoonsun Mo, Anthony E Zimmermann
T
he American Psychiatric Association’s Diagnostic and Statistical OBJECTIVE: To review recent clinical studies regarding the role of dexmedetomidine Manual of Mental Disorders, 4th revifor prevention and treatment of delirium in intensive care unit (ICU) patients. sion (DSM-IV), defines delirium as disDATA SOURCES: MEDLINE and PubMed searches (1988-Feburary 2013) were turbances of consciousness, attention, conducted, using the key words delirium, dexmedetomidine, Precedex, agitation, cognition, and perception that develop α-2 agonists, critical care, and intensive care. References from relevant articles were reviewed for additional information. over a short period and fluctuate over 1,2 time. Delirium is associated with proSTUDY SELECTION AND DATA EXTRACTION: Clinical trials comparing dexmedetomidine with other sedatives/analgesics or with antipsychotics for delirium were longed hospital stay and increased health selected. Studies that evaluated the use of dexmedetomidine for sedation for care costs.1 In addition, delirium is an inmore than 6 hours were included in this review. dependent predictor for increased morDATA SYNTHESIS: Dexmedetomidine is a highly selective α-2 receptor agonist that tality and long-term cognitive impairprovides sedation, anxiolysis, and modest analgesia with minimal respiratory 1,3 ment after critical illness. The incidepression. Its mechanism of action is unique compared with that of traditional dence of delirium is reported to be from sedatives because it does not act on γ-aminobutyric acid receptors. In addition, 11% to 80% in the intensive care unit dexmedetomidine lacks anticholinergic activity and promotes a natural sleep pattern. These pharmacologic characteristics may explain the possible antidelirium effects of (ICU) setting.4 Several studies have dexmedetomidine. Eight clinical trials, including 5 double-blind randomized trials, identified potential risk factors that may were reviewed to evaluate the impact of dexmedetomidine on ICU delirium. 3-6 precipitate delirium in ICU patients. CONCLUSIONS : Currently available evidence suggests that dexmedetomidine is a Ouimet et al.4 found that ICU delirium is promising agent, not only for prevention but also for treatment of ICU-associated related to a history of hypertension, alcodelirium. However, larger, well-designed trials are warranted to define the role of holism, high severity of illness, smoking, dexmedetomidine in preventing and treating delirium in the ICU. and exposure to sedatives and analAnn Pharmacother 2013;47:869-76. gesics. Furthermore, in a prospective coPublished Online, 21 May 2013, theannals.com, doi: 10.1345/aph.1A R708 hort study, Ely et al.5 suggested that use of benzodiazepines and narcotics is the most prevalent risk factor for ICU delirifusion Assessment Method for the ICU (CAM-ICU) and um. Although the pathophysiologic mechanism of delirithe Intensive Care Delirium Screening Checklist (ICDSC) um is poorly understood, studies suggest that neurotransare the most valid and reliable ICU delirium assessment mitter imbalances, especially an excess of dopamine and tools.3 These monitoring tools allow clinicians without depletion of acetylcholine, play a significant role.7,8 With psychiatric training to diagnose delirium even in nonverregard to detecting and monitoring ICU delirium, the Conbal, mechanically ventilated patients.9 Early mobilization has been studied in the ICU setting as a nonpharmacologic intervention to improve patients’ Author information provided at end of text. functional outcomes. These studies demonstrated that early © 1967-2013 Harvey Whitney Books Co. All rights reserved. No part of this document may be reproduced or transmitted in any form or and aggressive mobilization may reduce the incidence and by any means without prior written permission of Harvey Whitney duration of ICU delirium.10 Currently, the pain, agitation, Books Co. For reprints of any article appearing in The Annals, and delirium (PAD) guidelines supported by the American please contact
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College of Critical Care Medicine and the Society of Critical Care Medicine recommend performing early mobilization of ICU patients to reduce the incidence and duration of delirium.11 However, there is little evidence supporting the efficacy of pharmacologic strategies for the treatment and prevention of ICU delirium. Although haloperidol has been commonly used to treat delirium in ICU patients, this practice is solely based on retrospective studies and non–placebo-controlled trials.3 Furthermore, haloperidol has the potential to cause a number of adverse effects, including extrapyramidal symptoms, neuroleptic malignant syndrome, and QTc interval prolongation.3 Atypical antipsychotics, such as olanzapine, quetiapine, ziprasidone, and risperidone, have also been considered for the treatment and prevention of ICU delirium. Several small studies suggested that atypical antipsychotics may be as effective as haloperidol and have a more favorable safety profile for the treatment of ICU delirium.12,13 Recently, the first randomized, double-blind, placebo-controlled trial evaluating the efficacy of haloperidol for ICU delirium was published.14 In this MIND (Modifying the Incidence of Delirium) trial,15 patients were randomly assigned to receive haloperidol (n = 35), ziprasidone (n = 30), or placebo (n = 36) for up to 14 days. No difference was found in the primary end point, the median number of days that patients were alive without delirium or coma, between the 3 groups (haloperidol 14 days, ziprasidone 15 days, placebo 12.5 days; p = 0.66). The authors concluded that neither haloperidol nor ziprasidone effectively treats delirium in mechanically ventilated ICU patients. A much larger multicenter trial is warranted to determine whether continued use of antipsychotics improves outcomes associated with delirium in ICU patients. Recently, studies have demonstrated that dexmedetomidine, a potent α-2 adrenoreceptor agonist, may have considerable potential for preventing or reducing ICU delirium because of its favorable pharmacologic properties, which include γ-aminobutyric acid (GABA) receptor-sparing activity.14,16 Nonetheless, a meta-analysis by Tan and Ho17 failed to show a reduction in risk of delirium after dexmedetomidine use. This result needs to be interpreted with caution because of several crucial limitations of this meta-analysis, including significant heterogeneity and inconsistent delirium measurements in the pooled studies. Therefore, the objective of this article is to further explore the role of dexmedetomidine on the prevention and treatment of delirium in adult ICU patients, based on currently available evidence.
Data Sources and Selection
A literature search was performed (1988-Feburary 2013) in MEDLINE and PubMed for English-language articles. The following key words were used: delirium, dexmedetomidine, Precedex, agitation, α-2 agonists, critical care, and intensive care. In addition, eligible articles 870
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were manually searched, using reference lists of the relevant literature, including other systematic review articles. The search was limited to clinical trials. Abstracts and case reports were excluded from this analysis. To focus on the use of dexmedetomidine in the ICU, our reviews included only studies that used dexmedetomidine continuously for sedation in mechanically ventilated patients for at least 6 hours. Furthermore, because of little evidence regarding the use of dexmedetomidine for ICU delirium, eligible studies with delirium assessments using objective monitoring tools were extracted for this analysis. The summary of inclusion criteria is as follows: (1) English language, (2) comparison with other alternative sedatives/analgesics or antipsychotics for delirium, (3) assessment of delirium using objective methods, and (4) use of a continuous infusion of dexmedetomidine for sedation for more than 6 hours. The initial search yielded 122 citations. We included 8 clinical trials, including 5 double-blind randomized trials. The details of each study are summarized in Table 1. Clinical Pharmacology
Dexmedetomidine is a potent and highly selective α-2 adrenoceptor agonist and approximately 8 times more specific for α-2 adrenoceptors than clonidine.18 These receptors can be found throughout the body, including in the central and peripheral nervous systems and several organs, such as the liver, pancreas, kidney, and eye, at the presynaptic and postsynaptic sites.19,20 Activation of presynaptic α-2 adrenoceptors located in sympathetic nerve endings inhibits the release of norepinephrine. Postsynaptic stimulation of α-2 adrenoceptors inhibits sympathetic activity so that it subsequently causes decreases in blood pressure and heart rate.20 Dexmedetomidine exerts its major sedative and analgesic effects via stimulation of the α-2 adrenoceptors in the locus coeruleus, which is an important modulator of vigilance and nociceptive neurotransmission.20,21 Analgesic effects of dexmedetomidine are also produced by directly simulating α-2 adrenoceptors in the spinal cord. Importantly, dexmedetomidine has minimal effects on ventilation.22 As a result, it may facilitate spontaneous breathing trials and ventilator weaning attempts without discontinuation of the drug infusion prior to extubation. The most commonly reported adverse events associated with dexmedetomidine are bradycardia and hypotension.23 The SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial24 showed that patients in the dexmedetomidine group were more likely to develop bradycardia compared with midazolam-treated patients (42.2% vs 18.9%; p < 0.001). However, among dexmedetomidine-treated patients, only 4.9% required interventions for bradycardia, such as either stopping the infusion or administering atropine. With regard to hypotension, there was no significant difference between the
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dexmedetomidine and midazolam groups (56.1% vs 55.7%; p > 0.99). Many trials demonstrated that the risk of bradycardia was increased when both a loading dose and high maintenance doses were administered.17 Therefore, caution should be taken when using a loading dose and high maintenance doses of dexmedetomidine in general, but especially in patients with baseline bradycardia and heart block. Potential Effects of Dexmedetomidine on Delirium
Maldonado et al.25 proposed 2 theories to explain the potential mechanisms for a decrease in delirium with dexmedetomidine. The first suggests that dexmedetomidine has in-
Reference
Design
Dexmedetomidine for Prevention and Treatment of ICU Delirium
trinsic delirium-sparing properties, which can be explained by several unique characteristics of the drug. The α-2 adrenoceptor agonists like dexmedetomidine have little effect on cognitive impairment. Some studies have hypothesized that GABA, the primary inhibitory neurotransmitter in the central nervous system, plays a role in the pathogenesis of delirium; hence, GABAergic agents such as benzodiazepines and propofol are potentially major contributors to the development of delirium.26,27 In addition, sedation with dexmedetomidine induces a more natural sleep-like state than do GABAergic agents.28 Sleep disruption or deprivation are risk factors that may contribute to delirium and cognitive dysfunction in the ICU.20 Therefore, the normal sleep-preserving effect of dexmedetomidine may be associated with less delirium. Furthermore, dexmed-
Table 1. Studies Evaluating Dexmedetomidine in ICU Patients Characteristics
Delirium Assessment
Pandharipande DB, R (2007)29 Mechanically ventilated medical/surgical ICU
Dexmedetomidine 0.15-1.5 µg/kg/h (n = 52) Lorazepam 1-10 mg/h (n = 51)
Ruokonen (2009)31
DB, R, pilot Medical/surgical ICU
Riker (2009)24
DB, R Medical/surgical ICU
Dexmedetomidine 0.2-1.4 µg/kg/h (n = 244) Midazolam 0.02-0.1 mg/kg/h (n = 122)
CAM-ICU
Maldonado (2009)25
R, open-label Elective cardiac surgery
DSM-IV-TR
Incidence of postoperative delirium (%) dexmedetomidine 3; midazolam 50; propofol 50 (p < 0.001)
Shehabi (2009)34
R, DB Pump cardiac surgery
Dexmedetomidine 0.4 µg/kg loading dose, then 0.2-0.7 µg/kg/h (n = 30) Propofol 25-50 µg/kg/min (n = 30) Midazolam 0.5-2 mg/h (n = 30)
CAM-ICU
Incidence of delirium (%) dexmedetomidine 8.6; morphine 15 (p = 0.088) Duration of delirium (days) dexmedetomidine 2; morphine 5 (p = 0.03)
Reade (2009)33 R, OL, pilot Medical/surgical ICU
Yapici (2011)30
Observational Cardiac surgery
Jakob (2012)32
2 R, DB Mechanically ventilated ICU
Dexmedetomidine 0.3-1.4 µg/kg/h (n = 41) Standard care: propofol 0.85-3.66 mg/ kg/h (n = 28) or midazolam 0.04-0.16 mg/kg/h (n = 16)
CAM-ICU
Outcomes
CAM-ICU, adverse events
Days alive without delirium or coma dexmedetomidine 7; lorazepam 3 (p = 0.01) Prevalence of coma (%) dexmedetomidine 63; lorazepam 92 (p < 0.001) Delirium-free days alone dexmedetomidine 9; lorazepam 7 (p = 0.09)
Incidence of delirium (%) dexmedetomidine 43.9; standard care 25 (p = 0.035) Proportion of positive CAM-ICU (%) dexmedetomidine 17; standard care 17.9 (NS)
Incidence of delirium (%) dexmedetomidine 54; midazolam 76.6 (p < 0.001) Delirium-free days dexmedetomidine 2.5; midazolam 1.7 (p = 0.002)
Haloperidol 0.5-2 mg/h with or without ICDSC score Portion of time with satisfactory ICDSC score (24 hours).32 The MIDEX trial compared dexmedetomidine (n = 249) with midazolam (n = 251) and the PRODEX trial compared dexmedetomidine (n = 251) with propofol (n = 247). The primary end points were the proportion of time at target setheannals.com
Dexmedetomidine for Prevention and Treatment of ICU Delirium
dation level without the use of rescue therapy and duration of mechanical ventilation. The authors found no significant differences in time at target sedation between all sedatives (dexmedetomidine-midazolam ratio in time at target sedation, 1.07 [95% CI 0.97-1.18] and dexmedetomidine-propofol, 1 [95% CI 0.92-1.08]). Dexmedetomidine significantly shortened the median duration of mechanical ventilation compared with midazolam (123 hours vs 164 hours, respectively; p = 0.03) but not compared with propofol (97 hours vs 118 hours, respectively; p = 0.24). In the MIDEX trial, hypotension (20.6% vs midazolam 11.6%; p = 0.007) and bradycardia (14.2% vs midazolam 5.2%; p < 0.001) were more common with dexmedetomidine, whereas the incidences of hypotension and bradycardia were similar in the PRODEX trial. For the assessment of delirium, the CAMICU was used at the end of the 48-hour follow-up period. In addition, the authors included episodes of anxiety and agitation requiring resedation in an analysis of possible delirium. The number of patients who were CAM-ICU positive was similar in both trials (dexmedetomidine, n = 28 vs midazolam, n = 33; p = 0.393; and dexmedetomidine, n = 22 vs propofol, n = 31; p = 0.231). However, when compared with propofol, the incidence of the composite of neurocognitive disorders, including delirium, anxiety, and agitation, was lower in the dexmedetomidine group (dexmedetomidine 18.3% vs propofol 28.7%; p = 0.008). This observation should be further investigated because these results are based on a onetime CAM-ICU assessment, 48 hours after stopping study drugs. In addition, the effects of dexmedetomidine were most likely negligible due to its short half-life when the assessment of delirium was performed. This study suggested that dexmedetomidine is an effective sedative agent compared with both midazolam and propofol in ICU patients requiring prolonged mechanical ventilation. DEXMEDETOMIDINE VERSUS HALOPERIDOL
Reade et al.33 performed a randomized, open-label, parallel-group pilot study to evaluate the hypothesis that dexmedetomidine would be more effective than haloperidol in the treatment of ICU delirium in mechanically ventilated patients. Twenty patients requiring mechanical ventilation because of agitated delirium were randomized to receive either a continuous infusion of dexmedetomidine (0.2-0.7 µg/kg/h, with or without a loading dose of 1 µg/kg) or haloperidol (0.5-2 mg/h, with or without a loading dose of 2.5 mg). In this study, delirium was assessed using the ICDSC. Patients who received dexmedetomidine tended to have satisfactory ICDSC scores (
