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Study Overview
Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.
Design. Two-center, double-blind, placebo-controlled, randomized, trial.
Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.
Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.
Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.
Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.
Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.
Commentary
Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].
The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].
Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].
The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.
There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.
Applications for Clinical Practice
ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.
—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL
1. van den Boogaard M, Pickkers P, Slooter AJ, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012;344:e420.
2. Slooter AJ, Van De Leur RR, Zaal IJ. Delirium in critically ill patients. Handb Clin Neurol 2017;141:449–66.
3. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703–10.
4. Abraha I, Trotta F, Rimland JM, et al. Efficacy of non-pharmacological interventions to prevent and treat delirium in older patients: a systematic overview. The SENATOR project ONTOP Series. PLoS One 2015;10:e0123090.
5. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013;1:515–23.
6. Al-Qadheeb NS, Skrobik Y, Schumaker G, et al. Preventing ICU subsyndromal delirium conversion to delirium with low-dose IV haloperidol: a double-blind, placebo-controlled pilot study. Crit Care Med 2016;44:583–91.
7. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306.
8. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–99.
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;298:2644–53.
10. Wu XH, Cui F, Zhang C, et al. Low-dose dexmedetomidine improves sleep quality pattern in elderly patients after noncardiac surgery in the intensive care unit: a pilot randomized controlled trial. Anesthesiology 2016;125:979–91.
11. Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016;388:1893–1902.
12. Chen K, Lu Z, Xin YC, et al. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev 2015;1:CD010269.
Study Overview
Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.
Design. Two-center, double-blind, placebo-controlled, randomized, trial.
Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.
Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.
Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.
Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.
Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.
Commentary
Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].
The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].
Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].
The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.
There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.
Applications for Clinical Practice
ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.
—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL
Study Overview
Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.
Design. Two-center, double-blind, placebo-controlled, randomized, trial.
Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.
Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.
Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.
Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.
Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.
Commentary
Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].
The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].
Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].
The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.
There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.
Applications for Clinical Practice
ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.
—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL
1. van den Boogaard M, Pickkers P, Slooter AJ, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012;344:e420.
2. Slooter AJ, Van De Leur RR, Zaal IJ. Delirium in critically ill patients. Handb Clin Neurol 2017;141:449–66.
3. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703–10.
4. Abraha I, Trotta F, Rimland JM, et al. Efficacy of non-pharmacological interventions to prevent and treat delirium in older patients: a systematic overview. The SENATOR project ONTOP Series. PLoS One 2015;10:e0123090.
5. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013;1:515–23.
6. Al-Qadheeb NS, Skrobik Y, Schumaker G, et al. Preventing ICU subsyndromal delirium conversion to delirium with low-dose IV haloperidol: a double-blind, placebo-controlled pilot study. Crit Care Med 2016;44:583–91.
7. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306.
8. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–99.
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;298:2644–53.
10. Wu XH, Cui F, Zhang C, et al. Low-dose dexmedetomidine improves sleep quality pattern in elderly patients after noncardiac surgery in the intensive care unit: a pilot randomized controlled trial. Anesthesiology 2016;125:979–91.
11. Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016;388:1893–1902.
12. Chen K, Lu Z, Xin YC, et al. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev 2015;1:CD010269.
1. van den Boogaard M, Pickkers P, Slooter AJ, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012;344:e420.
2. Slooter AJ, Van De Leur RR, Zaal IJ. Delirium in critically ill patients. Handb Clin Neurol 2017;141:449–66.
3. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703–10.
4. Abraha I, Trotta F, Rimland JM, et al. Efficacy of non-pharmacological interventions to prevent and treat delirium in older patients: a systematic overview. The SENATOR project ONTOP Series. PLoS One 2015;10:e0123090.
5. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013;1:515–23.
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