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1.  Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care 
Critical Care  2000;4(5):302-308.
The respiratory effects of dexmedetomidine were retrospectively examined in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit (ICU). Morphine requirements were reduced by over 50% in patients receiving dexmedetomidine. There were no differences in respiratory rates, oxygen saturations, arterial pH and arterial partial carbon dioxide tension (PaCO2) between the groups. Interestingly the arterial partial oxygen tension (PaO2) : fractional inspired oxygen (FIO2) ratios were statistically significantly higher in the dexmedetomidine group. Dexmedetomidine provides important postsurgical analgesia and appears to have no clinically important adverse effects on respiration in the surgical patient who requires intensive care.
Introduction:
The α2-agonist dexmedetomidine is a new class of sedative drug that is being investigated for use in ICU settings. It is an effective agent for the management of sedation and analgesia after cardiac, general, orthopaedic, head and neck, oncological and vascular surgery in the ICU [1]. Cardiovascular stability was demonstrated, with significant reductions in rate-pressure product during sedation and over the extubation period.
Dexmedetomidine possesses several properties that may additionally benefit those critically ill patients who require sedation. In spontaneously breathing volunteers, intravenous dexmedetomidine caused marked sedation with only mild reductions in resting ventilation at higher doses [2]. Dexmedetomidine reduces the haemodynamic response to intubation and extubation [3,4,5] and attenuates the stress response to surgery [6], as a result of the α2-mediated reduction in sympathetic tone. Therefore, it should be possible to continue sedation with dexmedetomidine over the stressful extubation period without concerns over respiratory depression, while ensuring that haemodynamic stability is preserved.
The present study is a retrospective analysis of the respiratory response to dexmedetomidine in 33 postsurgical patients (who were involved in a randomized, double-blind, placebo-controlled trial [1]) after extubation in the ICU.
Methods:
Patients who participated in the present study were admitted after surgery to our general or cardiothoracic ICUs, and were expected to receive at least 6 h of postsurgical sedation and artificial ventilation.
On arrival in the ICU after surgery, patients were randomized to receive either dexmedetomidine or placebo (normal saline) with rescue sedation and analgesia being provided, only if clinically needed, with midazolam and morphine boluses, respectively. Sedation was titrated to maintain a Ramsay Sedation Score [7] of 3 or greater while the patients were intubated, and infusions of study drug were continued for a maximum of 6 h after extubation to achieve a Ramsay Sedation Score of 2 or greater.
The patients were intubated and ventilated with oxygen-enriched air to attain acceptable arterial blood gases, and extubation occurred when clinically indicated. All patients received supplemental oxygen after extubation, which was delivered by a fixed performance device. Assessment of pain was by direct communication with the patient.
Results are expressed as mean ± standard deviation unless otherwise stated. Patient characteristics, operative details and morphine usage were analyzed using the Mann-Whitney U-test. Statistical differences for respiratory measurements between the two groups were determined using analysis of variance for repeated measures, with the Bonferroni test for post hoc comparisons.
Results:
Of the 40 patients who participated in the study, seven patients could not be included in the analysis of respiratory function because they did not receive a study drug infusion after extubation. Consequently, data from 33 patients are used in the analysis of respiratory function; 16 received dexmedetomidine and 17 placebo. Inadequate arterial blood gas analysis was available in five patients (two from the dexmedetomidine group, and three from the placebo group). There were no significant differences in patient characteristics and operative details between the groups.
Requirements for morphine were reduced by more than 50% in patients receiving dexmedetomidine when compared with placebo after extubation (0.003 ± 0.004 vs 0.008 ± 0.006 mg/kg per h; P= 0.040).
There were no statistically significant differences between placebo and dexmedetomidine for oxygen saturations measured by pulse oximetry (P= 0.26), respiratory rate (P= 0.16; Fig. 1), arterial pH (P= 0.77) and PaCO2 (P= 0.75; Fig. 2) for the 6 h after extubation.
The dexmedetomidine group showed significantly higher PaO2: FIO2 ratios throughout the 6-h intubation (P= 0.036) and extubation (P= 0.037) periods (Fig. 3). There were no adverse respiratory events seen in either the dexmedetomidine or placebo group.
Respiratory rate for the 6-h periods before and after extubation. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaCO2 (PCO2) for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaO2 : FIO2 ratio for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
Discussion:
Lack of respiratory depression in patients sedated with α2-adrenoceptor agonists was first reported by Maxwell [8] in a study investigating the respiratory effects of clonidine. However, more recent data suggests that clonidine may cause mild respiratory depression in humans [9], and α2-adrenoceptor agonists are well known to produce profound intraoperative hypoxaemia in sheep [10,11]. The effects of dexmedetomidine on other ventilation parameters also appear to be species specific [12].
Belleville et al [2] investigated the ventilatory effects of a 2-min intravenous infusion of dexmedetomidine on human volunteers. According to those investigators, minute ventilation and arterial PaCO2 were mildly decreased and increased, respectively. There was a rightward shift and depression of the hypercapnic response with infusions of 1.0 and 2.0 μg/kg.
Previous studies that investigated the respiratory effects of dexmedetomidine have only been performed in healthy human volunteers, who have received either single intramuscular injections or short (= 10 min) intravenous infusions of dexmedetomidine. It is therefore reassuring that no deleterious clinical effects on respiration and gas exchange were seen in the patients we studied, who were receiving long-term infusions. However, there are important limitations to the present results. No dose/response curve for dexmedetomidine can be formulated from the data, and further investigation is probably ethically difficult to achieve in the spontaneously ventilating intensive care patient. We also have no data on the ventilatory responses to hypercapnia and hypoxia, which would also be difficult to examine practically and ethically. The placebo group received more than twice as much morphine as patients receiving dexmedetomidine infusions after extubation, but there were no differences in respiratory rate or PaCO2 between the groups. We can not therefore determine from this study whether dexmedetomidine has any benefits over morphine from a respiratory perspective.
There were no differences in oxygen saturations between the groups because the administered oxygen concentration was adjusted to maintain satisfactory gas exchange. Interestingly, however, there were statistically significant higher PaO2 : FIO2 ratios in the dexmedetomidine group. This ratio allows for the variation in administered oxygen to patients during the study period, and gives some clinical indication of alveolar gas exchange. However, this variable was not a primary outcome variable for the present study, and may represent a type 1 error, although post hoc analysis reveals that the data have 80% power to detect a significant difference (α value 0.05). Further studies are obviously required.
Sedation continued over the extubation period, has been shown to reduce haemodynamic disturbances and myocardial ischaemia [13]. We have previously shown [1] that dexmedetomidine provides cardiovascular stability, with a reduction in rate-pressure product over the extubation period. A sedative agent that has analgesic properties, minimal effects on respiration and offers ischaemia protection would have enormous potential in the ICU. Dexmedetomidine may fulfill all of these roles, but at present we can only conclude that dexmedetomidine has no deleterious clinical effects on respiration when used in doses that are sufficient to provide adequate sedation and effective analgesia in the surgical population requiring intensive care.
PMCID: PMC29047  PMID: 11056756
α2-Adrenoceptor agonist; analgesia; dexmedetomidine; intensive care; postoperative; respiratory; sedation
2.  Dexmedetomidine Use in Pediatric Intensive Care and Procedural Sedation 
OBJECTIVE
Dexmedetomidine was approved by the Food and Drug Administration in 1999 for the sedation of adults receiving mechanical ventilation in an intensive care setting. It provides sedation with minimal effects on respiratory function and may be used prior to, during, and following extubation. Based on its efficacy in adults, dexmedetomidine is now being explored as an alternative or adjunct to benzodiazepines and opioids in the pediatric intensive care setting. This review describes the studies evaluating the safety and efficacy dexmedetomidine in infants and children and provides recommendations on dosing and monitoring.
METHODS
The MEDLINE (1950–November 2009) database was searched for pertinent abstracts, using the key term dexmedetomidine. Additional references were obtained from the bibliographies of the articles reviewed and the manufacturer. All available English-language case reports, clinical trials, retrospective studies, and review articles were evaluated.
RESULTS
Over two dozen case series and clinical studies have documented the utility of dexmedetomidine as a sedative in children requiring mechanical ventilation or procedural sedation. In several papers, dexmedetomidine use resulted in a reduction in the dose or discontinuation of other sedative agents. It may be of particular benefit in children with neurologic impairment or in those who do not tolerate benzodiazepines. The most frequent adverse effects reported with dexmedetomidine have been hypotension and bradycardia, in 10% to 20% of patients. These effects typically resolve with dose reduction.
CONCLUSIONS
Dexmedetomidine offers an additional choice for the sedation of children receiving mechanical ventilation in the intensive care setting or requiring procedural sedation. While dexmedetomidine is well tolerated when used at recommended doses, it has the potential to cause hypotension and bradycardia and requires close monitoring. In addition to clinical trials currently underway, larger controlled studies are needed to further define the role of dexmedetomidine in pediatric intensive care.
PMCID: PMC3017406  PMID: 22477789
analgesia; child; dexmedetomidine; infant; intensive care; sedation
3.  A Dose-Response Study of Dexmedetomidine Administered as the Primary Sedative in Infants Following Open Heart Surgery 
Objective
To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease post-operative from open heart surgery.
Design
Prospective open-label dose-escalation PK-PD study
Setting
Tertiary pediatric cardiac intensive care unit
Patients
36 evaluable infants, ages 1 month – 24 months, post-operative from open heart surgery requiring mechanical ventilation
Interventions
Cohorts of 12 infants were enrolled sequentially to one of three intravenous loading dose – continuous infusion dexmedetomidine regimens: 0.35–0.25, 0.7–0.5, or 1–0.75 mcg/kg – mcg/kg/hr for up to 24 hours.
Measurements and Main Results
Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs. 1) despite requiring minimal supplemental sedation (0 unit doses/hour) and fewer analgesic medications (0.07 vs. 0.15 unit doses/hour) while receiving dexmedetomidine when compared to the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion with only 1 patient remaining intubated due to oversedation during the infusion. There was a decrease in heart rate while receiving dexmedetomidine compared to baseline, 132 vs. 161 beats/minute (bpm), but a higher heart rate when compared to post-infusion values, 132 vs. 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure.
Conclusions
Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements leading to successful extubation while receiving a continuous infusion. The post-operative hemodynamic changes that occur in infants post-operative from open heart surgery are multi-factorial. Although dexmedetomidine may play a role in decreasing heart rate immediately post-operative, the changes were not clinically significant and did not fall below post-infusion heart rates.
doi:10.1097/PCC.0b013e31828a8800
PMCID: PMC3720685  PMID: 23628837
dexmedetomidine; sedation; pharmacodynamics; infant; congenital heart disease
4.  Evaluation of Adverse Events Noted in Children Receiving Continuous Infusions of Dexmedetomidine in the Intensive Care Unit 
OBJECTIVES
Dexmedetomidine is an α2-adrenergic receptor agonist with sedative and analgesic effects in mechanically ventilated adults and children. Safety and efficacy data are limited in children. The purpose of this study is to retrospectively identify the incidence and types of adverse events noted in children receiving continuous infusions of dexmedetomidine and evaluate potential risk factors for adverse events.
METHODS
Between July 1, 2006, and July 31, 2007, data were collected on all children (< 18 years) who received continuous infusions of dexmedetomidine. Data collection included demographics, dexmedetomidine regimen, and type/number of adverse events. The primary endpoint was the total number of adverse events noted, including: transient hypertension, hypotension, neurological manifestations, apnea, and bradycardia. Secondary endpoints included categorization of each type of adverse event and an assessment of risk factors. A logistic regression model was used to assess the relationship of adverse events with independent variables including length of ICU stay, cumulative dose, peak infusion rate, duration of therapy, PRISM III score, and bolus dose.
RESULTS
Thirty-six patients received dexmedetomidine representing 41 infusions. The median age was 16 months (range, 0.1–204 months) and median PRISM III score was 2 (range, 0–18). Eighteen (43.9%) patients received a bolus dose of dexmedetomidine. The median cumulative dose (mcg/kg) and peak dose (mcg/kg/hr) were 8.5 (range, 2.2–193.7) and 0.5 (range, 0.2–0.7), respectively. Dexmedetomidine was continued for a median of 20 (range, 3–263) hours. Six (14.6%) patients were slowly tapered off the continuous infusions. Twenty-one adverse events were noted in 17 patients, including 4 neurologic manifestations. Fourteen patients required interventions for adverse events. ICU length of stay was the only independent risk factor (p=0.036) for development of adverse events.
CONCLUSIONS
Several potential adverse events were noted with dexmedetomidine continuous infusions including possible neurological manifestations. Further studies are needed looking at adverse events associated with dexmedetomidine use in the pediatric population.
PMCID: PMC3017405  PMID: 22477790
adverse events; children; dexmedetomidine; intensive care unit; sedation
5.  Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial 
Critical Care  2009;13(3):R75.
Introduction
Agitated delirium is common in patients undergoing mechanical ventilation, and is often treated with haloperidol despite concerns about safety and efficacy. Use of conventional sedatives to control agitation can preclude extubation. Dexmedetomidine, a novel sedative and anxiolytic agent, may have particular utility in these patients. We sought to compare the efficacy of haloperidol and dexmedetomidine in facilitating extubation.
Methods
We conducted a randomised, open-label, parallel-groups pilot trial in the medical and surgical intensive care unit of a university hospital. Twenty patients undergoing mechanical ventilation in whom extubation was not possible solely because of agitated delirium were randomised to receive an infusion of either haloperidol 0.5 to 2 mg/hour or dexmedetomidine 0.2 to 0.7 μg/kg/hr, with or without loading doses of 2.5 mg haloperidol or 1 μg/kg dexmedetomidine, according to clinician preference.
Results
Dexmedetomidine significantly shortened median time to extubation from 42.5 (IQR 23.2 to 117.8) to 19.9 (IQR 7.3 to 24) hours (P = 0.016). Dexmedetomidine significantly decreased ICU length of stay, from 6.5 (IQR 4 to 9) to 1.5 (IQR 1 to 3) days (P = 0.004) after study drug commencement. Of patients who required ongoing propofol sedation, the proportion of time propofol was required was halved in those who received dexmedetomidine (79.5% (95% CI 61.8 to 97.2%) vs. 41.2% (95% CI 0 to 88.1%) of the time intubated; P = 0.05). No patients were reintubated; three receiving haloperidol could not be successfully extubated and underwent tracheostomy. One patient prematurely discontinued haloperidol due to QTc interval prolongation.
Conclusions
In this preliminary pilot study, we found dexmedetomidine a promising agent for the treatment of ICU-associated delirious agitation, and we suggest this warrants further testing in a definitive double-blind multi-centre trial.
Trial registration
Clinicaltrials.gov NCT00505804
doi:10.1186/cc7890
PMCID: PMC2717438  PMID: 19454032
6.  Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients 
Journal of Anesthesia  2013;28:38-50.
Purpose
We evaluated the safety and efficacy of long-term administration of dexmedetomidine in patients in the intensive care unit (ICU). Primary endpoint was the incidence of hypotension, hypertension, and bradycardia. Secondary endpoints were withdrawal symptoms, rebound effects, the duration of sedation with Richmond Agitation-Sedation Scale (RASS) ≤ 0 relative to the total infusion time of dexmedetomidine, and the dose of additional sedatives or analgesics.
Methods
Dexmedetomidine 0.2–0.7 μg/kg/h was continuously infused for maintaining RASS ≤ 0 in patients requiring sedation in the ICU. Safety and efficacy of short-term (≤24 h) and long-term (>24 h) dexmedetomidine administration were compared.
Results
Seventy-five surgical and medical ICU patients were administered dexmedetomidine. The incidence of hypotension, hypertension, and bradycardia that occurred after 24 h (long-term) was not significantly different from that occurring within 24 h (short-term) (P = 0.546, 0.513, and 0.486, respectively). Regarding withdrawal symptoms, one event each of hypertension and headache occurred after the end of infusion, but both were mild in severity. Increases of mean arterial blood pressure and heart rate after terminating the infusion of dexmedetomidine were not associated with the increasing duration of its infusion. The ratio of duration with RASS ≤ 0 was ≥ 85 % until day 20, except day 9 (70 %) and day 10 (75 %). There was no increase in the dose of additional sedatives or analgesics after the first 24-h treatment period.
Conclusions
Long-term safety of dexmedetomidine compared to its use for 24 h was confirmed. Dexmedetomidine was useful to maintain an adequate sedation level (RASS ≤ 0) during long-term infusion.
doi:10.1007/s00540-013-1678-5
PMCID: PMC3921449  PMID: 23912755
Dexmedetomidine; Long term; Sedation; Intensive care unit; Withdrawal
7.  Dexmedetomidine as an adjunct to epidural analgesia after abdominal surgery in elderly intensive care patients: A prospective, double-blind, clinical trial 
Background: The ideal postoperative analgesia management of elderly surgical patients in intensive care units (ICUs) is continually being investigated.
Objective: The purpose of this study was to assess the effectiveness and tolerability of IV administration of dexmedetomidine as an adjunct to a low-dose epidural bupivacaine infusion for postoperative analgesia after abdominal surgery in elderly patients in the ICU.
Methods: ICU patients aged >70 years undergoing abdominal surgery were eligible for the study. A lumbar epidural catheter was inserted at the beginning of the surgery with no medication. On arrival at the ICU, the catheter was loaded with 0.25% bupivacaine 25 mg at the T8 to T10 sensory level, and a continuous infusion of 0.125% bupivacaine was started at 4 to 6 mL/h in combination with patient-controlled epidural analgesia (PCEA) of fentanyl (4 μg/bolus) for pain treatment. Patients in the treatment group received dexmedetomidine as an IV loading dose of 0.6 pg/kg for 30 minutes followed by continuous infusion at 0.2 μg/kg · h-1. Patients in the control group were not administered dexmedetomidine. The effectiveness of the pain relief was determined using a visual analog scale (VAS) (0 = no pain to 10 = worst pain imaginable) at rest. VAS score, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure, and arterial blood gases were monitored periodically for 24 hours after surgery. If required, tenoxicam (20-mg IV bolus) was used to ensure a VAS score of ≤3. The number of times PCEA and tenoxicam were administered and the occurrence of adverse events (AEs) were also recorded.
Results: Sixty patients (34 men, 26 women; mean [SD] age, 75.96 [4.25] years; mean [SD] weight, 74.13 [10.62] kg) were included in the study. VAS scores were significantly lower in the dexmedetomidine group compared with the control group at hours 1, 2, and 12 (VAS [hour 1]: 2.8 [0.4], P < 0.001; VAS [hour 2]: 2.7 [0.5], P < 0.001; and VAS [hour 12]: 0.9 [0.7], P 0.044). The mean number of administrations of fentanyl via PCEA was significantly greater in the control group compared with the dexmedetomidine group (2.20 vs 6.63 times; P < 0.001). The mean number of administrations of tenoxicam was significantly lower in the treatment group than the control group (0.27 vs 1.07 times; P < 0.001). In the control group, the decreases in sedation at 0, 8, 12, 16, and 20 hours were significant compared with baseline (P = 0.024, P = 0.001, P = 0.020, P < 0.001, and P = 0.005, respectively). Mean HR, SBR and AEs (eg, bradycardia [HR <60 beats/min], respiratory depression [respiratory rate <8 breaths/min], hypotension \SBP <90 mm Hg], oversedation, hypoxia, and hypercapnia) decreased significantly in the dexmedetomidine group (all, P < 0.05). Significantly more patients in the dexmedetomidine group rated their satisfaction with postoperative pain control as excellent compared with the control group (12 vs 6 patients; P = 0.014).
Conclusion: Intravenous dexmedetomidine was effective and generally well tolerated as an analgesic adjunct to epidural low-dose bupivacaine infusion for pain treatment, with lower need for opioids after abdominal surgery in these elderly intensive care patients than in the control group.
doi:10.1016/j.curtheres.2008.02.001
PMCID: PMC3969974  PMID: 24692779
postoperative analgesia; elderly patients; dexmedetomidine; epidural analgesia
8.  Safety and Effectiveness of Dexmedetomidine in the Pediatric Intensive Care Unit (SAD–PICU) 
Background:
Critically ill children require sedation for comfort and to facilitate mechanical ventilation and interventions. Dexmedetomidine is a newer sedative with little safety data in pediatrics, particularly for therapy lasting longer than 48 h.
Objective:
To quantify the frequency of adverse events and withdrawal syndromes associated with dexmedetomidine and to describe the use of this drug for continuous sedation in critically ill children.
Methods:
In this retrospective study of patients who received dexmedetomidine for sedation in the pediatric intensive care unit, adverse events were assessed with the Naranjo scale to determine the likelihood of association with dexmedetomidine. Interventions in response to adverse events were also recorded.
Results:
One hundred and forty-four patients (median age 34 months, range 0 – 17.7 years) who underwent a total of 153 treatment courses were included. The mean infusion rate of dexmedetomidine was 0.42 μg/kg per hour (standard deviation 0.17 μg/kg per hour, range 0.05–2 μg/kg per hour). The median duration of therapy was 20.50 h (range 0.75–854.75 h), and 70 infusions (46%) lasted more than 24 h. At least one adverse event was observed in 115 (75%) of the treatment courses. Hypotension (81 [53%]) and bradycardia (38 [25%]) were the most common adverse events and were deemed “probably” attributable to dexmedetomidine in 17 (11%) and 9 (6%) of the treatment courses, respectively. In 55 of the 66 treatment courses with infusions lasting longer than 24 h for which post-infusion data were available, at least one withdrawal symptom was observed; agitation (41 [62%]) and hypertension (22 [33%]) were the most common withdrawal symptoms.
Conclusions:
Dexmedetomidine was commonly administered for longer than 24 h in the authors’ institution. Dexmedetomidine was generally well tolerated; however, the majority of patients experienced withdrawal symptoms. Patients receiving dexmedetomidine for more than 24 h should be monitored for withdrawal following discontinuation, and interventions should be provided if needed. Prospective, controlled studies are needed to characterize the safety of long-term dexmedetomidine therapy in critically ill children.
PMCID: PMC3583774  PMID: 23467635
dexmedetomidine; critical care; children; sedation; dexmédétomidine; soins intensifs; enfants; sédation
9.  Dexmedetomidine use in the ICU: Are we there yet? 
Critical Care  2013;17(3):320.
Expanded abstract
Citation
Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedeto midine for Long-Term Sedation Investigators: Dexmedetomidine vesus midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012, 307:1151-1160.
Background
Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
Methods
Objective
The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients' interaction with nursing care.
Design
Two phase 3 multicenter, randomized, double-blind trials were conducted.
Setting
The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.
Subjects
The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.
Intervention
After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.
Outcomes
For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.
Results
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380; P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P = 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).
Conclusions
Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.
doi:10.1186/cc12707
PMCID: PMC3706806  PMID: 23731973
10.  Economic Evaluation of Dexmedetomidine Relative to Midazolam for Sedation in the Intensive Care Unit 
Background
Dexmedetomidine is an α2-receptor agonist administered by continuous infusion in the intensive care unit (ICU) for sedation of critically ill patients who are undergoing mechanical ventilation following intubation. Relative to ICU patients receiving midazolam (a γ-aminobutyric acid agonist) for sedation, those receiving dexmedetomidine spent less time on ventilation, had fewer episodes of delirium, and had a lower incidence of tachycardia and hypertension.
Objective
To assess the economic impact, in a Canadian context, of dexmedetomidine, relative to midazolam, for sedation in the ICU.
Methods
This economic evaluation was based on a cost–consequences analysis, from the perspective of the Canadian health care system. The selected time horizon was an ICU stay (maximum 30 days). Clinical data were obtained from a previously published prospective, randomized, double-blind trial comparing dexmedetomidine and midazolam. This evaluation considered the costs of the medications, mechanical ventilation, and delirium episodes, as well as costs associated with adverse events requiring an intervention. All costs were adjusted to 2010 and are reported in Canadian dollars.
Results
The average cost of the medication was higher for dexmedetomidine than midazolam ($1929.57 versus $180.10 per patient), but the average costs associated with mechanical ventilation and management of delirium were lower with dexmedetomidine than with midazolam ($2939 versus $4448 for ventilation; $2127 versus $3012 for delirium). The overall cost per patient was lower with dexmedetomidine than with midazolam ($7022 versus $7680). Deterministic sensitivity analysis confirmed the robustness of the difference.
Conclusions
The use of dexmedetomidine was, in most contexts, a more favourable strategy than the use of midazolam, in terms of clinical consequences and economic impact. Dexmedetomidine was less expensive than midazolam and was associated with lower occurrence of delirium and shorter duration of mechanical ventilation.
PMCID: PMC3329902  PMID: 22529402
dexmedetomidine; sedation; intensive care unit; economic evaluation; dexmédétomidine; sédation; unité de soins intensifs; évaluation économique
11.  A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens 
Critical care medicine  2007;35(3):724-730.
Objective
Patients with severe alcohol withdrawal and delirium tremens are frequently resistant to standard doses of benzodiazepines. Case reports suggest that these patients have a high incidence of requiring intensive care and many require mechanical ventilation. However, few data exist on treatment strategies and outcomes for these subjects in the medical intensive care unit (ICU). Our goal was a) to describe the outcomes of patients admitted to the medical ICU solely for treatment of severe alcohol withdrawal and b) to determine whether a strategy of escalating doses of benzodiazepines in combination with phenobarbital would improve outcomes.
Design
Retrospective cohort study.
Setting
Inner-city municipal hospital.
Patients
Subjects admitted to the medical ICU solely for the treatment of severe alcohol withdrawal.
Interventions
Institution of guidelines emphasizing escalating doses of diazepam in combination with phenobarbital.
Measurements and Main Results
Preguideline (n = 54) all subjects were treated with intermittent boluses of diazepam with an average total and maximal individual dose of 248 mg and 32 mg, respectively; 17% were treated with phenobarbital. Forty-seven percent required intubation due to inability to achieve adequate sedation and need for constant infusion of sedative-hypnotics. Intubated subjects had longer length of stay (5.6 vs. 3.4 days; p = .09) and higher incidence of nosocomial pneumonia (42 vs. 21% p = .08). Postguideline (n = 41) there were increases in maximum individual dose of diazepam (32 vs. 86 mg; p = .001), total amount of diazepam (248 vs. 562 mg; p = .001), and phenobarbital use (17 vs. 58%; p = .01). This was associated with a reduction in the need for mechanical ventilation (47 vs. 22%; p = .008), with trends toward reductions in ICU length of stay and nosocomial pneumonia.
Conclusions
Patients admitted to a medical ICU solely for treatment of severe alcohol withdrawal have a high incidence of requiring mechanical ventilation. Guidelines emphasizing escalating bolus doses of diazepam, and barbiturates if necessary, significantly reduced the need for mechanical ventilation and showed trends toward reductions in ICU length of stay and nosocomial infections.
doi:10.1097/01.CCM.0000256841.28351.80
PMCID: PMC3417045  PMID: 17255852
alcohol withdrawal; benzodiazepines; phenobarbital; intensive care unit
12.  Update on dexmedetomidine: use in nonintubated patients requiring sedation for surgical procedures 
Dexmedetomidine was introduced two decades ago as a sedative and supplement to sedation in the intensive care unit for patients whose trachea was intubated. However, since that time dexmedetomidine has been commonly used as a sedative and hypnotic for patients undergoing procedures without the need for tracheal intubation. This review focuses on the application of dexmedetomidine as a sedative and/or total anesthetic in patients undergoing procedures without the need for tracheal intubation. Dexmedetomidine was used for sedation in monitored anesthesia care (MAC), airway procedures including fiberoptic bronchoscopy, dental procedures, ophthalmological procedures, head and neck procedures, neurosurgery, and vascular surgery. Additionally, dexmedetomidine was used for the sedation of pediatric patients undergoing different type of procedures such as cardiac catheterization and magnetic resonance imaging. Dexmedetomidine loading dose ranged from 0.5 to 5 μg kg−1, and infusion dose ranged from 0.2 to 10 μg kg−1 h−1. Dexmedetomidine was administered in conjunction with local anesthesia and/or other sedatives. Ketamine was administered with dexmedetomidine and opposed its bradycardiac effects. Dexmedetomidine may by useful in patients needing sedation without tracheal intubation. The literature suggests potential use of dexmedetomidine solely or as an adjunctive agent to other sedation agents. Dexmedetomidine was especially useful when spontaneous breathing was essential such as in procedures on the airway, or when sudden awakening from sedation was required such as for cooperative clinical examination during craniotomies.
PMCID: PMC2857611  PMID: 20421911
dexmedetomidine; sedation; nonintubated patients
13.  Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial 
Critical Care  2010;14(2):R38.
Introduction
Benzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.
Methods
In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis.
Results
Of the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11).
Conclusions
In this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results.
Trial Registration
NCT00095251.
doi:10.1186/cc8916
PMCID: PMC2887145  PMID: 20233428
14.  Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients 
Critical Care  2011;15(5):R257.
Introduction
Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.
Methods
Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.
Results
The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.
Conclusions
The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.
Trial Registration
ClinicalTrials.gov: NCT00747721
doi:10.1186/cc10518
PMCID: PMC3334808  PMID: 22030215
15.  Dexmedetomidine Versus Standard Therapy with Fentanyl for Sedation in Mechanically Ventilated Premature Neonates 
OBJECTIVE
To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates.
METHODS
This was a retrospective, observational case-control study in a level III neonatal intensive care unit. Forty-eight premature neonates requiring mechanical ventilation were included. Patients received fentanyl (n=24) or dexmedetomidine (n=24) for pain or sedation. Each group also received fentanyl and lorazepam boluses as needed for agitation. The primary outcomes were efficacy and frequency of acute adverse events associated with each drug. Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated.
RESULTS
There were no significant differences in baseline demographics between the dexmedetomidine and fentanyl patients. Patients in the dexmedetomidine group required less adjunctive sedation and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p<0.0001). There were no differences in hemodynamic parameters between the 2 groups. Duration of mechanical ventilation was shorter in the dexmedetomidine group (14.4 vs. 28.4 days, p<0.001). Meconium passage (7.5 vs. 22.4 days, p<0.0002) and time from initiation to achievement of full enteral feeds (26.8 vs. 50.8 days, p<0.0001) were shorter in the dexmedetomidine group. Incidence of culture-positive sepsis was lower in the dexmedetomidine group (48% vs. 88%). The incidence of either severe intraventricular hemorrhage or periventricular leukomalacia was not statistically significantly reduced (2% vs. 7%).
CONCLUSIONS
Dexmedetomidine was safe and effective for sedation in the premature neonates included in this study. Prospective randomized-controlled trials are needed before routine use of dexmedetomidine can be recommended.
doi:10.5863/1551-6776-17.3.252
PMCID: PMC3526929  PMID: 23258968
dexmedetomidine; fentanyl; mechanical ventilation; neonate; sedation
16.  Sedation improves early outcome in severely septic Sprague Dawley rats 
Critical Care  2009;13(4):R136.
Introduction
Sepsis, a systemic inflammatory response to infective etiologies, has a high mortality rate that is linked both to excess cytokine activity and apoptosis of critical immune cells. Dexmedetomidine has recently been shown to improve outcome in a septic cohort of patients when compared to patients randomized to a benzodiazepine-based sedative regimen. We sought to compare the effects of dexmedetomidine and midazolam, at equi-sedative doses, on inflammation and apoptosis in an animal model of severe sepsis.
Methods
After central venous access, Sprague Dawley rats underwent cecal ligation and intestinal puncture (CLIP) with an 18 G needle without antibiotic cover and received either saline, or an infusion of comparable volume of saline containing midazolam (0.6 mg.kg-1.h-1) or dexmedetomidine (5 ug.kg-1.h-1) for 8 hours. Following baseline measurements and CLIP, blood was sampled for cytokine measurement (tumour necrosis factor (TNF)-alpha and interleukin (IL)-6; n = 4-6 per group) at 2, 4 and 5 hours, and animal mortality rate (MR) was monitored (n = 10 per group) every 2 hours until 2 hours had elapsed. In addition, spleens were harvested and apoptosis was assessed by immunoblotting (n = 4 per group).
Results
The 24 hour MR in CLIP animals (90%) was significantly reduced by sedative doses of either dexmedetomidine (MR = 20%) or midazolam (MR = 30%). While both sedatives reduced systemic levels of the inflammatory cytokine TNF-alpha (P < 0.05); only dexmedetomidine reduced the IL-6 response to CLIP, though this narrowly missed achieving significance (P = 0.05). Dexmedetomidine reduced splenic caspase-3 expression (P < 0.05), a marker of apoptosis, when compared to either midazolam or saline.
Conclusions
Sedation with midazolam and dexmedetomidine both improve outcome in polymicrobial severely septic rats. Possible benefits conveyed by one sedative regimen over another may become evident over a more prolonged time-course as both IL-6 and apoptosis were reduced by dexmedetomidine but not midazolam. Further studies are required to evaluate this hypothesis.
doi:10.1186/cc8012
PMCID: PMC2750194  PMID: 19691839
17.  Evaluation of an Alcohol Withdrawal Protocol and a Preprinted Order Set at a Tertiary Care Hospital 
Background:
Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear.
Objective:
To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital.
Methods:
A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications.
Results:
A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups.
Conclusions:
Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal.
PMCID: PMC3242577  PMID: 22479099
alcohol withdrawal protocol; Clinical Institute Withdrawal Assessment for Alcohol; revised; symptom-triggered therapy; fixed-schedule therapy; benzodiazepine; protocole de sevrage alcoolique; Clinical Institute Withdrawal Assessment for Alcohol; révisée; traitement adapté à la symptomatologie; traitement à horaire fixe; benzodiazépine
18.  Highly variable pharmacokinetics of dexmedetomidine during intensive care: a case report 
Introduction
Dexmedetomidine is a selective and potent alpha2-adrenoceptor agonist licensed for use in the sedation of patients initially ventilated in intensive care units at a maximum dose rate of 0.7 μg/kg/h administered for up to 24 hours. Higher dose rates and longer infusion periods are sometimes required to achieve sufficient sedation. There are some previous reports on the use of long-term moderate to high-dose infusions of dexmedetomidine in patients in intensive care units, but none of these accounts have cited dexmedetomidine plasma concentrations.
Case presentation
We describe the case of a 42-year-old Caucasian woman with severe hemorrhagic pancreatitis following laparoscopic cholecystectomy who received dexmedetomidine for 24 consecutive days at a maximum dose rate of 1.9 μg/kg/h. Samples for the measurement of dexmedetomidine concentrations in her plasma were drawn at intervals of eight hours. On average, the observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine. There was, however, marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate.
Conclusion
The pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care.
doi:10.1186/1752-1947-4-73
PMCID: PMC2848065  PMID: 20184754
19.  Sedation during noninvasive mechanical ventilation with dexmedetomidine or midazolam: A randomized, double-blind, prospective study 
Background: Effective noninvasive mechanical ventilation (NIV) requires a patient to be comfortable and in synch with the ventilator, for which sedation is usually needed. Choice of the proper drug for sedation can lead to improved clinical outcomes.
Objective: The aim of this study was to compare the effectiveness of dexmedetomidine and midazolam on sedation and their effects on hemodynamics and gas exchange.
Methods: In this randomized, double-blind study, intensive care unit patients with acute respiratory failure due to acute exacerbations of chronic obstructive pulmonary disease undergoing NIV were equally randomized to receive a loading dose of 1 μg/kg IV dexmedetomidine or 0.05 μg/kg midazolam over 10 minutes followed by a maintenance infusion of 0.5 μg/kg/h dexmedetomidine (group D) or 0.1 mg/kg/h midazolam (group M). The following parameters were measured by a blinded clinician at baseline and 1, 2, 4, 6, 8, 12, and 24 hours after the loading dose was administered: Ramsay Sedation Score (RSS), Riker Sedation-Agitation Scale (RSAS), Bispectral Index (BIS), arterial blood gases, and vital signs. A second blinded investigator determined dosing changes according to the outcome of maintaining a target sedation level of RSS 2 to 3, RSAS 3 to 4, and BIS >85.
Results: A total of 45 patients were assessed for enrollment in the study; 4 did not meet the inclusion criteria and 1 refused to participate (men/women 19/21; mean age 58/60; all patients were receiving bronchodilators, steroids, antibiotics, and mucolytics). In both groups (n = 20), RSS significantly increased and RSAS levels and BIS values significantly decreased after the loading dose, compared with baseline (P < 0.05). RSS levels were significantly lower beginning at 4 hours in group D compared with group M (P < 0.05). RSAS levels were not significantly different between the 2 groups in the first 8 hours. However, RSAS levels were significantly higher at 8 hours after the loading dose was administered in group D compared with group M (P < 0.01). BIS was significantly higher in group D throughout the study period (P < 0.05). Respiratory rates and gas exchange values were not significantly different between the Accepted for publication April 7, 2010. 2 groups. The number of times a change in infusion dose was needed was significantly lower in group D (2 patients with 1 change each) than in group M (3 patients with 1 change, 1 patient with 2 changes, and 3 patients with 3 changes each) (P < 0.01).
Conclusions: Dexmedetomidine and midazolam are both effective sedatives for patients with NIV. Dexmedetomidine required fewer adjustments in dosing compared with midazolam to maintain adequate sedation.
doi:10.1016/j.curtheres.2010.06.003
PMCID: PMC3967280  PMID: 24683260
bispectral index; midazolam; dexmedetomidine; sedation; mechanical ventilation
20.  Comparison of the effects of dexmedetomidine versus fentanyl on airway reflexes and hemodynamic responses to tracheal extubation during rhinoplasty: A double-blind, randomized, controlled study 
Background: Stimulation of various sites, from the nasal mucosa to the diaphragm, can evoke laryngospasm. To reduce airway reflexes, tracheal extubation should be performed while the patient is deeply anesthetized or with drugs that do not depress ventilation. However, tracheal extubation during rhinoplasty may be difficult because of the aspiration of blood and the possibility of laryngospasm. Dexmedetomidine and fentanyl both have sedative and analgesic effects, but dexmedetomidine has been reported to induce sedation without affecting respiratory status.
Objective: The aim of this study was to compare the effects of dexmedetomidine and fentanyl on airway reflexes and hemodynamic responses to tracheal extubation in patients undergoing rhinoplasty.
Methods: This double-blind, randomized, controlled study was conducted at the Erciyes University Medical Center, Kayseri, Turkey. Patients classified as American Society of Anesthesiologists physical status I or II who were undergoing elective rhinoplasty between January 2007 and June 2007 with general anesthesia were eligible for study entry. Using a sealed-envelope method, the patients were randomly divided into 2 groups (20 patients per group). Five minutes before extubation, patients received either dexmedetomidine 0.5 μg/kg in 100 mL of isotonic saline or fentanyl 1 μg/kg in 100 mL of isotonic saline intravenously. All patients were extubated by anesthesiologists who were blinded to the study drugs, and all were continuously monitored for 15 minutes after extubation. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and oxygen saturation using pulse oximetry (SpO2) were recorded before anesthesia, after drug administration, after skin incision, at the completion of surgery, and 1, 5, and 10 minutes before and after tracheal extubation. Any prevalence of laryngospasm, bronchospasm, or desaturation was recorded.
Results: Forty patients (25 men, 15 women; mean [SD] age, 24.86 [7.43] years) were included in the study. Dexmedetomidine was associated with a significant increase in extubation quality compared with fentanyl, reflected in the prevalence of cough after extubation (85% [17/20] vs 30% [6/20] of patients, respectively; P = 0.001). There were no clinically significant decreases in HR, SBP, DBP, or SpO2 after extubation with dexmedetomidine or fentanyl. In the dexmedetomidine group, HR was not significantly increased after extubation; however, in the fentanyl group, HR was significantly increased compared with the preextubation values (all, P = 0.007). HR was significantly higher in the fentanyl group compared with the dexmedetomidine group at 1, 5, and 10 minutes after extubation (all, P = 0.003). Compared with preextubation values, SBP was significantly increased at 1 and 5 minutes after extubation in the dexmedetomidine group (both, P = 0.033) and at 1, 5, and 10 minutes after extubation in the fentanyl group (all, P = 0.033). The postoperative sedation scores and the extubation, awakening, and orientation times were not significantly different between the 2 groups. In the dexmedetomidine group, bradycardia (HR <45 beats/min) was observed in 2 patients and emesis was observed in 2 patients. In the fentanyl group, emesis was observed in 3 patients, bradycardia in 2 patients, vomiting in 1 patient, and shivering in 1 patient; vertigo was reported in 1 patient. There were no significant differences in the prevalence of adverse events between the 2 groups.
Conclusion: The findings in the present study suggest that dexmedetomidine 0.5 μg/kg IV, administered before extubation, was more effective in attenuating airway reflex responses to tracheal extubation and maintaining hemodynamic stability without prolonging recovery compared with fentanyl 1 μg/kg IV in these patients undergoing rhinoplasty.
doi:10.1016/j.curtheres.2009.06.003
PMCID: PMC3967279  PMID: 24683231
dexmedetomidine; fentanyl; tracheal extubation; rhinoplasty
21.  Neurologic Withdrawal Symptoms Following Abrupt Discontinuation of a Prolonged Dexmedetomidine Infusion in a Child 
Dexmedetomidine is a α2-adrenergic agonist which possesses sedative, analgesic, and anxiolytic properties. It is approved for short-term use in adults to provide sedation while mechanically ventilated and for noninvasive procedural sedation. An increased number of anecdotal reports describe the use dexmedetomidine in children. Cardiovascular withdrawal symptoms have been reported in the literature. However, there have been few published reports of neurologic withdrawal symptoms following discontinuation of prolonged infusions of dexmedetomidine. We describe a 2 year-old child who received a prolonged continuous infusion (263 hours) of dexmedetomidine as an adjunctive sedative agent. Following abrupt discontinuation of dexmedetomidine, the patient presented with symptoms suggestive of neurological withdrawal. The symptoms gradually resolved over two days without further intervention, and the patient had full resolution of symptoms and was discharged home with no further neurologic sequelae.
PMCID: PMC3017408  PMID: 22477791
children; dexmedetomidine; sedation; withdrawal
22.  Withdrawal-induced delirium associated with a benzodiazepine switch: a case report 
Introduction
Introduced in the early 1960s, diazepam remains among the most frequently prescribed benzodiazepine-type sedatives and hypnotics. Patients with chronic use of short-acting benzodiazepines are frequently switched to diazepam because the accumulating, long-acting metabolite, N-desmethyl-diazepam, prevents benzodiazepine-associated withdrawal symptoms, which can occur during trough plasma levels of short-acting benzodiazepines. Although mild to moderate withdrawal symptoms are frequently observed during benzodiazepine switching to diazepam, severe medical complications associated with this treatment approach have thus far not been reported.
Case presentation
A 64-year-old female Caucasian with major depression, alcohol dependence and benzodiazepine dependence was successfully treated for depression and, after lorazepam-assisted alcohol detoxification, was switched from lorazepam to diazepam to facilitate benzodiazepine discontinuation. Subsequent to the benzodiazepine switch, our patient unexpectedly developed an acute delirious state, which quickly remitted after re-administration of lorazepam. A newly diagnosed early form of mixed dementia, combining both vascular and Alzheimer-type lesions, was found as a likely contributing factor for the observed vulnerability to benzodiazepine-induced withdrawal symptoms.
Conclusion
Chronic use of benzodiazepines is common in the elderly and a switch to diazepam often precedes benzodiazepine discontinuation trials. However, contrary to common clinical practice, benzodiazepine switching to diazepam may require cross-titration with slow tapering of the first benzodiazepine to allow for the build-up of N-desmethyl-diazepam, in order to safely prevent severe withdrawal symptoms. Alternatively, long-term treatment with low doses of benzodiazepines may be considered, especially in elderly patients with chronic use of benzodiazepines and proven vulnerability to benzodiazepine-associated withdrawal symptoms.
doi:10.1186/1752-1947-5-207
PMCID: PMC3117827  PMID: 21615891
23.  The Hemodynamic Response to Dexmedetomidine Loading Dose in Children With and Without Pulmonary Hypertension 
Anesthesia and analgesia  2013;117(4):10.1213/ANE.0b013e3182a15aa6.
BACKGROUND
Dexmedetomidine, an α-2 receptor agonist, is widely used in children with cardiac disease. Significant hemodynamic responses, including systemic and pulmonary vasoconstriction, have been reported after dexmedetomidine administration. Our primary goal of this prospective, observational study was to quantify the effects of dexmedetomidine initial loading doses on mean pulmonary artery pressure (PAP) in children with and without pulmonary hypertension.
METHODS
Subjects were children undergoing cardiac catheterization for either routine surveillance after cardiac transplantation (n = 21) or pulmonary hypertension studies (n = 21). After anesthetic induction with sevoflurane and tracheal intubation, sevoflurane was discontinued and anesthesia was maintained with midazolam 0.1 mg/kg IV (or 0.5 mg/kg orally preoperatively) and remifentanil IV infusion 0.5 to 0.8 μg/kg/min. Ventilation was mechanically controlled to maintain Pco2 35 to 40 mm Hg. When end-tidal sevoflurane was 0% and fraction of inspired oxygen (Fio2) was 0.21, baseline heart rate, mean arterial blood pressure, PAP, right atrial pressure, pulmonary artery occlusion pressure, right ventricular end-diastolic pressure, cardiac output, and arterial blood gases were measured, and indexed systemic vascular resistance, indexed pulmonary vascular resistance, and cardiac index were calculated. Each subject then received a 10-minute infusion of dexmedetomidine of 1 μg/kg, 0.75 μg/kg, or 0.5 μg/kg. Measurements and calculations were repeated at the conclusion of the infusion.
RESULTS
Most hemodynamic responses were similar in children with and without pulmonary hypertension. Heart rate decreased significantly, and mean arterial blood pressure and indexed systemic vascular resistance increased significantly. Cardiac index did not change. A small, statistically significant increase in PAP was observed in transplant patients but not in subjects with pulmonary hypertension. Changes in indexed pulmonary vascular resistance were not significant.
CONCLUSION
Dexmedetomidine initial loading doses were associated with significant systemic vasoconstriction and hypertension, but a similar response was not observed in the pulmonary vasculature, even in children with pulmonary hypertension. Dexmedetomidine does not appear to be contraindicated in children with pulmonary hypertension.
doi:10.1213/ANE.0b013e3182a15aa6
PMCID: PMC3830564  PMID: 23960035
24.  Dexmedetomidine hydrochloride as a long-term sedative 
Dexmedetomidine undoubtedly is a useful sedative in the intensive care setting because it has a minimal effect on the respiratory system. Dexmedetomidine infusions lasting more than 24 hours have not been approved since the first approval was acquired in the US in 1999. However, in 2008, dexmedetomidine infusions for prolonged use were approved in Colombia and in the Dominican Republic, and the number of countries that have granted approval for prolonged use has been increasing every year. This review discusses the literature examining prolonged use of dexmedetomidine and confirms the efficacy and safety of dexmedetomidine when it is used for more than 24 hours. Dexmedetomidine was administered at varying doses (0.1–2.5 μg/kg/hour) and durations up to 30 days. Dexmedetomidine seems to be an alternative to benzodiazepines or propofol for achieving sedation in adults because the incidences of delirium and coma associated with dexmedetomidine are lower than the corresponding incidences associated with benzodiazepines and propofol, although dexmedetomidine administration can cause mild adverse effects such as bradycardia. Controlled comparative studies on the efficacy and safety of dexmedetomidine and other sedatives in pediatric patients have not been reported. However, dexmedetomidine seems to be effective in managing extubation, reducing the use of conventional sedatives, and as an alternative for inducing sedation in patients for whom traditional sedatives induce inadequate sedation. Prolonged dexmedetomidine infusion has not been reported to have any serious adverse effects. Dexmedetomidine appears to be an alternative long-term sedative, but further studies are needed to establish its efficacy and safety.
doi:10.2147/TCRM.S14581
PMCID: PMC3150475  PMID: 21845052
dexmedetomidine; prolonged sedation; long-term
25.  CYP2A6 genetic variation and dexmedetomidine disposition 
Purpose
There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.
Methods
In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of 5 plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n=33), intermediate (n=5), and slow metabolizers (n=2).
Results
Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1 L/hr (posterior mean; 95% credible interval, 41.4 to 57.6 L/hr). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.
Conclusion
Genetic variation in CYP2A6 is not an important determinant of dexmedetomidine clearance in ICU patients.
doi:10.1007/s00228-011-1208-z
PMCID: PMC3352974  PMID: 22271297
CYP2A6; Dexmedetomidine; Pharmacogenetics; Bayesian Modeling

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