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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.  Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal 
Background
In severe alcohol withdrawal (AW), benzodiazepines may be inadequate to control symptoms. In many situations, benzodiazepine dosing escalates despite no additional efficacy and introduces potential toxicities. Severe cases of AW may require additional agents to control symptoms. Case reports and studies have shown benefits with dexmedetomidine and propofol in severe AW, but these agents have not been compared with one another. This study compares the effects of dexmedetomidine and propofol on benzodiazepine and haloperidol utilization in patients with AW.
Methods
A retrospective chart review was completed on 41 patients with AW who received adjunctive dexmedetomidine or propofol. The primary objective was to compare benzodiazepine and haloperidol utilization before and after initiation of dexmedetomidine or propofol. Secondary measures included AW and sedation scoring, analgesic use, intensive care unit length of stay, rates of intubation, and adverse events.
Results
Among the dexmedetomidine and propofol groups, significant reductions in benzodiazepine (P≤0.0001 and P=0.043, respectively) and haloperidol (P≤0.0001 and P=0.026, respectively) requirements were observed. These reductions were comparable between groups (P=0.933 and P=0.465, respectively). A trend toward decreased intensive care unit length of stay in the dexmedetomidine group (123.6 hours vs 156.5 hours; P=0.125) was seen. Rates of intubation (14.7% vs 100%) and time of intubation (19.9 hours vs 97.6 hours; P=0.002) were less in the dexmedetomidine group. Incidence of hypotension was 17.6% in the dexmedetomidine group vs 28.5% in the propofol group. Incidence of bradycardia was 17.6% in the dexmedetomidine group vs 0% in the propofol group. No differences were observed in other secondary outcomes.
Conclusion
In patients with severe AW who require sedation, both dexmedetomidine and propofol have unique and advantageous properties. Both agents appear to have equivalent efficacy in reducing AW-related symptoms and benzodiazepine and haloperidol requirements. These results should be validated in a larger, prospective trial.
doi:10.2147/CPAA.S70490
PMCID: PMC4222895  PMID: 25382987
dexmedetomidine; propofol; benzodiazepines; alcohol; withdrawal
3.  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
4.  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
5.  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
6.  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
7.  Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation 
Critical Care  2015;19(1):67.
Introduction
Dexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation.
Methods
The total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only.
Results
Based on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs—€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)—and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam).
Conclusions
From an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation.
Trial registration
ClinicalTrials.gov NCT00479661 (PRODEX), NCT00481312 (MIDEX).
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0787-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-015-0787-y
PMCID: PMC4391080  PMID: 25887576
8.  Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients 
Journal of Anesthesia  2013;28(1):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
9.  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
10.  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
11.  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
12.  Identification of Patient Predictors for Dexmedetomidine Effectiveness for ICU Sedation 
Background
Effective sedation is paramount in the care of critically ill patients. Dexmedetomidine, a selective α2- adrenergic receptor agonist, is an agent that is being increasingly used in the ICU despite its variability of patient response.
Objective
To report dexmedetomidine effectiveness and to identify specific patient characteristics that play a role in the achievement of adequate sedation with dexmedetomidine.
Methods
We conducted a 6 month, pilot, prospective observational study in a medical intensive care unit (MICU) at an academic medical center. Patients receiving dexmedetomidine were followed until drug discontinuation and were grouped into non-responders and responders. Effective sedation was defined as the achievement of a Sedation Agitation Scale (SAS) score of 3-4 after the addition of dexmedetomidine. Patient characteristics, laboratory values, home and inpatient medications, and dexmedetomidine dosing information were collected to identify predictors of clinical response.
Results
Thirty eight patients received dexmedetomidine in a 6 month time period, with dexmedetomidine being ineffective in 19/38 (50%) patients, effective in 11/38 (28.95%) patients, and effectiveness was unable to be assessed in 8 patients due to clinical confounders. Based upon the standard multiple logistic regression analysis, patients with a lower APACHE II (β coefficient −0.24; 95% CI, −0.39 to −0.03) and patients that received home antidepressants (β coefficient 2.33; 95% CI, 0.23 to 4.43) were more likely to achieve successful sedation with dexmedetomidine as compared to patients with a higher APACHE II score or no home antidepressant use.
Conclusions
Variability in effective sedation occurred with dexmedetomidine use. Future large scale investigations should be conducted to confirm the association of a lower APACHE II score and home antidepressant use and dexmedetomidine effectiveness.
doi:10.4037/ajcc2014678
PMCID: PMC4132632  PMID: 24585165
Dexmedetomidine; critically ill; sedation
13.  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
14.  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
15.  Comparison of clonidine and dexmedetomidine for short-term sedation of intensive care unit patients 
Background and Objectives:
Patients on mechanical ventilation in intensive care unit (ICU) are often uncomfortable because of anxiety, pain, and endotracheal intubation; therefore, require sedation. Alpha-2 agonists are known to produce sedation. We compared clonidine and dexmedetomidine as sole agents for sedation.
Study Design:
Prospective, randomized, controlled open-label study.
Materials and Methods:
A total of 70 patients requiring a minimum of 12 h of mechanical ventilation with concomitant sedation, were randomly allocated into two groups. Group C (n = 35) received intravenous (IV) clonidine (1 μg/kg/h titrated up to 2 μg/kg/h to attain target sedation), and Group D (n = 35) received IV dexmedetomidine for sedation (loading 0.7 μg/kg and maintenance 0.2 μg/kg/h titrated up to 0.7 μg/kg/h to achieve target sedation). A Ramsay Sedation Score of 3-4 was considered as target sedation. Additional sedation with diazepam was given when required to achieve target sedation. The quality of sedation, hemodynamic changes and adverse effects were noted and compared between the two groups.
Results:
Target sedation was achieved in 86% observations in Group D and 62% in Group C (P = 0.04). Additional sedation was needed by more patients in Group C compared with Group D (14 and 8 in Groups C and D, respectively, P = 0.034), mainly due to concomitant hypotension on increasing the dose of clonidine. Hypotension was the most common side-effect in Group C, occurring in 11/35 patients of Group C and 3/35 patients of Group D (P = 0.02). Rebound hypertension was seen in four patients receiving clonidine, but none in receiving dexmedetomidine.
Conclusion:
Both clonidine and dexmedetomidine produced effective sedation; however, the hemodynamic stability provided by dexmedetomidine gives it an edge over clonidine for short-term sedation of ICU patients.
doi:10.4103/0972-5229.136071
PMCID: PMC4118508  PMID: 25097355
Clonidine; dexmedetomidine; intensive care unit sedation
16.  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
17.  Clinical effectiveness of a sedation protocol minimizing benzodiazepine infusions and favoring early dexmedetomidine: a before-after study 
Critical Care  2015;19(1):136.
Introduction
Randomized controlled trials suggest clinical outcomes may be improved with dexmedetomidine as compared with benzodiazepines; however, further study and validation are needed. The objective of this study was to determine the clinical effectiveness of a sedation protocol minimizing benzodiazepine use in favor of early dexmedetomidine.
Methods
We conducted a before-after study including adult surgical and medical intensive care unit (ICU) patients requiring mechanical ventilation and continuous sedation for at least 24 hours. The before phase included consecutive patients admitted between 1 April 2011 and 31 August 31 2011. Subsequently, the protocol was modified to minimize use of benzodiazepines in favor of early dexmedetomidine through a multidisciplinary approach, and staff education was provided. The after phase included consecutive eligible patients between 1 May 2012 and 31 October 2012.
Results
A total of 199 patients were included, with 97 patients in the before phase and 102 in the after phase. Baseline characteristics were well balanced between groups. Use of midazolam as initial sedation (58% versus 27%, P <0.0001) or at any point during the ICU stay (76% versus 48%, P <0.0001) was significantly reduced in the after phase. Dexmedetomidine use as initial sedation (2% versus 39%, P <0.0001) or at any point during the ICU stay (39% versus 82%, P <0.0001) significantly increased. Both the prevalence (81% versus 93%, P =0.013) and median percentage of days with delirium (55% (interquartile range (IQR), 18 to 83) versus 71% (IQR, 45 to 100), P =0.001) were increased in the after phase. The median duration of mechanical ventilation was significantly reduced in the after phase (110 (IQR, 59 to 192) hours versus 74.5 (IQR, 42 to 148) hours, P =0.029), and significantly fewer patients required tracheostomy (20% versus 9%, P =0.040). The median ICU length of stay was 8 (IQR, 4 to 12) days in the before phase and 6 (IQR, 3 to 11) days in the after phase (P =0.252).
Conclusions
Implementing a sedation protocol that targeted light sedation and reduced benzodiazepine use led to significant improvements in the duration of mechanical ventilation and the requirement for tracheostomy, despite increases in the prevalence and duration of ICU delirium.
doi:10.1186/s13054-015-0874-0
PMCID: PMC4403893  PMID: 25887495
18.  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
19.  Comparison of Dexmedetomidine versus Propofol for Sedation in Mechanically Ventilated Patients after Cardiovascular Surgery 
Many cardiovascular surgeries are fast-tracked to extubation and require short-term sedation. Dexmedetomidine and propofol have very different mechanisms of action and pharmacokinetic profiles that make them attractive sedative agents in this patient population. Recently, there has been increased use of dexmedetomidine in the intensive care unit (ICU), but few studies exist or have been published directly comparing both agents in this setting. We conducted a retrospective cohort study with patients admitted to the ICU after cardiovascular surgery from January through June 2011. Adult patients who underwent coronary artery bypass and/or cardiac valve surgery received either dexmedetomidine or propofol continuous infusion for short-term sedation after cardiovascular surgery. The primary end point was time (hours) on mechanical ventilation after surgery. Secondary end points included ICU length of stay (LOS), hospital LOS, incidence of delirium, and requirement of a second sedative agent. A total of 352 patients met study inclusion criteria, with 33 enrolled in the dexmedetomidine group and 319 in the propofol group. Time on mechanical ventilation was shorter in the dexmedetomidine group (7.4 hours vs. 12.9 hours, P = .042). No difference was seen in ICU or hospital LOS. The need for a second sedative agent to achieve optimal sedation (24% vs. 27%, P = .737) and incidence of delirium (9% vs. 7.5%, P = .747) were similar between both groups. Sedation with dexmedetomidine resulted in a significant reduction in time on mechanical ventilation. However, no difference was seen in ICU or hospital LOS, incidence of delirium, or mortality.
PMCID: PMC4117329  PMID: 25114763
sedation; dexmedetomidine; propofol; cardiovascular surgery; delirium
20.  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
21.  Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement 
Indian Journal of Anaesthesia  2011;55(4):352-357.
Background:
Dexmedetomidine, an α-2 adrenoreceptor agonist, is gaining popularity for its sympatholytic, sedative, anaesthetic sparing and haemodynamic stabilising properties without significant respiratory depression.
Methods:
We assessed the efficacy of dexmedetomidine in attenuating sympathoadrenal response to tracheal intubation and analysed reduction in intraoperative anaesthetic requirement. Sixty patients scheduled for elective surgery of more than 3 hours were randomly selected. Control group received isoflurane–opioid and study group received isoflurane–opioid-dexmedetomidine anaesthesia. Dexmedetomidine infusion in a dose of 1 μg/kg was given over 10 min before the induction of anaesthesia and was continued in a dose of 0.2–0.7 μg/kg/Hr until skin closure. All patients were induced with thiopentone, fentanyl and vecuronium. Haemodynamic variables were continuously recorded.
Results:
The need for thiopentone and isoflurane was decreased by 30% and 32%, respectively, in the dexmedetomidine group as compared to the control group. After tracheal intubation, maximal average increase was 8% in systolic and 11% in diastolic blood pressure in dexmedetomidine group, as compared to 40% and 25%, respectively, in the control group. Similarly, average increase in heart rate was 7% and 21% in the dexmedetomidine and control groups, respectively. Fentanyl requirement during the operation was 100±10 μg in the control group and 60±10 μg in the dexmedetomidine group.
Conclusion:
Perioperative infusion of dexmedetomidine is effective in attenuating sympathoadrenal response to tracheal intubation. It has significant anaesthetic and opioid sparing effect.
doi:10.4103/0019-5049.84846
PMCID: PMC3190508  PMID: 22013250
α-2 adrenoreceptor; dexmedetomidine; sympathoadrenal response; tracheal intubation
22.  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
23.  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
24.  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
25.  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

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