08 Apr 12
By S M Jakob, MD, E Ruokonen, R M Grounds, T Sarapohja, C Garratt, S J Pocock, J R Bratty, J Takala for the Dexmedetomidine for Long-Term Sedation Investigators
Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients’ interaction with nursing care.
Design, setting, and patients
Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).
Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.
Main outcome measures
For each trial, we 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 patients’ ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients’ interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).
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 patients’ ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.
16 Mar 10
By T Strøm, T Martinussen, P Toft
The Lancet 2010;375:475-480
Standard treatment of critically ill patients undergoing mechanical ventilation is continuous sedation. Daily interruption of sedation has a benefi cial eff ect, and in the general intesive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation. We aimed to establish whether duration of mechanical ventilation could be reduced with a protocol of no sedation versus daily interruption of sedation.
Of 428 patients assessed for eligibility, we enrolled 140 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 24 h. Patients were randomly assigned in a 1:1 ratio (unblinded) to receive: no sedation (n=70 patients); or sedation (20 mg/mL propofol for 48 h, 1 mg/mL midazolam thereafter) with daily interruption until awake (n=70, control group). Both groups were treated with bolus doses of morphine (2·5 or 5 mg). The primary outcome was the number of days without mechanical ventilation in a 28-day period, and we also recorded the length of stay in the intensive care unit (from admission to 28 days) and in hospital (from admission to 90 days). Analysis was by intention to treat.
27 patients died or were successfully extubated within 48 h, and, as per our study design, were excluded from the study and statistical analysis. Patients receiving no sedation had signifi cantly more days without ventilation (n=55; mean 13·8 days, SD 11·0) than did those receiving interrupted sedation (n=58; mean 9·6 days, SD 10·0; mean diff erence 4·2 days, 95% CI 0·3–8·1; p=0·0191). No sedation was also associated with a shorter stay in the intensive care unit (HR 1·86, 95% CI 1·05–3·23; p=0·0316), and, for the fi rst 30 days studied, in hospital (3·57, 1·52–9·09; p=0·0039), than was interrupted sedation. No diff erence was recorded in the occurrences of accidental extubations, the need for CT or MRI brain scans, or ventilator-associated pneumonia. Agi tat ed delirium was more frequent in the intervention group than in the control group (n=11, 20% vs n=4, 7%; p=0·0400).
No sedation of critically ill patients receiving mechanical ventilation is associated with an increase in days without ventilation. A multicentre study is needed to establish whether this eff ect can be reproduced in other facilities.
02 Nov 09
By M Treggiari, J Romand, N Yanez, S Deem, J Goldberg, L Hudson, C Heidegger
Critical Care Medicine 2009;37:2527-2534
To investigate if light sedation favorably affects subsequent patient mental health compared with deep sedation. Symptoms of posttraumatic stress disorder are common in patients after they have undergone prolonged mechanical ventilation and are associated with sedation depth.
Randomized, open-label, controlled trial.
Single tertiary care center.
Adult patients requiring mechanical ventilation.
Patients were randomized to receive either light (patient awake and cooperative) or deep sedation (patient asleep, awakening upon physical stimulation).
Measurements and main results
Self-reported measures of posttraumatic stress disorder, anxiety, and depression were collected at intensive care unit discharge and 4 wks later. The primary outcomes were symptoms of posttraumatic stress disorder, anxiety, and depression 4 wks after intensive care unit discharge. A total of 137 patients were assigned to either the light (n = 69) or the deep sedation (n = 68) group. Seven patients withdrew consent and one patient was randomized in error, leaving 129 patients (n = 65 in light sedation and n = 64 in deep sedation) available for analysis. At the 4-wk follow-up, patients in the deep sedation group tended to have more posttraumatic stress disorder symptoms (p = .07); the deep sedation group had more trouble remembering the event (37% vs. 14%; p = .02) and more disturbing memories of the intensive care unit (18% vs. 4%; p = .05). Patients in the light sedation group had an average one day less being ventilated and 1.5 fewer days in the intensive care unit. There were no differences between the two groups in the occurrence of anxiety and depression, and also no difference in mortality or in the incidence of adverse events.
These data suggest that a strategy of light sedation affords benefits with regard to reduction of intensive care unit stay and duration of ventilation without negatively affecting subsequent patient mental health or patient safety.
27 Aug 09
By M Reade, K O’Sullivan, S Bates, D Goldsmith, W Ainslie and R Bellomo
Critical Care 2009, 13:R75
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.
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.
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.
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.