The management of patients in an intensive care unit (ICU) should include strategies to make them comfortable and pain-free, relieve anxiety, enable them to feel calm and sleep when undisturbed, and tolerate the measures required for nursing care and organ support.1,2 Treatment includes analgesia, typically with an opioid such as fentanyl, and sedation.1
Sedating agents share a common set of problems that may complicate management (Box 1).2 The drugs currently most widely used are midazolam and propofol,3,4 both of which act via GABAergic mechanisms. Midazolam has a rapid onset of action, making it suitable for the acute treatment of agitated patients. Drawbacks include the risk of prolonged sedation in patients with renal insufficiency due to accumulation of its active metabolite,1 and it has been identified as a risk factor for delirium in ICU patients.5 Propofol has a rapid onset and short duration of action; it may cause bradycardia and dose-related hypotension.1 Midazolam and propofol provide similar onset and comparable levels of sedation, although waking from deeper sedation is generally much more rapid with propofol.1
Dexmedetomidine is a recently launched therapeutic option for ICU patients who require sedation; it offers a distinct mechanism of action and clinical profile compared with current alternatives.6
Overview of dexmedetomidine
Dexmedetomidine is licensed for the sedation of adult ICU patients requiring a level of sedation not deeper than arousal in response to verbal stimulation (corresponding to a Richmond Agitation Sedation Scale [RASS] score of 0 to –3).7Dexmedetomidine is an alpha-2 adrenergic receptor agonist, and is 1620 times more potent for alpha-2 than alpha-1 receptors;8 it is eight-fold more selective for alpha-2 receptors than clonidine.8 Clonidine is only a partial alpha-2 agonist and its meta bolites are inactive. Unlike midazolam and propofol, dexmedetomidine is believed to have no GABA receptor agonist activity.6
Dexmedetomidine causes ‘rousable’ sedation, where patients respond promptly to verbal stimuli or light touch. Dexmedetomidine’s sedative effects are due to dose-dependent inhibition of noradrenaline release in the locus coeruleus, an area of the brainstem that is an important modulator of vigilance and attention.9 This effect may involve natural sleep pathways,9 resulting in sedation resembling normal physiological non-rapid eye movement sleep.10 Dexmedetomidine has analgesic activity, with evidence of a sparing effect for other analgesics.7
Dexmedetomidine is not believed to cause respiratory depression in ICU patients7and can be considered relatively free from respiratory depressive effects.7 Its cardiovascular effects depend on the dose given. At low infusion rates, central effects are dominant, resulting in decreased heart rate and blood pressure.7 At higher doses, peripheral vasoconstricting effects predominate, causing increased systemic vascular resistance and blood pressure, and a greater decrease in heart rate.7
After intravenous (iv) infusion, dexmedetomidine is rapidly distributed. It undergoes extensive hepatic metabolism to metabolites that have negligible
pharmacological activity, and is predominantly excreted as metabolites in the urine. It is rapidly eliminated, with a half-life of approximately 1.5 hours, and there is no accumulation during continued administration for up to 14 days.
The pharmacokinetics of dexmedetomidine are not affected by renal function
and no dose adjustment is required for patients with renal impairment. Hepatic
impairment decreases protein binding of dexmedetomidine and reduces hepatic clearance; the mean elimination half-life in mild, moderate or severe hepatic
impairment is 3.9, 5.4 and 7.4 hours, respectively. Although the dose of dexmedetomidine is titrated according to the patient’s response, a lower initial and maintenance dose should be considered in patients with hepatic impairment.
By contrast with midazolam and propofol, no dose adjustment is recommended
according to age.
Co-administration of dexmedetomidine with anaesthetics, sedatives, hypnotics
and opioids may enhance its effects. This has been confirmed with isoflurane,
propofol, alfentanil and midazolam; a lower dose of dexmedetomidine and/or
these agents may therefore be required. No pharmacokinetic interaction between
dexmedetomidine and these agents has been demonstrated.
Likewise, bradycardia and reduction in blood pressure associated with dexmedetomidine may be enhanced by drugs with similar effects (such as beta-blockers).
It is possible that dexmedetomidine may interact with other drugs that are substrates for hepatic CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4 enzymes, but the clinical significance of this is not yet known.
Dexmedetomidine must be administered only as a diluted iv infusion using a controlled infusion device (2ml of dexmedetomidine added to 48ml of either normal saline, 5% glucose or lactated Ringer’s solution). Loading doses are
generally not recommended as they are associated with an increased risk of adverse effects.
Patients already intubated and sedated may switch to dexmedetomidine with an initial infusion rate of 0.7 microgram/kg/hour, which may then be adjusted
stepwise within the dose range 0.2–1.4 microgram/kg/hour to achieve the desired level of sedation, depending on the patient’s response. A lower starting infusion rate should be considered for frail patients.
There is no need to stop dexmedetomidine infusion before extubation.
Dexmedetomidine reduced the median time to extubation compared with midazolam and propofol1
Clinical trial data
Two phase 3 double-blind trials of identical design have compared
dexmedetomidine with propofol (n=498) and midazolam (n=500) as continuous
sedation in mechanically ventilated ICU patients.11 Eligible patients were adults with a clinical need for sedation after intubation (or tracheostomy) and ventilation who had been prescribed light-tomoderate sedation with propofol or midazolam. Exclusion criteria included acute severe neurological disorder, mean arterial pressure <55mmHg (despite appropriate intravenous volume replacement
and vasopressors), heart rate <50 beats per minute, atrioventricular conduction grade II or III (unless a pacemaker is installed) and the use of alpha-2 agonists or antagonists 24 hours prior to randomisation.12
Patients were randomised within 72 hours of ICU admission or within 48 hours of initiating sedation to continue their original treatment or switch to dexmedetomidine. The dose was initially 0.7 microgram/kg/hour for one hour, then adjusted to 0.25–1.4 microgram/kg/hour to maintain the required level of sedation.12 Treatment was for a minimum of 24 hours and a maximum of 14 days.12
Both trials had two co-primary endpoints. The first was non-inferiority of dexmedetomidine compared with propofol and midazolam in maintaining the target level of sedation. The other, evaluated only if non-inferiority was shown, was the duration of invasive and non-invasive mechanical ventilation during treatment with dexmedetomidine compared with midazolam and propofol.11Worse ranking rule was applied.
The main primary and secondary endpoints are summarised in Table 1. Dexmedetomidine was non-inferior to both propofol and midazolam for time spent at the target sedation level. It reduced the median duration of mechanical ventilation compared with midazolam, but not propofol, and reduced the median time to extubation compared with both drugs.11 Figure 1 shows the median time to extubation for dexmedetomidine compared with midazolam and propofol. Nurse assessments rated dexmedetomidine as superior for patients’ ability to communicate, rousability and co-operativeness (Figure 2). Length of hospital stay was not significantly different between the drugs. Discontinuations due to adverse events were of a similar frequency with each treatment (38.8%–48.3%).12
Dexmedetomidine is associated with a lower risk of developing delirium compared with a benzodiazepine in medical and surgical intensive care unit patients requiring mechanical ventilation13
Development of delirium
Two trials (including a combined total of 481 patients)6,13 have shown that dexmedetomidine is associated with a lower risk of developing delirium compared with a benzodiazepine in medical and surgical ICU patients requiring mechanical ventilation.
At similar levels of sedation, dexmedetomidine was associated with a lower prevalence of delirium than midazolam (54% versus 77%; p<0.001).6 Median time to extubation was significantly shorter with dexmedetomidine (3.7 versus 5.6 days;p=0.01), but, as in the key efficacy trials, the difference in length of stay was not statistically significant (5.9 versus 7.6 days with midazolam; p=0.24).
Compared with lorazepam, dexmedetomidine was associated with a similar median number of days free of delirium during the first 12 days after initiating ventilation (9 versus 7 days with lorazepam; p=0.09), with about 40% of patients in each treatment arm having delirium; patients treated with dexmedetomidine had significantly more days free of coma (10 versus 8 days with lorazepam;p<0.001).13 Figure 3 shows the percentage of patients that developed delirium while taking dexmedetomidine, midazolam or propofol.
Dexmedetomidine reduces heart rate and blood pressure, but at higher concentrations it causes peripheral vasoconstriction leading to hypertension. Analysis of pooled data from all comparator-controlled studies in ICU patients has shown that cardiovascular events were reported more frequently with dexmedetomidine than propofol or midazolam.12
The most common adverse events were bradycardia, hypotension, tachycardia, diastolic hypotension and systolic hypertension, as detailed in Table 2.12 However, compared with propofol, dexmedetomidine was significantly less frequently associated with atrial fibrillation and pleural effusion.12
Bradycardia (2.3%) and hypotension (1.5%) resulted in treatment discontinuation more frequently with dexmedetomidine than propofol (0.4% and 1.1%) or midazolam (each 0.3%).12 Treatment discontinuation was due to agitation in 2.2% of patients treated with dexmedetomidine, 0.7% of patients treated with propofol and 1.8% of patients treated with midazolam; and to sedation in 0.1%, 0% and 1.5% of patients, respectively.12 Mortality was 11% with dexmedetomidine and propofol, but 24% with midazolam.12
Patients should have continuous cardiac monitoring during treatment with dexmedetomidine. Alpha-2 agonists have rarely been associated with withdrawal reactions when stopped abruptly after prolonged use. This possibility should be considered if the patient develops agitation and hypertension shortly after stopping dexmedetomidine.
Implications for clinical practice
Unlike propofol and midazolam,dexmedetomidine does not cause sedation via GABAergic mechanisms, but through selective alpha-2 adrenergic receptor agonism. For mild-to-moderate sedation it offers efficacy comparable with that of propofol and midazolam, but, at similar levels of sedation, patients are more communicative and co-operative, and the time to extubation is shorter.11Compared with midazolam, dexmedetomidine is associated with a lower prevalence of delirium,6 but adverse cardiovascular events are more frequent with dexmedetomidine than either propofol or midazolam.11
Dexmedetomidine is therefore a useful treatment option for patients requiring sedation at RASS level 0 to –3, and may offer advantages for those at risk of accumulation from other sedating agents. It is also an option when midazolam or propofol have been unsuccessful, or when a shorter time to extubation would be an advantage.
Mechanical ventilation increases ICU costs compared with patients not requiring ventilation14,15 and most patients who need mechanical ventilation require sedation.16 Dexmedetomidine may therefore offer savings by reducing the time to extubation compared with other agents.