By Samuel T. Nadler, MD, PhD
Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle; Clinical Instructor, University of Washington, Seattle
The need for sedation and analgesia is common in patients requiring invasive mechanical ventilation in the intensive care unit (ICU). Previously, benzodiazepine infusions were commonly used, but this prompted concern for the development of delirium and long-term neurocognitive deficits. Recent trials have explored alternative sedative agents that might lead to better outcomes for patients. Subsequently, many have moved away from benzodiazepine infusions, using propofol instead. The use of dexmedetomidine has increased as an alternative to propofol and benzodiazepines, although the use of ketamine also has been increasing. This special feature will focus on dexmedetomidine as a sedative for invasive mechanical ventilation in the ICU.
Pharmacology of Dexmedetomidine
Dexmedetomidine is a highly selective α-2 adrenergic receptor agonist.1,2 It was initially approved in the United States in 1999 for short-term sedation of intubated patients, with expansion of this indication to include perioperative and procedural sedation in 2008. Dexmedetomidine acts within both the central nervous system and spinal cord to cause salutary and adverse effects. The locus coeruleus within the pons mediates vigilance and arousal via synthesis of norepinephrine (NE). Presynaptic activation by dexmedetomidine leads to decreased NE efflux into the locus coeruleus, while post-synaptic agonism causes hyperpolarization of neuronal membranes leading to sedation. Unlike GABA-ergic sedatives such as benzodiazepines and propofol, there is no associated respiratory depression. Activation of α-2 receptors in the rostral ventrolateral medulla combined with parasympathetic activation in the nucleus ambiguous mediates bradycardia and vasodilatory hypotension. Within the spinal cord, descending medullo-spinal nociceptive pathways are repressed, and the release of excitatory neurotransmitters in the dorsal horn is decreased, mediating analgesia. Dexmedetomidine is lipophilic and highly protein-bound, leading to a large volume of distribution. Infusions of dexmedetomidine at doses 0.2 mcg/kg/hour to 1.4 mcg/kg/hour demonstrate linear kinetics, with a rapid distribution half-life of about six minutes. It has extensive hepatic metabolism to inactive metabolites primarily excreted into the urine.
Trials of Dexmedetomidine for Sedation
The 2002 clinical practice guidelines for the use of sedatives in the ICU recommended lorazepam, a benzodiazepine, be used for sedation after adequate analgesia had been achieved.3 However, there were concerns that use of benzodiazepines might lead to delirium, brain dysfunction, increased ICU length of stay, and duration of mechanical ventilation. This led to the search for alternative sedation strategies. In 2007, the MENDS trial compared the effect of dexmedetomidine vs. lorazepam on delirium as a primary outcome.4 This study further evaluated the effects of these medications on mechanical ventilation, ICU length of stay, hospital length of stay, neurocognitive decline, and mortality. This study included 103 patients requiring sedation for invasive mechanical ventilation and showed that when compared with lorazepam, dexmedetomidine led to more coma- and delirium-free days (7 vs. 3 days, P = 0.01), driven primarily by coma-free days. Although not statistically significant, there were trends toward decreased duration of mechanical ventilation and 28-day mortality. There was a higher incidence of bradycardia and heavier reliance on fentanyl in the dexmedetomidine group compared with lorazepam. The median cost of care was noted to be $22,500 higher in the dexmedetomidine group. In showing improved outcomes with dexmedetomidine, this seminal study opened the door for further studies of alternatives to benzodiazepines for sedation.
Subsequently, many other trials evaluated the role of dexmedetomidine for sedation in the ICU. The SEDCOM study, published in 2009, was a prospective, double-blind, randomized controlled trial that enrolled 375 adults who were expected to require sedation for mechanical ventilation for at least 72 hours.5 Notable exclusion criteria included the use of neuromuscular blockade other than for induction for intubation, liver disease, cardiac dysfunction, and the need for two or more vasopressors. There was no difference in the primary outcome of time at the targeted sedation level between the dexmedetomidine group and the control group receiving midazolam. However, at similar levels of sedation, patients receiving dexmedetomidine had a lower prevalence of delirium (54% vs. 76.6%, P < 0.001) and decreased time to extubation (3.7 vs. 5.6 days, P = 0.01). Neither ICU length of stay nor 30-day mortality was statistically different between the two groups, but the dexmedetomidine group again had a higher rate of bradycardia (42.2% vs. 18.9%, P < 0.001) as well as hyperglycemia (56.6% vs. 42.6%,P = 0.02). Unexpectedly, the dex-medetomidine group also evidenced a lower risk of infection (10.2% vs. 19.7%, P = 0.02). This finding raised the question of whether dexmedetomidine might have a special role in patients with sepsis.
The MIDEX and PRODEX studies published in 2012 compared the ability of dexmedetomidine with midazolam and propofol, respectively, to reduce the duration of mechanical ventilation while maintaining sedation.6 Each study enrolled about 500 adult patients who were expected to need mechanical ventilation for at least 24 hours. In the MIDEX trial, the duration of mechanical ventilation for patients receiving dexmedetomidine was less than for those on midazolam (123 vs. 164 hours, P = 0.03). The median ICU and hospital lengths of stay were similar. However, patients on dexmedetomidine were better able to participate with nursing care.
In the PRODEX trial, the duration of mechanical ventilation was similar between the two groups, but the median time to extubation was less in the dexmedetomidine group (93 vs. 69 hours, P = 0.01). Patients receiving dexmedetomidine again were better able to participate with their care. Patients on dexmedetomidine had a higher prevalence of severe cardiovascular instability (5.8% vs. 3.2%, P = 0.02) compared with those who received propofol. The conclusions from these studies were that dexmedetomidine was noninferior to either midazolam or propofol for long-term sedation in the ICU and may enable patients to liberate from mechanical ventilation faster. They did not evaluate outcomes such as mortality.
Two more recent studies asked whether dexmedetomidine compared with usual care improved mortality in patients requiring sedation in the ICU. The DESIRE study, published in 2017, randomized 201 patients with sepsis and the need for sedation for mechanical ventilation to either dexmedetomidine or usual care consisting of either midazolam or propofol.7 While not reaching statistical significance, this study hinted at a trend toward decreased 28-day mortality (19% vs. 28%, P = 0.14) and more ventilator-free days (20 vs. 18 days, P = 0.2) in the dexmedetomidine group compared with usual care. The SPICE III investigators enrolled 4,000 patients in the ICU on mechanical ventilation requiring sedation to receive either dexmedetomidine or usual care.8 This study was powered with a 90% chance to detect a 4.5% change in 90-day mortality assuming a baseline 26% mortality rate. Despite the larger enrollment, no change in 90-day mortality was seen. Furthermore, there was no difference in several metrics of cognitive function. A one-day decrease in coma- or delirium-free days and a one-day increase in ventilator-free days was noted in the dexmedetomidine group. Of note, 1,235 of the 1,910 patients in the dexmedetomidine group also received propofol to achieve sedation targets, limiting interpretation of this study. There also was a dichotomy of outcomes when stratified by age, with younger patients benefiting more from usual care, while older patients did better with dexmedetomidine.
The most recent study to evaluate the effect of dexmedetomidine on ICU outcomes was the MENDS2 trial published in 2021.9 This was a multicenter, randomized, double-blind trial in 422 adults with sepsis and the need for mechanical ventilation. Patients were randomized 1:1 to dexmedetomidine or propofol, with the primary outcome being days alive without delirium or coma within the 14-day intervention period. Secondary outcomes included ventilator-free days within 28 days, mortality at 90 days, and cognitive status. This study did not demonstrate a difference in number of days alive without delirium or any of the secondary outcomes. Notably, there was substantial midazolam exposure in both the dexmedetomidine and propofol groups (53% and 43%, respectively) that likely blunted differences in outcomes between the two groups. In addition, 42% of each group received antipsychotics, showing additional medications were needed for sedation.
These studies together suggest that dexmedetomidine can be used for sedation in patients requiring invasive mechanical ventilation. Although no clear mortality benefit has been found consistently, some studies show a trend toward earlier extubation and decreased delirium or coma, with the most recent MENDS2 study being a notable exception. It should be stated that patients randomized to the dexmedetomidine arms in these trials often required additional sedatives, and in some studies, higher doses of narcotic pain medications to achieve equal levels of sedation.
Use of Dexmedetomidine in Patients with Sepsis Requiring Mechanical Ventilation
Since most sedatives lead to hypotension, there is concern about their use in the context of sepsis and vasopressor support. In fact, the SEDCOM trial excluded patients taking two or more vasopressors, but, interestingly, noted a lower rate of infection in patients receiving dexmedetomidine.5 In contrast, there were experimental data that dexmedetomidine might blunt inflammation in rat models of sepsis.10 This led to reevaluations of multiple studies focusing specifically on patients with sepsis who also required sedation and mechanical ventilation. A subgroup analysis of the MENDS study identified 63 patients with sepsis who had been randomized to either lorazepam or dexmedetomidine.11 While the original study showed statistically significant improvement in delirium- and coma-free days with dexmedetomidine, in septic patients, there also were improvements in mechanical ventilator-free days (15.2 vs. 10.1 days, P = 0.03) and 28-day mortality (165 vs. 41%, P = 0.03). Subgroup analysis of the SPICE III trial showed that less vasopressor was required to achieve target mean arterial pressure in patients receiving dexmedetomidine.12 A prespecified analysis of the DESIRE trial13 compared 201 septic patients receiving sedation for mechanical ventilation. While there was no change in mortality, there were statistically significant decreases in C-reactive peptide levels and procalcitonin in patients receiving dexmedetomidine compared with usual care. These studies confirm that dexmedetomidine is a safe sedative in patients with sepsis and further suggest that it may have anti-inflammatory effects.
Dexmedetomidine represents an alternative to propofol and benzodiazepines for sedation in patients requiring mechanical ventilation. Common side effects include bradycardia and hypotension; despite this, it appears safe in patients with sepsis. Compared with other common sedatives, dexmedetomidine may reduce delirium and may facilitate earlier extubation, but study results are notably mixed. (See Table 1.)
- Nguyen V, Tiemann D, Park E, Salehi A. Alpha-2 agonists. Anesthesiol Clin 2017;35:233-245.
- Keating GM. Dexmedetomidine: A review of its use for sedation in the intensive care setting. Drugs 2015;75:1119-1130.
- Jacobi J, Freaser GF, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119-141.
- Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechancially ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-2653.
- Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients. JAMA 2009;301:489-499.
- Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA 2012;307:1151-1160.
- Kawazoe Y, Miyamoto K, Morimoto T, et al. Effect of dexmedetomidine on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: A randomized clinical trial. JAMA 2017;317:1321-1328.
- Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-2517.
- Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis. N Engl J Med 2021;384:1424-36.
- Taniguchi T, Kidani Y, Kanakura H, et al. Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med 2004;32:1322-1326.
- Pandharipande PP, Sanders RD, Girard TD, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care 2010;14:R38.
- Cioccari L, Luethi N, Bailey M, et al. The effect of dexmedetomidine on vasopressor requirements in patients with septic shock: A subgroup analysis of the Sedation Practice in Intensive Care Evaluation [SPICE III] Trial. Crit Care 2020;24:441.
- Ohta Y, Miyamoto K, Kawazoe Y, et al. Effect of dexmedetomidine on inflammation in patients with sepsis requiring mechanical ventilation: A sub-analysis of a multicenter randomized clinical trial. Crit Care 2020;24:493.