By Vibhu Sharma, MD

Associate Professor of Medicine, University of Colorado, Denver

SYNOPSIS: The MENDS2 trial found that dexmedetomidine, when used for light sedation, had outcomes similar to those for propofol.

SOURCE: Hughes CG, Mailloux PT, Devlin JW, et al.; MENDS2 Study Investigators. Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis. N Engl J Med 2021;384:1424-1436.

The MENDS2 (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study randomized mechanically ventilated adults with sepsis to dexmedetomidine or propofol, targeting a Richmond Agitation-Sedation Scale (RASS) of 0 to -2 (i.e., light sedation or the ability to open eyes to verbal stimulation). Groups were assigned in a 1:1 ratio using computer-generated blocks stratified by age and enrollment site. All caregivers (clinicians and bedside nurses) were blinded to the study group assignment. The actual range achieved in each group was a RASS of -3 to -1. The dexmedetomidine dose administered ranged from 0.2 mcg to 1.5 mcg per kilogram body weight per hour and propofol was administered at 5 mcg to 50 mcg per kilogram per minute. Sedation was titrated at 30-minute intervals to a target RASS, and sedation was stopped for daily spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) or in the event bradycardia or hypotension developed. There was rigorous adherence to the Society of Critical Care Medicine (SCCM) intensive care unit (ICU) liberation bundle in both groups. 

Approximately one-third of patients were admitted to a surgical ICU; the rest were admitted to a medical ICU. All were mechanically ventilated and needed continuous sedation. Major exclusion criteria included: baseline cognitive dysfunction, a moribund state, conditions considered contraindications to the use of dexmedetomidine (e.g., bradycardia requiring intervention or second-/third-degree heart block), requirement for neuromuscular blockade, allergies to either medication, or indications for benzodiazepines. Of 432 patients recruited, 422 were randomized: 214 to dexmedetomidine and 208 to propofol. Approximately half of the patients in each group had vasopressor-dependent shock. Median doses of medications administered were 0.27 mcg per kilogram of body weight per hour of dexmedetomidine and 10.2 mcg per kilogram per minute of propofol. The mean duration of use of either sedative was three days. For the purposes of the study, the authors requested and received Food and Drug Administration (FDA) approval for an investigational new drug application for dexmedetomidine administered for more than 24 hours and for doses up to 1.5 mcg per kilogram per hour.

The primary study end point was days alive without delirium or coma during the intervention periods of 14 days. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU) bedside tool when the patient was maximally awake at the end of a daily awakening and spontaneous breathing trial. Pain was measured using the Critical Care Pain Observation Tool and was treated using either bolus opioid dosing or a continuous fentanyl infusion. Secondary end points included: death at 90 days, ventilator-free days at 28 days, and global cognition using the age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire total (TICS-T) at six months. The latter is a validated score that enables assessment of cognition over the phone with scores ranging from 0 to 100, with lower scores indicating worse cognition.

Overall, the trial found no difference between the groups in terms of the primary end point of number of days alive without delirium or coma over the 14-day intervention period. In addition, there were no differences in ventilator-free days at 28 days, death at 90 days, or global cognition at six months between the dexmedetomidine and propofol groups. Safety end points were similar in the two groups.

COMMENTARY

Dexmedetomidine has been shown to be superior to lorazepam infusion with respect to the incidence of delirium and coma among mechanically ventilated critically ill patients.1 Prior to this randomized trial, propofol had not been compared directly to dexmedetomidine exclusively in patients with suspected or documented infection who were mechanically ventilated. This trial failed to demonstrate any differences in primary or secondary outcomes between propofol and dexmedetomidine, suggesting that either drug may be used to target light sedation when used in addition to rigorous adherence to the SCCM ICU liberation bundle. Most importantly, there was no difference in the incidence of delirium in the hospital or the incidence of cognitive dysfunction at long-term follow-up with the use of either drug.

There are some practical aspects that deserve to be mentioned. Bradycardia was more common in the dexmedetomidine group (26%) compared with the propofol group (6%). Compared to propofol, dexmedetomidine was associated with more temporary infusion interruption due to bradycardia (2% vs. 12%, respectively) and hypotension (15% vs. 21%, respectively). In contrast, oversedation was a more common reason for a temporary hold on infusion with propofol (20%) compared with dexmedetomidine (14%).

In patients with shock admitted to the intensive care unit, the hemodynamic effect of sedation is an important consideration for clinicians. The study authors did not delineate the proportion of patients with moderate to severely reduced cardiac dysfunction in either group. For that subpopulation, the effects of bradycardia and hypotension induced by dexmedetomidine may be exaggerated. Among patients without septic shock, a small study showed that both propofol and dexmedetomidine have similar frequencies for negative hemodynamic effects; however, propofol was associated with a greater degree of hypotension when it did occur.2 In this study, only a small number of patients had heart failure. Findings were similar in those with septic shock.3 Another study assessed the incidence of severe hemodynamic derangements while using propofol and dexmedetomidine infusions in a neurocritical care population and found severe hypotension and bradycardia occurred at similar frequencies.4

In the aggregate, it appears that there are no relevant differences with respect to the primary end points of delirium- and coma-free days between the two drugs when used for light sedation. Caution may be warranted with dexmedetomidine in the face of bradycardia. 

REFERENCES

  1. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-2653.
  2. Benken S, Madrzyk E, Chen D, et al. Hemodynamic effects of propofol and dexmedetomidine in septic patients without shock. Ann Pharmacother 2020;54:533-540.
  3. Nelson KM, Patel GP, Hammond DA. Effects from continuous infusions of dexmedetomidine and propofol on hemodynamic stability in critically ill adult patients with septic shock. J Intensive Care Med 2020;35:875-880.
  4. Erdman MJ, Doepker BA, Gerlach AT, et al. A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. Crit Care Med 2014;42:1696-1702.