By Betty Tran, MD, MSc

Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago

SYNOPSIS: In this post hoc analysis of the SPICE III trial, a greater percentage of patients receiving dexmedetomidine had temperatures greater than or equal to 38.3ºC and 39.0ºC compared to usual care. Although there was a significant dose response relationship between dexmedetomidine received and increase in temperature, there was no difference between groups in terms of paracetamol, antimicrobial, neuromuscular blocker, neuroleptic drug use, blood cultures performed, or initiation of renal replacement therapy.

SOURCE: Grayson KE, Bailey M, Balachandran M, et al. The effect of early sedation with dexmedetomidine on body temperature in critically ill patients. Crit Care Med 2021;49:1118-1128.

This was a post hoc analysis of the Sedation Practice in Intensive Care Evaluation (SPICE) III trial, which enrolled 4,000 mechanically ventilated patients in eight countries to receive solely dexmedetomidine or usual care (propofol, midazolam, or other sedatives).1 Patients enrolled in SPICE III were expected to remain on ventilator support beyond the calendar day following randomization, were enrolled within 12 hours of intubation, and required immediate sedatives for comfort and safety; notably, primary brain or spinal cord injury patients were excluded. Randomization was 1:1 and stratified by center and according to the presence/absence of sepsis. Sedation was targeted to a Richmond Agitation Sedation Score (RASS) of -2 (light sedation) to +1 (restless). If target sedation was not achieved with maximum dose dexmedetomidine, propofol was added at the lowest dose to reach the RASS goal. All sedatives were administered open label.

For this study, only 708 patients (17.7%) from four intensive care units (ICUs) contributed data for analysis (50.1% randomized to dexmedetomidine). The primary outcome was mean body temperature from randomization to day 5, ICU discharge, or death (temperature was measured every six hours). Secondary outcomes were measured within the same time frame and included highest daily body temperature and percentage of patients in each group with mild (> 38.3ºC) and severe (> 39ºC) body temperature elevations. Data were collected on the use of paracetamol, intravenous (IV) antibiotics, neuromuscular blockers, neuroleptic drugs, renal replacement therapy, and blood cultures drawn. A priori subgroups to evaluate for effect modification included below/above the median age of 63.7 years in SPICE III, presence/absence of sepsis, and weight less/more than 120 kg.

Mean daily temperature was not significantly different between the dexmedetomidine and usual care groups (absolute difference, 0.06ºC; 95% confidence interval [CI], -0.03ºC to 0.15ºC; P = 0.16). However, more patients receiving dexmedetomidine vs. usual care recorded a mild temperature elevation > 38.3ºC (absolute difference, 10.6%; 95% CI, 3.5-17.8%; P = 0.004) and severe temperature elevation > 39ºC (absolute difference, 6.9%; 95% CI, 1.5-12.3%; P = 0.013). These between-group differences equate to a number needed to harm (NNH) to cause a temperature > 38.3ºC and > 39ºC of 9.4 and 14.5, respectively.

When dexmedetomidine usage was analyzed as a continuous variable, for every additional 1 µg/kg/hour, temperature increased by 0.30ºC + 0.08ºC (P < 0.0002). The daily and total doses of paracetamol, number of antibiotic days, use of neuromuscular blockers and neuroleptic agents, number of blood cultures collected, and use renal replacement therapy were similar between groups. Patients receiving dexmedetomidine who were greater than 120 kg were more likely to have elevated temperatures compared to patients with lower body weight (P = 0.02), despite the dose calculation being capped at 100 kg. There was no significant heterogeneity of dexmedetomidine effect in the other subgroups of age and sepsis.

COMMENTARY

Dexmedetomidine has generated recent interest as a primary sedative in the ICU, given its ability to induce sedation while maintaining respiratory drive and some arousability. Its potential benefits include a reduction in ICU length of stay, delirium, duration of mechanical ventilation, and, possibly, mortality.2-5 Commonly reported side effects include bradycardia and hypotension. There are case series documenting hyperthermia, some of which have required other interventions, such as dantrolene and initiation of renal replacement therapy, as usual cooling methods were ineffective.6,7

Although this study did report that a greater percentage of patients had elevations in temperature associated with dexmedetomidine, this was not the primary outcome. In addition, although this was the first randomized controlled data reporting an association between dexmedetomidine and temperature elevation, it was a post hoc analysis, and as such, all differences between the two groups studied should not be considered definitive given underlying multiple statistical comparisons.

Nevertheless, the results do support the observation that hyperthermia can be a side effect of dexmedetomidine, which was reported in prior case series. However, whether this side effect results in significant untoward complications is unclear. There was no increase in the number of blood cultures performed or number of days of antibiotic and/or paracetamol use in patients assigned to dexmedetomidine. However, given that this was an open-label trial, it is possible that clinicians were aware that dexmedetomidine may be responsible for the temperature elevations observed. Indeed, this study highlights an important take-home message for the ICU practitioner: In patients receiving mechanical ventilation, dexmedetomidine should be considered as a potential cause of unexplained temperature elevations.

REFERENCES

  1. Shehabi Y, Howe BD, Bellomo R, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med 2019;380:2506-2517.
  2. Constantin JM, Momon A, Mantz J, et al. Efficacy and safety of sedation with dexmedetomidine in critical care patients: A meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med 2016;35:7-15.
  3. Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients. A randomized trial. JAMA 2009;301:489-499.
  4. Jakob SM, Ruokonen E, Grounds M, et al. Dexmedetomidine vs midazolam or propofol for sedation during mechanical ventilation. Two randomized controlled trials. JAMA 2012;307:1151-1160.
  5. 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.
  6. Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidine-associated hyperthermia: A series of 9 cases and a review of the literature. Anesth Analg 2017;125:1898-1906.
  7. Grayson K, Tobin AE, Lim TK, et al. Dexmedetomidine-associated hyperthermia: A retrospective cohort study of intensive care unit admissions between 2009 and 2016. Anaesth Intensive Care 2017;45:727-736.