Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Dexmedetomidine-associated hyperthermia : A series of 9 cases and a review of the literature Kurmann, Judith Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-160040 Dissertation Published Version Originally published at: Kurmann, Judith. Dexmedetomidine-associated hyperthermia : A series of 9 cases and a review of the literature. 2018, University of Zurich, Faculty of Medicine. Anesthetic Clinical Pharmacology Anesthetic Clinical Pharmacology Section Editor: Ken B. Johnson Preclinical Pharmacology Section Editor: Markus W. Hollmann E BRIEF REPORT Dexmedetomidine-Associated Hyperthermia: A Series of 9 Cases and a Review of the Literature Bernard D. Krüger, MD,* Judith Kurmann, MM,* Natascia Corti, MD,† Donat R. Spahn, MD,* Dominique Bettex, MD,* and Alain Rudiger, MD* Dexmedetomidine, an α2-adrenergic agonist, can be used to perform mild to moderate sedation in critically ill patients. In this case series, 9 cardiovascular intensive care unit patients with hyperthermia during dexmedetomidine administration, suggestive of drug fever, are presented. Hyperthermia (>38.5°C) occurred 6 (4–10) hours (median [interquartile range]) after dexme- detomidine initiation at a dose of 1.0 (0.8–1.3) μg/kg/h and was resolved 3 (1–8) hours after discontinuation of dexmedetomidine. All patients were screened for infectious and noninfec- tious causes of hyperthermia, and the findings were analyzed by 2 adverse drug reaction (ADR) assessment methods—the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) Causality Assessment and the Naranjo ADR scale. This resulted in a “probable” ADR in all 9 patients (WHO) and a “probable” and “possible” ADR in 1 and 8 patients (Naranjo), respec- tively. This case series supports published case reports, suggesting that dexmedetomidine administration may be associated with the occurrence of clinically relevant hyperthermia. The underlying mechanisms and risk factors are uncertain and require further research. (Anesth Analg 2017;125:1898–906) ever in critically ill patients may have various etiologies. dexmedetomidine administration. Our goal is to increase It usually triggers a multimodal diagnostic workup.1 awareness and stimulate further research on this topic. FInfectious disease should primarily be ruled out to pre- clude possible evolution to sepsis, multiple organ dysfunction, METHODS and eventual death.2 However, any empirical antibiotic therapy Data collection from the electronic patient information and other interventions triggered by hyperthermia may poten- system was approved by the Institutional Review Board tially be harmful, if unjustified.1 This is particularly true when (Kantonale Ethikkommission Zurich, BASEC-ID: PB_2016- 00333) and the need for informed consent waived. Statistics an elevated body temperature is actually drug-induced.3,4 are descriptive, and results are given as median (inter- Dexmedetomidine is a highly selective α2-adrenergic quartile range) or numbers (percentage). Of 1918 patients, agonist used to perform mild to moderate sedation in criti- admitted to our ICU during 2013 and 2014 after cardiac or 5 cally ill patients. Febrile episodes have been attributed to major vascular surgery, 200 (10.4%) patients were treated dexmedetomidine administration in several case reports.6–11 with dexmedetomidine. Nine (4.5%) of these patients were Here, we present 9 patients in a cardiovascular intensive care selected for this case series (convenience sample) because of unit (ICU) with the onset of hyperthermia >38.5°C during the occurrence of hyperthermia >38.5°C during dexmedeto- midine administration. In our ICU, dexmedetomidine is used for long-term From the *Intensive Care Unit for Cardiovascular Surgery, Institute of sedation, during weaning from mechanical ventilation, Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland; and †Unit of General Internal Medicine, Hirslanden and for the treatment of hyperactive delirium. It is usu- Clinic, Zurich, Switzerland. ally started at a dose of 0.7–1.0 μg/kg/h and titrated up to Accepted for publication June 9, 2017. 1.4 μg/kg/h, according to clinical needs.5 Dexmedetomidine Funding: None. is discontinued if (1) continuous sedation can be omitted or Conflicts of Interest: See Disclosures at the end of the article. delirium has improved, (2) hemodynamic instability occurs Supplemental digital content is available for this article. Direct URL citations (norepinephrine >0.3 μg/kg/min, atrioventricular block ≥II°, appear in the printed text and are provided in the HTML and PDF versions of or bradycardia <55 bpm in the absence of a pacemaker), or (3) this article on the journal’s website (www.anesthesia-analgesia.org). drug fever is suspected. In our ICU, microbiological sampling B. D. Krüger and J. Kurmann are equally contributing first authors. is usually triggered by a rise of the body temperature >38.5°C. D. Bettex and A. Rudiger are equally contributing last authors. An empirical antibiotic therapy is subsequently started if an All investigators met all 4 criteria for authorship according to the recommen- dations of the International Committee of Medical Journal Editors (ICMJE). infection is suspected or if organ functions deteriorate. Reprints will not be available from the authors. All patients were screened for potential infectious and non- 1 Address correspondence to Alain Rudiger, MD, Cardio-surgical Intensive infectious causes of hyperthermia. The association between Care Unit, Institute of Anaesthesiology, University of Zurich and University dexmedetomidine and hyperthermia was assessed by 2 differ- Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. Address e-mail to [email protected]. ent ADR algorithms: The World Health Organization-Uppsala Copyright © 2017 International Anesthesia Research Society Monitoring Centre (WHO-UMC) Causality Assessment DOI: 10.1213/ANE.0000000000002353 and the Naranjo ADR scale. A causality assessment by the 1898 www.anesthesia-analgesia.org December 2017 • Volume 125 • Number 6 Copyright © 2017 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Dexmedetomidine-Associated Hyperthermia WHO-UMC criteria is accomplished by comparison of the hyperthermia was found exclusively for dexmedetomidine drug-effect relationship in question with a table of predefined in all patients. The likelihood of an ADR was categorized by statements and yields the following categorization: unclas- the WHO-UMC criteria as “probable” in all patients and by sifiable, unclassified, unlikely, possible, probable, and cer- the Naranjo ADR scale as “probable” in 1 patient (patient 3) tain (http://www.whoumc.org/Graphics/26649.pdf). The and “possible” in 8 patients (Table 1). Naranjo ADR scale is a questionnaire-based scoring system Individual case descriptions, a table summarizing all (0 to ≥9 points), grading a drug-effect relationship into the drugs given prior to or during dexmedetomidine expo- following categories: doubtful (0), possible (1–4), probable sure, and the Naranjo questionnaire scores are provided in (5–8), and definite (≥9).12 Two ADR assessment methods were Supplemental Digital Content 1–3, Material 1, http://links. applied because the level of causality has been reported to dif- lww.com/AA/B942, Table 1, http://links.lww.com/AA/ fer between different pharmacovigilance algorithms.13,14 B943, and Table 2, http://links.lww.com/AA/B944. RESULTS DISCUSSION Nine patients (age 67 [64–72] years, 5 [56%] male) under con- In this case series, we present 9 (4.5%) patients with clini- sideration underwent cardiac surgery (n = 8) or major vas- cally relevant hyperthermia of 200 patients with exposure cular surgery (n = 1). Cardiac surgery was performed with to dexmedetomidine during a 2-year period in our ICU. cardiopulmonary bypass in 7 (78%) patients. Table 1 indi- The observed drug-effect relationship is highly suggestive cates the patients’ characteristics, details of dexmedetomi- of drug fever.3 Because our 9 patients represent a conve- dine administration, and the occurrence of hyperthermia. nience sample, the true incidence of dexmedetomidine- Dexmedetomidine was initiated on postoperative day 1 (1–4) associated hyperthermia in our ICU cannot be determined for the treatment of delirium in 2 patients (patients 4 and with certainty. However, in 2 multicenter, randomized 6) and for sedation in 7 patients. The commencement dose trials involving ventilated ICU patients, pyrexia has been was 1.0 (0.6–1.0) μg/kg/h. Hyperthermia was detected after reported as an adverse drug event in the dexmedetomi- 6 (4–10) hours at a dexmedetomidine dose of 1.0 (0.8–1.3) dine group in 16 of 247 (6.5%) patients (MIDEX trial) and μg/kg/h. The maximum body temperature of 39.0°C (38.8– in 13 of 246 (5.3%) patients (PRODEX trial).15 The Swiss 39.2°C) was observed after 11 (6–29) hours at a dexmedeto- Drug Compendium reports an incidence of between 1% midine dose of 1.0 (0.8–1.0) μg/kg/h. Hyperthermia was and 10% of treated patients, without providing further present during 34 (12–38) hours, while dexmedetomidine details or references (https://compendium.ch/mpro/ was administered during 26 (9–35) hours. In no patient did mnr/23800/html/de). the administration of acetaminophen and/or metamizole Our results are supported by several case reports that or