Record Setting Temperatures in the Setting of SARS-CoV-2 Suggests Dexmedetomidine Drug-Induced Fever: A Case Report

Abstract

Patients infected with COVID-19 can develop coinfections or acute respiratory disorder that result in ventilation. Dexmedetomidine is a common medication used to sedate ventilated patients in the intensive care unit and for nonintubated patients prior to a surgical procedure. As a highly selective alpha-2 agonist, dexmedetomidine provides sedation while reducing the need for anxiolytics or opioids. However, previous case reports suggest dexmedetomidine can induce fever in a variety of conditions. The purpose of this case report is to describe a patient who acquired a fever of 42.6°C in the setting of COVID-19 after administration of dexmedetomidine.

Introduction

Dexmedetomidine (Precedex) has been Food and Drug Administration (FDA) approved since 1999. ¹ It is a highly selective alpha₂-adrenergic agonist and approximately 8 times more selective compared to clonidine.^1,2 It is commonly used as a sedative for ventilated patients in intensive care units (ICUs) due to its reduction in mechanical ventilation duration and ICU length of stay compared to traditional sedatives such as propofol and benzodiazepines. In addition, dexmedetomidine may be used for nonintubated patients prior to surgical procedures. The elimination half-life of dexmedetomidine in adults is 3 hours. Common side effects include hypotension, hypertension, nausea, bradycardia, atrial fibrillation, hypoxia, and less commonly hyperthermia or fever.^1,2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus discovered in 2019. ¹ Coronaviruses are enveloped positive-stranded RNA viruses. ³ COVID-19 is the disease resulting from SARS-CoV-2. Signs and symptoms of COVID-19 include fever, cough, shortness of breath, fatigue, myalgia, headache, loss of taste or smell, congestion, nausea, vomiting, and diarrhea. Risk factors related to negative outcomes of COVID-19 include age, asthma, cancer, chronic kidney disease, chronic obstructive pulmonary disease (COPD), liver diseases, diabetes mellitus, hypertension, heart failure, primary immunodeficiencies, smoking, and a body mass index (BMI) >30 kg/m². Patients infected with COVID-19 may develop coinfections or acute respiratory disorders as well. ³ Patients in critical condition with these conditions may require sedatives, such as dexmedetomidine, for intubation. ¹

Although fever is both a common symptom in patients with COVID-19 and also a potential side effect of dexmedetomidine, a temperature of 42.6°C is significantly higher than what would be expected in a 51-year-old COVID positive male with multiple COVID-19 risk factors after an increase in dexmedetomidine’s administration rate. This case report aims to understand dexmedetomidine’s common and rare adverse effects, as well as its role as an adjunct therapy in the management of SARS-CoV-2. In addition, this case report will investigate if dexmedetomidine contributes to a SARS-CoV-2 patient’s drug-induced fever.

Case Report

A 51-year-old male known to be COVID-19 positive confirmed by polymerase chain reaction (PCR) testing presents to the emergency department with headache, chest pain, and worsening shortness of breath. His past medical history includes hypertension, type II diabetes mellitus, and overweight (BMI = 29.5 kg/m²). Patient is intubated in the emergency department secondary to respiratory failure. Initial sedatives used for intubation include fentanyl, propofol, and etomidate. Patient experiences initial fever of 37.8°C due to COVID-19 infection. He starts a 5-day course of ceftriaxone/azithromycin and completes 3 days prior to return of fever.

Sedation medications over the course of his admission include etomidate, propofol, and dexmedetomidine. On the 13th day of intubation, dexmedetomidine is titrated to a maximum dose of 1.5 mcg/kg/h at a rate of 37.65 mL/h (see Figure 1). Nearly 1 day later, the patient becomes febrile at 38.4°C (see Figure 2). Cefepime/vancomycin is started the same day. Urine antigens negative for Streptococcus and Legionella, whereas respiratory cultures 1 day later indicate light growth of Pseudomonas putida with rare polymorphonuclear neutrophils (PMNs). Procalcitonin levels continue to downtrend.

Figure 1.

Dexmedetomidine day 1.

Figure 2.

Dexmedetomidine day 2.

Five hours following fever onset, the patient reaches a maximum temperature of 42.6°C (see Figure 3). Dexmedetomidine is discontinued on April 4, 2020 6:59 p.m. (see Figure 3). Following discontinuation, the patient’s temperature begins to decline and returns to baseline 9 hours later (see Figure 3). The patient’s temperature remains stable between 36.7 and 38.7°C during the remainder of hospitalization and controlled with acetaminophen. External cooling continued until 4 days after the fever spike.

Figure 3.

Dexmedetomidine day 2 continued.

Discussion and Conclusions

Given the novelty of COVID-19, the number of existing case reports regarding dexmedetomidine in the setting of COVID-19 is limited. To further support the findings of this case, a PubMed search using keywords “dexmedetomidine,” “fever,” and “case report” resulted in 6 relevant case studies. These case studies suggest dexmedetomidine can induce fever in patients with a variety of conditions including COVID-19.

Okabe et al ⁴ is the first to illustrate dexmedetomidine-induced fever in a postoperative setting. Another case report by Kressin et al ⁵ addresses a critically ill 31-year-old patient with hyperthermia. The patient with history of morbid obesity is admitted to the ICU for acute hypoxic respiratory failure requiring ventilation. Fifteen hours following initial dexmedetomidine administration, the patient’s temperature rises to 41.4°C. Once discontinued patient’s temperature decreases and plateaus at 37.5°C. ⁵ Another case of dexmedetomidine-associated fever is noted in a report of a 54-year-old admitted to hospital for surgical resection of thymic squamous cell carcinoma. ⁶ At 18 hours postoperation, dexmedetomidine is initiated. By 23 hours postoperation, the patient is febrile, and at 24 hours postoperation, patient reaches a maximum temperature of 39.1°C. Noting a lack of infectious sources contributing to fever, dexmedetomidine was tapered over the course of 12 hours, and by 41 hours postoperation, the patient is afebrile. ⁶ In addition, Straw et al ⁷ case report records a 39.2°C fever and delirium after dexmedetomidine administration. Moreover, Kruger et al ⁸ shows 9 adult patients experiencing fever with a maximum temperature of 39°C after 11 hours of dexmedetomidine administration.

In addition to these previous case reports, we describe an unprecedented fever after dexmedetomidine administration in the setting of COVID-19, which has only been reported in one other 2020 case report that notes 3 patients hospitalized for COVID-19. The first patient (patient 1) discussed in case report is 60-year-old female with type 2 diabetes, latent tuberculosis, hypertension, cerebrovascular accident, hypothyroidism, and class II obesity. The second patient (patient 2) is a 43-year-old female with hypertension, hyperlipidemia, reactive airway disease, and class I obesity. The final patient (patient 3) is a 46-year-old male with type 2 diabetes and hyperlipidemia. The first patient’s dexmedetomidine is titrated to a dose of 1.5 mcg/kg/h, whereas the second and third patient is titrated to a dose of 2 mcg/kg/h. Our patient is similar in age and comorbidities to this previous case report; however, our patient was titrated to a dose of 1.5 mcg/kg/h. Patients 2 and 3 in previous case report did not reach a maximum temperature until 2 mcg/kg/h of dexmedetomidine. Each of the 3 patients became febrile after titration of dexmedetomidine resulting in a maximum temperature of 42.4°C. ⁹ Per a PubMed search, no other case reports have been published.

Another PubMed search using keywords “SARS-CoV-2” and “fever” did not indicate a maximum temperature in SARS-CoV-2, but did show a higher mortality associated with a fever greater than 40°C. ⁹ This showcases that fever and degree of inflammation in COVID-19 patients can predict risk of mortality. ¹⁰

The patient in our case report develops a fever after dexmedetomidine initiation in the setting of COVID-19. Patient has risk factors such as type 2 diabetes mellitus, hypertension, and a BMI classified as overweight, all of which indicate worse outcomes for a COVID-19 patient. ³ Patient did have an initial fever due to COVID-19 infection, but was treated with a 5-day course of ceftriaxone/azithromycin completed 3 days prior to return of fever. He receives dexmedetomidine for 25 hours before acquiring a fever. After nearly 28 hours of dexmedetomidine administration, patient’s fever reaches 42.6°C. Owing to the novelty and severity of COVID-19 at the time of patient’s hospital admission, it is likely that the potential for extreme fevers were not considered prior to initiating dexmedetomidine. In addition, patient’s down trending procalcitonin and negative urinary antigens argue against a coinfection inducing the fever. Upon documentation of record fevers, dexmedetomidine is discontinued. Patient’s temperature returns to baseline 9 hours or 3 half-lives following discontinuation resulting in approximately 87.5% of dexmedetomidine eliminated. It is acknowledged that ventilator-associated pneumonia (VAP) is diagnosed and treated with cefepime for 9 days just 2 days following patient’s temperature spike and 1 day following temperature returning to baseline.

Dexmedetomidine has been used in medical practice since the 1990s; however, SARS-CoV-2 is a novel virus and knowledge surrounding dexmedetomidine use in the setting of SARS-CoV-2 is limited. The unprecedented temperature reached after the administration of dexmedetomidine reveals the potential risks of using dexmedetomidine in the setting of COVID-19. With the potential eradication of SARS-CoV-2 unknown, medical professionals should be educated on the risks and consider alternative sedatives.