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Abstract

Introduction: Previous literature showed an association between hyperthermia and dexmedetomidine (DEX) use for ongoing sedation in non-obese patients. The purpose of this study is to evaluate DEX’s effect on temperature in obese critically ill patients. Methods: This single center, retrospective, cohort study included patients ≥18 years, admitted to a surgical or medical ICU, received DEX for ≥8 hours as a single continuous infusion sedative, and weighed ≥120% of ideal body weight. Patients were excluded if they had a fever (≥38°C) and positive cultures within 48 hours of DEX initiation. The primary endpoint was a fever (Tmax of ≥38°C) within 48 hours of DEX initiation. Results: A total of 186 patients were included for evaluation. Forty-two patients (22.5%) had a fever during the first 48 hours of DEX initiation. Median weight was not different between the febrile and afebrile groups (99.4 [90.6-122.4] vs 97.6 [81.6-114.2] kg, P = .6). Median change from baseline temperature for all patients within 48 hours was an increase of .5 (.1-.8) °C, P < .001. In multiple regression analysis, duration of DEX and baseline temperature were the only significant predictors of fever development with an adjusted odds ratio of 1.041 (95% CI 1.009-1.074, P = .012) and 7.058 (95% CI 3.307-15.064, P < .001), respectively. Conclusions: This study suggests that there is a significant increase in body temperature from baseline for obese patients on DEX. Duration of DEX and baseline temperature were found to be risk factors for fever development in this population. Further studies are warranted.

Keywords

dexmedetomidine drug dosing critical care obesity temperature fever hyperthermia

Introduction

Drug-induced fever is a reaction that results after drug administration; fever abates upon discontinuation of the offending drug establishing a cause and effect relationship between a drug and fever.¹ Drug-induced fever is a condition that is frequently misdiagnosed.^1,2 Misdiagnosis of drug-induced fever can lead to overutilization of antimicrobial agents due to suspected infection and antipyretic agents which can lead to antibiotic resistance and adverse effects.² Terms such as hyperthermia, pyrexia, and fever are often used interchangeably. Hyperthermia is defined as an elevation in body temperature that occurs without an increase in the hypothalamic set point, such as in response to specific environmental, pharmacologic, or endocrine stimuli. On the other hand, pyrexia and fever refer to the increase in body temperature that occurs in response to a vast list of infectious and noninfectious etiologies in association with an increase in the hypothalamic set point.³

Dexmedetomidine, a commonly utilized sedative in critically ill patients, is a dose-dependent, centrally acting alpha-2 adrenergic receptor agonist, with sedative and analgesic properties. Common adverse events associated with dexmedetomidine use are hypotension and bradycardia which are related to the alpha-2 adrenergic receptor agonism.⁴ The alpha-2 adrenergic receptor has 3 subtypes: alpha-2A, alpha-2B, and alpha-2C. Alpha-2A adrenergic receptor activation is associated with thermoregulation, potentially leading to drug-induced fever.^5,6 Polymorphisms of the alpha-2A adrenergic receptors may be a factor for the varying degrees of hyperthermia that develop.⁶

In the Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation (MIDEX and PRODEX) trial, the incidence of hyperthermia was not statistically significant at 45-day follow-up when comparing dexmedetomidine to midazolam (3.2% vs .8%; P = .062).⁷ Similarly, the incidence of hyperthermia was .8% with dexmedetomidine compared to 0% with propofol at 45-day follow-up.⁷ Of note, this trial did not report incidences of hyperthermia shortly after the initiation of the sedative agents. Recent case series, case reports, and a post hoc analysis have all suggested a link between dexmedetomidine use and hyperthermia.^5,6,8-13 A post hoc analysis of the patients included in the Sedation Practice in Intensive Care Evaluation (SPICE) III study showed that over the first 5 ICU days more patients had a temperature greater than or equal to 38.3°C in the dexmedetomidine group compared to the usual care group (43.3% vs 32.7%; P = .004).^9,14 There was no difference found in the mean daily temperature between the dexmedetomidine group vs the usual care group (36.84°C vs 36.78°C; P = .16); however, this study found a significant difference in the highest daily temperature between the dexmedetomidine group and the usual care group (37.41°C vs 37.29°C; P = .01). In a subgroup analysis, this study found that patients >120 kg were more likely to experience a higher mean daily temperature compared with patients with a lower body weight (37.16°C vs 36.82°C; P = .02). Therefore, the purpose of this study was to evaluate dexmedetomidine’s effect on body temperature and describe risk factors that contribute to an elevated temperature in obese critically ill patients requiring sedation.

Materials and Methods

A single center, retrospective, post hoc analysis was conducted using body temperature data collected from participants from our previously published study evaluating dexmedetomidine dosing in obese critically ill patients for ongoing ICU sedation.¹⁵ Patients were identified through the information warehouse by running a report for all patients who received dexmedetomidine within the study timeframe. Records were analyzed until the pre-specified sample size was achieved for our previous study.¹⁵ All potential patients for screening during the study timeframe were randomized and then screened until the total desired sample size was attained. All patients were initiated, per protocol, on a dexmedetomidine infusion at an initial rate of .2-.4 mcg/kg/hr and titrated by .1-.2 mcg/kg/hr increments no more frequently than every 30 minutes to achieve a goal RASS of 1 to -1.¹⁶ Study data were collected and managed using the Research Electronic Data Capture (REDCap) electronic data capture tools hosted at The Ohio State University Wexner Medical Center.^17-19 REDCap is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources. This publication was supported by Award Number Grant UL1TR002733 from the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Patients were included if they were ≥18 years of age, admitted to the surgical ICU (SICU) or medical ICU (MICU), required dexmedetomidine for at least 8 hours as a single continuous infusion sedative, and weighed ≥120% of IBW (IBW [males] = 50 kg + 2.3 * kg for every inch over 5 feet; IBW [females] = 45.5 kg + 2.3 * kg for each inch over 5 feet). Propofol and/or fentanyl and dexmedetomidine were allowed to be overlapped for no more than 8 hours. However, data collection was started after propofol and/or fentanyl were discontinued. All other continuous infusion sedatives and analgesics must have been discontinued prior to starting dexmedetomidine to be included. Patients were excluded if they were pregnant, incarcerated, admitted for a neurologic condition (eg, moderate to severe traumatic brain injury, ischemic or hemorrhagic stroke, status epilepticus, or management of elevated intracranial pressure), being treated for alcohol withdrawal, or had a fever (≥38°C) and positive cultures within 48 hours after dexmedetomidine initiation (Figure 1).

Figure 1.

Patient enrollment and treatment flow. Abbreviation: IBW, ideal body weight; AWS, alcohol withdrawal syndrome.

The primary outcome was the percent of patients with a maximum temperature (Tmax) 38°C or greater within 48 hours of dexmedetomidine initiation. A temperature cut off of 38°C or greater was chosen as that is threshold that our institution uses for a fever workup. The secondary outcome was change from baseline temperature to Tmax at 24 hours in the febrile vs afebrile group. Additional data points collected were median dexmedetomidine dose, median maximum dexmedetomidine dose, duration of dexmedetomidine, temperature prior to dexmedetomidine initiation, Tmax within 24 hours of dexmedetomidine initiation, and Tmax at hours 24-48 after dexmedetomidine initiation. All data points were assessed for the first 48 hours, until time of dexmedetomidine discontinuation, or until the addition of a supplementary continuous infusion sedative and/or analgesic agent, whichever occurred first. Per institutional policy, temperature assessments should be completed at least every 4 hours while in the ICU.

All pertinent variables to assess the primary and secondary outcomes were collected in addition to the following variables: patient demographics (collected at admission), body mass index (BMI = weight [kg]/height² [m²]), Acute Physiology and Chronic Health Evaluation II (APACHE II) score at hospital admission, mechanical ventilation at time of dexmedetomidine initiation, receiving antibiotics prior to dexmedetomidine initiation (patients receiving one dose of antibiotics for surgical prophylaxis were not included), received non-steroidal anti-inflammatory drugs (NSAIDs) and/or acetaminophen within 48 hours after dexmedetomidine initiation, on continuous renal replacement therapy, and required surgical intervention 24 hours preceding or following dexmedetomidine initiation.

Continuous parametric data are presented as a mean (± standard deviation) and analyzed using Student’s t-test. Continuous nonparametric data are presented as median (25-75% interquartile range) and were analyzed using Mann-Whitney U-test. Nominal data are presented as frequency and percentages and were analyzed using the Fisher’s exact test or Chi-square test as appropriate. Following univariate analyses of patients with and without fever, multivariable logistic regression was conducted to determine factors independently associated with development of fever. Risk factors significant at the P-value < .20 level in the univariate analysis were considered for inclusion into a step-wise backward multiple logistical regression model. Results are reported as adjusted odds ratio with corresponding 95% confidence intervals. Two-tailed statistical tests were utilized, with significance level set at P-value < .05. All data were analyzed using IBM® SPSS Statistics, Version 27 (SPSS Inc., Chicago, IL). Institutional Data Quality Release approval was granted by the Chief Quality Officer.

Results

A total of 1238 patients were screened for inclusion; 186 patients were included in the analysis with 42 (22.5%) developing a fever within 48 hours of dexmedetomidine initiation (Figure 1). Most patients were excluded because they were <120% IBW, had a sedative or analgesic agent overlapping with dexmedetomidine that did not meet our preset inclusion criteria, or had a duration of dexmedetomidine <8 hours. Table 1 describes baseline characteristics between the two groups. No differences were noted in baseline characteristics other than a lower mean age in the febrile group (56 [45-63] vs 61 [49.5-68] years; P = .028). The median baseline weight (99.4 [90.6-122.4] vs 97.6 [81.6-114.2] kg; P = .6) and BMI (34.9 [30.4-42.6] vs 33.4 [30.1-39.6] kg/m²; P = .6) were similar between the febrile and the afebrile group, respectively. Majority of patients in both groups were mechanically ventilated (90.5% vs 81.9%; P = .24). While the median duration of dexmedetomidine was significantly longer (48 [31-48] vs 34 [22-48] hours; P = .03) in the febrile group, the median dexmedetomidine dosage was similar (.53 [.32-.68] vs .45 [.28-.7] mcg/kg/h, P = .11).

Table 1.

Patient Demographics, Baseline Characteristics, and Outcomes. All Data are Presented as Median (25-75% Interquartile Range) Unless Otherwise Noted.

Characteristics/Outcomes	Febrilen = 42	Afebrilen = 144	P Value
Age (years), mean ± SD	56 [45-63]	61 [49.5-68]	.028
Male, n (%)	23 (54.8)	64 (44.4)	.29
Ethnicity, n (%)
Caucasian	33 (78.6)	116 (80.4)	.54
African American	8 (19)	20 (13.9)
Other	1 (2.4)	8 (5.6)
Admission unit, n (%)			.097
MICU	31 (73.8)	124 (86.1)
SICU	11 (26.2)	20 (13.9)
APACHE II	16 [11-22]	16 [11-21]	.82
Weight (kg)	99.4 [90.6-122.4]	97.6 [81.6-114.2]	0.6
Height (centimeters)	172.7 [162.6-180.3]	165.8 [160-175.3]	.22
Weight used for dex dosing, n (%)			.86
Actual body weight	20 (47.6)	73 (50.7)
Adjusted body weight	22 (52.4)	71 (49.3)
BMI (kg/m²)	34.9 [30.4-42.6]	33.4 [30.1-39.6]	0.6
Mechanical ventilation, n (%)	38 (90.5)	118 (81.9)	.24
Median dex dose within 48 hours (mcg/kg/hr)	.53 [.32-.68]	.45 [.28-.7]	.11
Median maximum dex dose within 48 hours (mcg/kg/hr)	.9 [.6-1.2]	.8 [.6-1.2]	.37
Cumulative dex dose (mcg) - hours 0-24 (day 1)	934 [670.5-1283]	693.9 [430.5-1280.4]	.07
Cumulative dex dose (mcg) - hours 24-48 (day 2)	932 [599.1-2017.7]N = 36	856 [453.8-1311.8]N = 89	.165
Duration of dex (hours)	48 [31-48]	34 [22-48]	.03
Temperature prior to dex initiation (°C)	37.7 [37.2-37.9]	36.9 [36.7-37.2]	<.0001
Change in baseline temperature to Tmax at 24 hours (°C)	.6 [.4-1]	.3 [0-.6]	<.01
Tmax in hours 0-24 after dex initiation (°C)	38.3 [38.1-38.6]	37.3 [36.9-37.7]	<.0001
Tmax in hours 24-48 after dex initiation (°C)	38.2 [37.5-38.8]	37.2 [36.8-37.5]	<.0001
Receiving antibiotics prior to dex initiation, n (%)	39 (92.8)	117 (81.3)	.094
NSAIDs or acetaminophen, n (%)	19 (45.2)	17 (11.8)	<.0001
On CRRT, n (%)	2 (4.8)	14 (9.7)	.313
Surgery in 24 hours preceding or following dex initiation, n (%)
Prior	6 (14.3)	11 (7.6)	.188
Post	4 (9.5)	9 (6.3)	.931

Abbreviation: SD, standard deviation; MICU, Medical Intensive Care Unit; SICU, Surgical Intensive Care Unit; APACHE II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; IBW, ideal body weight; dex dexmedetomidine; NSAIDs, Non-steroidal anti-inflammatory drugs; CRRT, continuous renal replacement therapy.

The febrile group had a median change in baseline temperature to Tmax at 24 hours of .6°C [.4-1] vs .3°C [0-.6] in the afebrile group (P < .01). Temperature prior to dexmedetomidine initiation, Tmax within 24 hours of dexmedetomidine initiation, and Tmax at hours 24-48 after dexmedetomidine initiation were all significantly higher in the febrile group, respectively (37.7 [37.2-37.9] vs 36.9 [36.7-37.2], P < .0001; 38.3 [38.1-38.6] vs 37.3 [36.9-37.7], P < .0001; 38.2 [37.5-38.8] vs 37.2 [36.8-37.5], P < .0001). Significantly more patients in the febrile group received NSAIDs and/or acetaminophen (45.2% vs 11.8% P < .0001) (Table 1). Nominal variables considered for inclusion for multiple logistical regression model included admission unit, receipt of antibiotics prior to dexmedetomidine, and surgery 24 hours proceeding dexmedetomidine. Continuous variables included for the multiple logistical regression model included age, duration of dexmedetomidine, and temperature prior to dexmedetomidine initiation. In multiple regression analysis, duration of dexmedetomidine and temperature prior to dexmedetomidine were the only significant predictors of development of fever with an adjusted odds ratio of 1.041 (95% CI 1.009-1.074, P = .012) and 7.058 (95% CI 3.307-15.0640.071-.33, P < .001), respectively (Table 2).

Table 2.

Multiple Logistic Regression Analysis. Hosmer-Lemeshow goodness-of-fit test P =.40.

Variables	Adjusted odds ratio (95% CI)	P Value
Duration of dex	1.041 (1.009-1.074)	.012
Receiving antibiotics prior to dex initiation	.249 (.058-1.079)	.063
Temperature prior to dex initiation	7.058 (3.307-15.064)	<.001

Abbreviation: dex, dexmedetomidine.

Discussion

This study found a statistically significant difference in body temperature at baseline, Tmax within 24 hours of dexmedetomidine initiation, and Tmax at hours 24-48 after dexmedetomidine initiation in the febrile group compared to the afebrile group for obese patients on dexmedetomidine for ongoing ICU sedation. Additionally, we describe predictors of fever in this population. To our knowledge, this is the first study to evaluate elevations in temperature due to dexmedetomidine including only obese critically ill patients. Due to the lack of evidence, there is no single size descriptor that is established as the standard of care for describing pharmacokinetics of drugs in the obese population. We chose to define obesity as ≥ 120% of IBW as that is what is established in previous literature when evaluating drug dosing for the obese population.^20,21 When comparing our results to what is reported in the literature for non-obese patients and in case reports for obese patients, our rates of hyperthermia (22.5%) were lower than previously reported likely due to the fact that all febrile patients with positive cultures were excluded. A study by Grayson et al observed a substantially higher proportion of patients experiencing a temperature ≥38.3°C were receiving dexmedetomidine (43.3%) compared to those that did not receive dexmedetomidine (32.7%). In a subgroup analysis by Grayson et al, the authors report patients >120 kg were more likely to experience temperature elevations compared to patients with a lower body weight (P = .02).⁹ Of note, in this study, dexmedetomidine was dosed based on a maximum weight of 100 kg irrespective of patient actual or adjusted weight unlike our patient population where no maximum weight was utilized. Additionally, a recent systematic review evaluating fever associated with dexmedetomidine found that 4 of the 12 (33%) individual case reports occurred in obese patients.⁴

Adipose tissue is a secretory organ controlling energy homeostasis.⁶ Dosing of dexmedetomidine has traditionally been weight-based, therefore, obese patients may be receiving higher doses and may be at increased risk for adverse events such as hyperthermia and hypotension. Besides thermoregulation, the alpha-2A receptor is a vasodilator while the alpha-2B receptor is a vasoconstrictor. It is thought the as the dosing of dexmedetomidine increases, hypotension incidence is reduced.²² In our previous study, we found hypotension (SBP < 90 mmHg) was statistically more common in those that were dosed on adjusted body weight compared to actual body weight.¹⁵ It is thought that as the concentration of dexmedetomidine increases, selectivity for the alpha-2A receptor diminishes and the vasoconstriction that occurs in response to the alpha-2B agonism blunts hypotension. It is unknown, based on this study, if the incidence of hyperthermia is concentration dependent or a result of excess adipose tissue. However, the median duration of dexmedetomidine in our study was significantly longer in the febrile group which supports the theory that higher drug exposure may contribute to hyperthermia.

This study also showed a lower median age in the febrile group. A previous study evaluating drug fever induced by parenteral administration of antibiotics found that the incidence of drug fever was higher in patients aged 49 years and less than those aged 70 years and above (P < .05).²³ Coexisting chronic diseases, biological changes with normal aging, and the use of medications contribute to the broad physiological heterogeneity observed in the elderly. Previous literature consistently finds that baseline temperatures are lower in frail elderly patients than in healthy younger patients.²⁴ This may have contributed to the results found in this study.

The true incidence of dexmedetomidine-induced fever is difficult to establish because drug-induced fever is a diagnosis of exclusion and is challenging to confirm, especially retrospectively.⁴ Therefore, we excluded patients with fever and positive cultures and also patients that were admitted for a neurologic condition to better evaluate the incidence of true drug-induced fever. Therefore, we cannot explain why the febrile group had a higher baseline temperature than what was seen in the SPICE III trial (37.7 vs 36.7°C). Unfortunately, other causes of fever apart from surgery in the 24 hours proceeding or following dexmedetomidine initiation were not collected (ie, venous thromboembolism, drug withdrawal, central fever, blood product transfusions, trauma, myocardial infarction, etc.). In addition, apart from continuous renal replacement therapy and NSAID and/or acetaminophen use, factors that could mask a fever were not collected (ie, immunosuppression, nonpharmacologic cooling measures, etc.). We also could not determine if NSAIDS and/or acetaminophen were prescribed for analgesia or hyperthermia due to the retrospective nature of this study. Other limitations to our study include the small sample size, selection bias as more patients in the febrile group received NSAIDs and/or acetaminophen, and lack of Naranjo scoring, which was not collected due to the difficulty of obtaining this information retrospectively.

There are several strengths to our study. Only patients that were on dexmedetomidine as a sole sedative agent were included in the study and temperature data for 48 hours after initiation of dexmedetomidine were evaluated. A recently published systematic review of literature showed that the duration of dexmedetomidine exposure prior to fever onset ranged from 4 to 24 hours after initiation in 8 case reports. Therefore, based on this literature, dexmedetomidine-induced fever should have been captured in our study based on inclusion criteria. This review also found that in 9 cases, time until fever resolution after dexmedetomidine discontinuation ranged from 45 minutes to 12 hours.⁴ Unfortunately, this study did not capture temperature data after dexmedetomidine discontinuation. Additionally, another strength to our study is that we captured patients that had surgery prior to or after dexmedetomidine initiation and those that received NSAIDs and/or acetaminophen as these may have affected body temperature regulation.

Unexplained fever, particularly in the ICU, leads to extensive infectious workups and increased exposure to antimicrobial and antipyretic agents (as seen in this study). A study by Toro et al showed an average of 9 days of inappropriate antibiotics because of fever associated with dexmedetomidine.²⁵ Therefore, clinicians should be aware that dexmedetomidine can be a cause of hyperthermia to minimize inappropriate therapies.

Conclusions

Our study suggests that there is a statistically significant increase in body temperature at baseline, Tmax within 24 hours of dexmedetomidine initiation, and Tmax at hours 24-48 after dexmedetomidine initiation in the febrile group compared to the afebrile group for critically ill obese patients initiated on dexmedetomidine. Duration of dexmedetomidine and baseline temperature were found to be risk factors for development of fever in this population. Further studies are warranted to confirm these findings.

Footnotes

Acknowledgements

We wish to thank Minh C. Tong,PharmD on his assistance in data collection.

Author’s Contribution

Dr. Atyia contributed to the design of the study,acquisition of data,analysis of the data,and drafting the article. Drs. Gerlach and Smetana contributed to the design of the study,analysis of the data,and revising the article for intellectual content. Dr. Thompson contributed to design of the study and revising the article for intellectual content. Dr. May contributed to the design of the study,acquisition of data,and revising the article for intellectual content.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The author(s) received no financial support for the research,authorship,and/or publication of this article.

ORCID iDs

Sara A. Atyia

Keaton S. Smetana

Casey C. May

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