Abstract
Introduction and objective:
Dexmedetomidine is a potent adrenergic alpha-2 agonist, and analgesic, sedative, anxiolytic and sympatholytic. Given there have been reports of dexmedetomidine associated temperature changes, in which these events have been associated with complications, our objective was to describe both temperature increase and decrease, during the intra and postoperative period (initial 24 hours), and factors associated, in patients who received dexmedetomidine for anesthesia/sedation in the surgical suite.
Method:
Retrospective observational study, analyzing charts of patients ≥ 18 years submitted to anesthesia/sedation with dexmedetomidine, between 1/1/2017 and 31/12/2017. Upper temperature threshold was considered ≥ 37.8°C, and lower, < 35°C. The association with dexmedetomidine was assessed by the OMS/UMC causality system and by the Naranjo algorithm.
Results:
The sample included 42 patients who received dexmedetomidine and whose temperature data were available, with predominance of men 26 (62%), 49.4/16.5 years old (mean/standard deviation), and weight 65/35.8 kg. None of the patients presented intraoperative temperature equal to or above 37.8°C or below 35°C. During the postoperative period, one patient presented an increase ≥ 37.8°C (2.4%) and three, temperature decrease < 35°C (7%). Surgery/anesthesia time and exposure time to dexmedetomidine were not appropriate linear predictors of maximum temperature. Older age (p < 0.01), longer exposure to dexmedetomidine (p < 0.05) and shorter surgery time (p < 0.01) were significant linear predictors for lower minimum temperature.
Abbreviations:
MH, malignant hyperthermia; UMC, Uppsala Monitoring Centre; ICU, Intensive Care Unit; WHO, World Health Organization.
Conclusions:
Increase ≥ 37.8°C/decrease < 35°C of temperature possibly associated with dexmedetomidine did not occur in the intraoperative period and had a low frequency during the postoperative period.
KEYWORDS
Dexmedetomidine; Anesthesia; Body temperature
Introduction
Dexmedetomidine is an adrenergic alpha-2 agonist and is analgesic/sedative/anxiolytic/sympatholytic.11 Villela NR, Junior PN. Dexmedetomidine in anesthesiology. Rev Bras Anestesiol. 2003;53:97-113. It is frequently used at the Intensive Care Unit (ICU) for mild sedation/ventilation weaning, and at the surgical suite as a sedative/adjuvant, to decrease consumption of opioid/inhalation agents.11 Villela NR, Junior PN. Dexmedetomidine in anesthesiology. Rev Bras Anestesiol. 2003;53:97-113.,22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906. Patients sedated with dexmedetomidine wake up/cooperate when asked and high doses do not result in respiratory depression.11 Villela NR, Junior PN. Dexmedetomidine in anesthesiology. Rev Bras Anestesiol. 2003;53:97-113. The main side effects are hypotension/bradycardia.11 Villela NR, Junior PN. Dexmedetomidine in anesthesiology. Rev Bras Anestesiol. 2003;53:97-113.
Both temperature decrease and increase have been associated with dexmedetomidine.22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906.
3 Harding A, Heine A, Gerlach A. Dexmedetomidine induced hyperthermia. Crit Care Med. 2013;41:A340.
4 Okabe T, Takeda S, Akada S, et al. Postoperative intensive care unit drug fever caused by dexmedetomidine. Anesth Analg. 2009;108:1589-91.
5 Straw LB, Dodson CR, Schrift DS. Dexmedetomidine induced fever and delirium: a case report. J Clin Pharm Ther. 2018;43:430 3.
6 Shukry M, Guruli ZV, Ramadhyani U. Case report: suspected malignant hyperthermia in a child with laminin a2 (merosin) deficiency in the absence of a triggering agent. Paediatr Anesth. 2006;16:462 5.
7 Faust AC, Sutton SE. Dexmedetomidine associated fever in the intensive care unit. Ther Adv Drug Saf. 2015;6:234 7.-88 Finkel JC, Quezado ZMN. Hypothermia-induced bradycardia in a neonate receiving dexmedetomidine. J Clin Anesth. 2007;19:290 2. Temperature decrease would be due to the agonist action at the central alpha-2 receptor, reducing vasoconstriction/tremor thresholds and physiological responses to increase in body temperature.11 Villela NR, Junior PN. Dexmedetomidine in anesthesiology. Rev Bras Anestesiol. 2003;53:97-113.,88 Finkel JC, Quezado ZMN. Hypothermia-induced bradycardia in a neonate receiving dexmedetomidine. J Clin Anesth. 2007;19:290 2.,99 Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87:835 41. Plasma concentration of dexmedetomidine of 0.8 ng.mL-1 reduces the tremor threshold to roughly 34°C.99 Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87:835 41. Increase in temperature would result from change in thermoregulation (slight increase in sudoresis threshold) and/or from immunological response (allergic febrile reaction to drug).22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906.
3 Harding A, Heine A, Gerlach A. Dexmedetomidine induced hyperthermia. Crit Care Med. 2013;41:A340.
4 Okabe T, Takeda S, Akada S, et al. Postoperative intensive care unit drug fever caused by dexmedetomidine. Anesth Analg. 2009;108:1589-91.
5 Straw LB, Dodson CR, Schrift DS. Dexmedetomidine induced fever and delirium: a case report. J Clin Pharm Ther. 2018;43:430 3.
6 Shukry M, Guruli ZV, Ramadhyani U. Case report: suspected malignant hyperthermia in a child with laminin a2 (merosin) deficiency in the absence of a triggering agent. Paediatr Anesth. 2006;16:462 5.-77 Faust AC, Sutton SE. Dexmedetomidine associated fever in the intensive care unit. Ther Adv Drug Saf. 2015;6:234 7.,1010 Lopes CG, Nunes RR. Temperatura corporal e anestesia. In: Manica JT, editor. Anestesiologia: Princípios e Técnicas. 4th ed. Porto Alegre, RS: Artmed; 2018. p. 554 62. Increased temperatures did not correlate to malignant hyperthermia (MH), given there were no signs of hypermetabolism; moreover, patients susceptible to MH anesthetized with dexmedetomidine did not present characteristic presentation/complications.1111 Dewhirst E, Naguib A, Tobias JD. Dexmedetomidine as part of balanced anesthesia care in children with malignant hyperthermia risk and egg allergy. J Pediatr Pharmacol Ther. 2011;16:113 7.,1212 Naguib A, McKee C, Phillips A, et al. Dexmedetomidine as the primary anesthetic agent during cardiac surgery in an infant with a family history of malignant hyperthermia. Saudi J Anaesth. 2011;5:426 9. Additionally, dexmedetomidine is an option for patients susceptible to MH and allergic to egg protein, contraindicating propofol.1111 Dewhirst E, Naguib A, Tobias JD. Dexmedetomidine as part of balanced anesthesia care in children with malignant hyperthermia risk and egg allergy. J Pediatr Pharmacol Ther. 2011;16:113 7.
Detailed data on the effect at temperature of dexmedetomidine administered during general anesthesia in adults are scarce. A Cochrane Review1313 Lewis SR, Nicholson A, Smith AF, et al. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia. Cochrane Database of Sys Rev. 2015;8:CD011107. on alphaadrenergics to prevent shivering after general anesthesia emphasizes that it is not possible to establish a relationship between dexmedetomidine and temperature decrease because, of the seven articles analyzed, two did not refer temperature and only one reported the frequency of temperature decrease (44.1%).1414 Abdelmageed WM, Al Taher WM. Intramuscular dexmedetomidine for prevention of shivering after general anesthesia in patients undergoing arthroscopic anterior cruciate ligament reconstruction. Ain-Shams J Anesthesiol. 2014;07:156-62. In the four other articles, there was a decrease in temperature with dexmedetomidine, but two articles did not provide details on the statistical study,1515 Karaman S, Gunusen I, Ceylan MA, et al. Dexmedetomidine infusion prevents postoperative shivering in patients undergoing gynecologic laparoscopic surgery. Turk J Med Sci. 2013;43:232-7.,1616 Kim YS, Kim YI, Seo KH, et al. Optimal dose of prophylactic dexmedetomidine for preventing postoperative shivering. Int J Med Sci. 2013;10:1327-32. one article reported no difference between groups without/with dexmedetomidine,1717 Bicer C, Esmaoglu A, Akin A, et al. Dexmedetomidine and meperidine prevent postanaesthetic shivering. Eur J Anaesthesiol. 2006;23:149-53. and another referred more pronounced decrease in temperature in the group with dexmedetomidine, only during the postoperative period.1818 Elvan EG, Oc B, Uzun S, et al. Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol. 2008;25:357-64. Additionally, a retrospective study on the effect of dexmedetomidine on postoperative inflammation after percutaneous nephrolithotomy showed a significant decrease in fever/systemic inflammatory response syndrome.1919 Tan F, Gan X, Deng Y, et al. Intraoperative dexmedetomidine attenuates postoperative systemic inflammatory response syndrome in patients who underwent percutaneous nephrolithotomy: a retrospective cohort study. Ther Clin Risk Manag. 2018;14:287-93. Finkel (2007) reported decrease in temperature while using dexmedetomidine at the ICU on neonates.88 Finkel JC, Quezado ZMN. Hypothermia-induced bradycardia in a neonate receiving dexmedetomidine. J Clin Anesth. 2007;19:290 2.
Regarding temperature increase associated with dexmedetomidine, data come from ICU studies22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906.
3 Harding A, Heine A, Gerlach A. Dexmedetomidine induced hyperthermia. Crit Care Med. 2013;41:A340.
4 Okabe T, Takeda S, Akada S, et al. Postoperative intensive care unit drug fever caused by dexmedetomidine. Anesth Analg. 2009;108:1589-91.-55 Straw LB, Dodson CR, Schrift DS. Dexmedetomidine induced fever and delirium: a case report. J Clin Pharm Ther. 2018;43:430 3.,77 Faust AC, Sutton SE. Dexmedetomidine associated fever in the intensive care unit. Ther Adv Drug Saf. 2015;6:234 7. or experimental models, in addition to a report on anesthesia of a child with suspected MH in the absence of triggering agents.66 Shukry M, Guruli ZV, Ramadhyani U. Case report: suspected malignant hyperthermia in a child with laminin a2 (merosin) deficiency in the absence of a triggering agent. Paediatr Anesth. 2006;16:462 5. Dogs anesthetized with sevoflurane/opioid versus sevoflurane/dexmedetomidine presented both increase and decrease in temperature in both groups, but with no significant difference, both in the intra and postoperative periods.2020 Marquez-Grados F, Vettorato E, Corletto F. Sevoflurane with opioid or dexmedetomidine infusions in dogs undergoing intracranial surgery: a retrospective observational study. J Vet Sci. 2020;21:e8. In rodents, temperature was significantly lower with isoflurane than with dexmedetomidine/ketamine/midazolam and more animals had temperature decrease with isoflurane, leading the authors to propose that dexmedetomidine could protect against skin heat loss by peripheral vasoconstriction, and preserve central temperature by central blood redistribution.2121 Browning GR, Eshar D, Beaufrere H. Comparison of dexmedetomidine-ketamine-midazolam and isoflurane for anesthesia of black-tailed prairie dogs (Cynomys ludovicianus). J Am Assoc Lab Anim Sci. 2019;58:50-7.
Thus, there is a gap in detailed studies on the effects of dexmedetomidine on temperature during the intra/postoperative period.
Objective
To describe both increase and decrease in intra/postoperative temperature variation (initial 24 hours), and factors associated, in patients receiving dexmedetomidine for anesthesia/sedation at the surgical suite.
Methods
The study was performed in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsink), approved by the Ethics and Research Committee (CAAE 08688512.0.0000.5505; 115.960, 05/OCT/2012), and given it was a retrospective study, informed consent was waived. Following STROBE guidelines, an observational retrospective study was performed at a tertiary hospital, on patients who received intraoperative dexmedetomidine at the surgical suite during the 01/JAN/2017-31/DEC/2017 period.
First, an author revised the electronic database of anesthesia/medical records of all patients included, registering maximum/minimum temperature/temperature amplitude during the intraoperative/initial 24 hours of the postoperative period. Intraoperative data were collected from the anesthesia record and postoperative data from nursing notes. The 24-h limit was based on detection of temperature increase, of adult ICU patients, up to 24 hours after dexmedetomidine, and normothermia up to 12 hours after discontinuation.22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906. Inclusion criteria were using dexmedetomidine and availability of temperature control data. Exclusion criteria were age below 18 years due to the specificity of thermogenesis in children, with production of heat by brown fat, and larger body surface in relation to mass.2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38.
The following data were collected from charts: demographics (age/gender), height-weight, history of current condition and surgical proposal, previous diseases, medications being used, type of anesthesia/sedation, anesthetic drugs used, beginning/end of procedures (anesthesia/sedation, surgery), incidents/complications from the beginning of anesthesia/sedation to discharge from postanesthesia recovery, maximum and minimum temperature data. Daytime temperature varies between 36.5-37.5°C and values < 36°C and > 38°C mark points in which thermoregulation is compromised and/or surpassed by changes in environment temperature/thermogenesis.2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38. To amplify any possible association between dexmedetomidine and change in temperature, increase in temperature ≥ 37.8°C and decrease in temperature < 35°C were considered as limits. Temperature ≥ 37.8°C was adopted to define acceptable limit for fever, while 34.6°C was the temperature that induced thermoregulatory response of peripheral vasoconstriction in normal individuals exposed to cooling.99 Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87:835 41.,2323 Santana LFE, Rodrigues MS, Silva MPA, et al. Fever of unknown origin in special groups. Rev Assoc Med Bras. 2019;65:1308-13.
In order to better assess the relationship between dexmedetomidine and change in temperature, possible infectious/non-infectious causes of temperature increase were considered. The association between dexmedetomidine and temperature increase/decrease was assessed by two algorithms: World Health Organization (WHO)/Uppsala Monitoring Centre (UMC) system for standardized case causality assessment and Naranjo algorithm.2424 Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10:93-102.,2525 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-45. WHO-UMC criteria compare the drug-effect relationship in question, with a table of pre-defined statements and six categories: non-classifiable, not classified, unlikely, possible, likely, and defined (Supplementary Material: Table 1).2424 Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10:93-102. The Naranjo scale is a point system with a questionnaire (0-13 points) that classifies the drug-effect relationship in four categories: doubtful (0), possible (1-4), probable (5-8) and definite (≥9) (Supplementary Material: Table 2).2525 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-45. Two evaluation methods were used because the level of causality has been reported as different among several pharmacovigilance algorithms.22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906.
Pearson correlation matrix of variables of interest (values refer to correlation coefficients r).
To calculate the sample size, we chose the increase in temperature variable because it is less studied/frequent. Increase in temperature with dexmedetomidine was considered as occurring in up to 6.5% of patients in previous studies on adults in the ICU2626 Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151-60.; thus, in order to replicate this proportion with a maximum estimation error of 5% and 80% level of confidence, a sample of 40 patients would suffice (calculation based on simple random sample without replacement). Categorical data were described as absolute (n) and relative (%) frequency, and continuous and semi-continuous gaussian data, as mean and standard deviation. Data were checked as to normality by the K-S distance test. Non-paired t-test was used to compare independent samples. Correlations were calculated/tested by the Pearson test. To better check the relationship between use of dexmedetomidine and patient temperature, linear regressions were performed including variables that presented a significant correlation on the Pearson test. Based on the assumption that time of dexmedetomidine and patient temperature correlate in a linear relationship, linear regression was performed to determine how much variation in patient temperatures would be explained by time of use of dexmedetomidine, surgery time and age in years, separately. Values of p < 0.05 were considered significant.
Results
The study included 42 patients who received dexmedetomidine during the intraoperative period and with temperature control available, 49.4/16.5 years old (mean/standard deviation; variation 19-81 years), 65/35.8 kg (data available for 39 patients; variation 42-115 Kg), and 26 (62%) men and 16 women (38%). Seven patients who received intraoperative dexmedetomidine were excluded due to unavailable temperature control data.
Two patients (4.76%) had baseline infectious conditions (infectious source surgically approached at pulmonary metastases and pulmonary infection). None of the patients were septic. Awake intubations were performed in 8 patients (19%). Elective procedures prevailed (36) over urgencies (6). Central nervous system surgeries were more frequent (13), followed by head/neck (8), gastrointestinal (5), orthopedic (4), ENT (3), vascular (2), urology (2), plastic (2), ophthalmology (1), gynecology (1), and heart (1). The abdominal cavity was opened in three surgeries (7.14%), and none of the thoracic cavity. None of the patients used extracorporeal circulation or had burns. One patient died at the hospital 21 days after the procedure. Mean time to discharge after surgical procedure was 3.46/3.29 days (variation 1-14 days). Dexmedetomidine was used as sedation in nine cases (21%) and as anesthesia adjuvant in the other 33 (25 also received isoflurane, opioid and propofol; seven, opioid and propofol; and one, local anesthetic). As adjuvant, dexmedetomidine was used alone in 76.2%, associated with clonidine in 7.1%, and to ketamine in 16.7% of cases. Dexmedetomidine was used for 202.73/150.9 minutes (range 30-660 minutes), at the dose of 0.47/0.09 micrograms.kg-1.h-1 (range 0.3-1).
Temperatures were measured during anesthesia/sedation with an esophageal thermometer and, at the postoperative period, with an axillary thermometer. All patients used thermal blankets adjusted to 38°C for warming after general anesthesia induction or beginning of sedation. None of the patients were cooled down. Among maximum temperatures, highest was 37.9°C, and lowest, 35.6°C (mean 36.7/0.54°C) (Fig. 1). Among minimum temperatures, highest was 36.6°C and lowest, 34.6°C (mean 35.6/0.56°C). The widest temperature range (maximum temperature minus minimum temperature) on the same patient was 2.9°C, and the lowest, 1°C (mean 1.03/0.61°C).
None of the patients presented temperature increase ≥ 37.8°C during the intraoperative period, and only one patient presented temperature increase ≥ 37.8°C in the postoperative period. The correlation between increase in temperature ≥ 37.8°C and use of dexmedetomidine for this patient was considered as possible by the WHO-UMC causality system, and by the Naranjo algorithm (Table 1).
None of the patients had a temperature < 35°C during the intraoperative period, but three patients (7%) did in the postoperative. For these patients, the correlation between temperature < 35°C and using dexmedetomidine was considered as possible by the WHO-UMC causality system for three, and by the Naranjo algorithm, as possible for two and likely for one (Table 1). The relationship between temperature decreases and dexmedetomidine was classified as possible when there were other medications/scenarios that could explain the increase/decrease in temperature. Additionally, none of the patients presented a temperature < 36°C during the intraoperative period, but 20 patients presented a temperature of 35-35.9°C in the initial 24 postoperative hours.
There was no difference in maximum temperature between females (36.8/0.5°C) and males (36.6/0.5°C) (non-paired t-test, p = 0.15) (Fig. 1), nor between patients aged up to 49 years (36.8/0.1°C) and those above 50 years or more (36.6/0.1°C) (non-paired t-test, p = 0.19). Likewise, there was no difference between minimum temperature between sexes nor between patients above/below 50 years. There was no significant difference in minimum (respectively 35.49/0.16°C vs. 35.68/0.93°C; p = 0.19, non-paired t-test) or maximum temperature (36.64/0.12°C vs. 36.68/0.1°C; p = 0.33, unpaired t-test) between the group that only received dexmedetomidine (n = 9) and the group in which dexmedetomidine was associated with other anesthetics (n = 33).
The period of use of dexmedetomidine presented a low positive correlation with maximum temperature (correlation coefficient r = 0.3; p < 0.05; Pearson correlation), and high correlation with surgical time (r = 0.7; p < 0.05; Pearson correlation) (Fig. 2; Table 2). Maximum temperature presented a low positive correlation with surgery time (r = 0.3; p < 0.05; Pearson correlation) and with minimum temperature (r = 0.3; p < 0.05; Pearson correlation), but a high positive correlation with temperature amplitude (r = 0.7; p < 0.05; Pearson correlation) (Table 2). Minimum temperature presented a low positive correlation with surgery time (r = 0.3; p < 0.05; Pearson correlation), low negative correlation with age (r = 0.3; p < 0.05; Pearson correlation) and high negative correlation with temperature amplitude (r = 0.7; p < 0.05; Pearson correlation) (Fig. 3; Table 2).
Dispersion and linear prediction of maximum temperature, minimum temperature, and temperature amplitude, by age.
Dispersion and linear prediction of maximum temperature, minimum temperature, and temperature amplitude, by time using dexmetedomidine.
Linear regression of temperature as a function of time using dexmedetomidine, surgery time and age (Table 3) presented a variance inflation rate (VIF) < 10 (1.04-2.44), excluding the possibility of collinearity. Analyzing first the regression in which the variable explained is maximum temperature, Table 3 shows that both surgery time and dexmedetomidine time and age did not have a statistically significant relation with maximum patient temperature. In turn, when analyzing minimum temperature of patients, time using dexmedetomidine was observed to have a negative relationship with minimum patient temperature (the more time using dexmedetomidine, lower minimum patient temperature). A similar relationship was found for age, that is, older individuals had lower temperatures. In turn, the longer surgery time, higher the minimum temperature. There was no statistically significant relationship of the variable dexmedetomidine alone/associated with minimum/maximum temperature.
Linear regression of maximum temperature and minimum temperature in relation to dexmedetomidine use time, surgical time, age (standard deviation between parentheses). Additionally, control was performed by variable dexmedetomidine alone or associated to other anesthetics.
Discussion
We detected both temperature > 37.8°C and < 35°C in less than 10% of the sample. In the present statistical modeling, temperature decrease could, independently, be due to both older age and more time using dexmedetomidine and longer surgery time. On the other hand, increase in temperature apparently depends on joint action of dexmedetomidine and surgery time.
Sessler (2008) underscored that individuals without thermoregulation problems would not present decrease in temperature only due to factors such as low temperature of the operating room, exposure of cavities, hemorrhage/transfusion, previous conditions (ASA 3-4), malnutrition, neuropathies and older age.1010 Lopes CG, Nunes RR. Temperatura corporal e anestesia. In: Manica JT, editor. Anestesiologia: Princípios e Técnicas. 4th ed. Porto Alegre, RS: Artmed; 2018. p. 554 62.,2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38. Decrease in intraoperative temperature would imply in inhibition of thermoregulation by anesthetics such as dexmedetomidine, with consequent lower threshold for tremor and vasoconstriction, loss of heat from central compartment to periphery by vasodilation, and up to 30% decrease in metabolism.1010 Lopes CG, Nunes RR. Temperatura corporal e anestesia. In: Manica JT, editor. Anestesiologia: Princípios e Técnicas. 4th ed. Porto Alegre, RS: Artmed; 2018. p. 554 62.,2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38. This would explain our findings of lower minimum temperatures associated with longer exposure time to dexmedetomidine when we isolated the effects of surgery time and age.99 Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87:835 41. Additionally, mechanisms that predisposed to temperature decrease during anesthesia apparently would stand out in relation to those that would cause temperature increase by dexmedetomidine, a different scenario from the studies performed at ICU. Prevention of temperature decrease is warranted by associated risks, such as coagulopathy (platelet/coagulation factors dysfunction), delay in anesthesia recovery, cardiac complications (increased noradrenaline, arterial hypertension, and tachycardia), shift in the hemoglobin dissociation curve to the left, and higher incidence of surgical wound infection.1010 Lopes CG, Nunes RR. Temperatura corporal e anestesia. In: Manica JT, editor. Anestesiologia: Princípios e Técnicas. 4th ed. Porto Alegre, RS: Artmed; 2018. p. 554 62.
A series of 200 ICU patients on dexmedetomidine detected a temperature increase of nine, on average after six hours (range 4-10 hours) from initial dexmedetomidine at a mean dose of 1.0 mcg.kg-1. h-1 (0.8-1.3), with a temperature decrease after discontinuation of dexmedetomidine to ≤ 38.5°C, on average in 3 hours (1-8), and to 38.0°C after 4 hours (3-9).22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906. Authors have suggested that dexmedetomidine could be associated with occurrence of clinically relevant temperature increases.22 Krüger BD, Kurmann J, Corti N, et al. Dexmedetomidineassociated hyperthermia: a series of 9 cases and a review of the literature. Anesth Analg. 2017;125:1898-906. Grayson et al. showed a significant correlation between using dexmedetomidine at the ICU and increased temperatures, mainly in the postoperative period of cardiac procedures and of the obese.2727 Grayson K, Tobin AE, Lim TK, et al. Dexmedetomidineassociated hyperthermia: a retrospective cohort study of intensive care unit admissions between 2009 and 2016. Anaesth Intensive Care. 2017;45:727-36. The same correlation was not found in the present study on intraoperative use of the medication, although, in agreement with Grayson et al., we also detected maximum temperature increase associated with long exposure time to dexmedetomidine.2727 Grayson K, Tobin AE, Lim TK, et al. Dexmedetomidineassociated hyperthermia: a retrospective cohort study of intensive care unit admissions between 2009 and 2016. Anaesth Intensive Care. 2017;45:727-36.
Malignant Hyperthermia (MH) and Neuroleptic Malignant Syndrome (NMS) should be considered as part of the differential diagnosis in any fever of unknown origin. However, temperature increase associated with dexmedetomidine is different because high creatinoquinase is not always present, and symptoms tend to stop after its interruption.2727 Grayson K, Tobin AE, Lim TK, et al. Dexmedetomidineassociated hyperthermia: a retrospective cohort study of intensive care unit admissions between 2009 and 2016. Anaesth Intensive Care. 2017;45:727-36. Beside external factors that can increase temperature, infection can explain temperature increase, as is the case of the patient with postoperative fever and infection in cervical metastases. The relationship between temperature increases and dexmedetomidine was classified as possible in this patient, because there is another disease that could explain temperature increase. Increased temperature due to drugs is a challenge for diagnosis, that frequently is only made by exclusion, with time/resources spent in cultures/antibiotics; with a subjacent infection, the diagnosis becomes even more difficult and sometimes is not made, even during follow-up.
Measures to minimize temperature decrease in anesthesia/sedation, such as thermal blankets, are confounding factors in the present study, by limiting the occurrence of intraoperative temperature decrease. Longer surgery time associated with higher minimum/maximum temperatures suggest that using a blanket may be a prevailing factor in this relationship. Another confounding factor in the present study was using distinct temperature measuring methods, esophageal at the surgical suite and skin in the initial 24 postoperative hours; thus, despite the reliability of intraoperative temperatures, they can be underestimated in the postoperative period. Skin temperature has a low correspondence with esophageal temperature, more efficient because it is closer to central temperature.2828 Patel N, Smith CE, Pinchak AC, et al. Comparison of esophageal, tympanic, and forehead skin temperatures in adult patients. J Clin Anesth. 1996;8:462-8. Lack of data on temperature measurements in all patients who used dexmedetomidine limited our work by decreasing the number of cases analyzed. Additionally, this study has limitations due to its retrospective method, with a heterogeneous sample as to variables such as type of surgical procedure, without monitoring/anesthesia protocol established previously, with anesthesia/sedation performed/registered by different anesthesiologists, and without room temperature control. In order to better determine the cause-effect relationship, it would be important to perform future prospective studies, controlling all variables. However, information from the present study is important for awareness on the topic and to provide data for prospective studies to base themselves on, mainly to calculate sample size.
The major temperature variation found for patients in our study can be related to a wider interval between thresholds for response to cold/heat which is inducted by anesthetics, ranging from 0.2-0.4°C to 2-4°C.2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38. Temperature variations with dexmedetomidine could lead to considering monitoring temperature during its use. The Federal Medical Council recommends determining temperature and the means to assure normothermia, for procedures above 60 minutes and, regardless of procedure duration in high-risk scenarios (premature, newborn, previous history of/risk of MH and NMS).2929 Ribeiro MLB, Silva HB. Resolução do Conselho Federal de Medicina n° 2.174, de 14 de dezembro de 2017. Dispõe sobre a prática do ato anestésico e revoga a Resolução CFM no 1.802/2006. Diário Oficial da União. Publicado em 27/02/2018. Edição 39. Seção 1. Página 75-76-84. Disponível em https://www.sbahq.org/wp-content/uploads/2018/03/RESOLUC%CC%A7A%CC%83O-2 174-de-14-de-dezembro-de-2017-Dia%CC%81rio-Oficial-da-Unia%CC%83o-Imprensa-Nacional.pdf [último acesso: 06/04/2020].
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Although maximum temperature presented a significant positive correlation with surgical time and exposure to dexmedetomidine, these variables were not significant on the linear regression, indicating that they are not appropriate independent linear predictors of maximum temperature. On the other hand, age, surgery time and exposure time to dexmedetomidine were significant linear predictors for minimum temperature, in that older age and longer time of exposure to dexmedetomidine related to lower minimum temperatures, while longer surgery time was linked to higher minimum temperatures. These results should be seen parsimoniously, because it is not possible to infer on causality, and because the magnitude/direction of these effects can vary when controlling for other characteristics of patients/procedures. Moreover, the number of observations was low, with little variability, and the coefficients found were low, indicating a weak relationship among variables.
The significant relationship between older age and lower maximum/minimum temperature is explained by less efficient central thermoregulation for the elderly than for young adults, because of decreased baseline metabolism, muscular mass, tremors, sensitivity to cold and vasoconstrictor response.1010 Lopes CG, Nunes RR. Temperatura corporal e anestesia. In: Manica JT, editor. Anestesiologia: Princípios e Técnicas. 4th ed. Porto Alegre, RS: Artmed; 2018. p. 554 62.,3030 Carretiero DC, Santiago FE, Motzko-Soares AC, et al. Temperature and toxic Tau in Alzheirmer’s disease: new insights. Temperature. 2015;2:491-8. The vasoconstriction threshold from 60-80 years falls 1°C in comparison to 30-50 years.2222 Sessler DI. Temperature monitoring and perioperative thermoregulation. Anesthesiology. 2008;109:318-38. Dexmedetomidine use may need more care in the elderly because of exacerbation of the trend to decrease temperature, especially in the postoperative period, when the patient is not subject to temperature monitorig and control implemented by the anesthesiologist.
Conclusion
None of the patients presented increase ≥ 37.8°C/decrease < 35°C in intraoperative temperatures. Increase ≥ 37.8°C/decrease < 35°C in postoperative temperatures possibly associated with dexmedetomidine (OMS/ UMC causality system, Naranjo algorithm) presented a low frequency.
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FundingThe present study was performed with the support of the Coordenaça˜o de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) - Financial Code 001.
Appendix A Supplementary data
Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.bjane.2021.02.062.
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28Patel N, Smith CE, Pinchak AC, et al. Comparison of esophageal, tympanic, and forehead skin temperatures in adult patients. J Clin Anesth. 1996;8:462-8.
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29Ribeiro MLB, Silva HB. Resolução do Conselho Federal de Medicina n° 2.174, de 14 de dezembro de 2017. Dispõe sobre a prática do ato anestésico e revoga a Resolução CFM no 1.802/2006. Diário Oficial da União. Publicado em 27/02/2018. Edição 39. Seção 1. Página 75-76-84. Disponível em https://www.sbahq.org/wp-content/uploads/2018/03/RESOLUC%CC%A7A%CC%83O-2 174-de-14-de-dezembro-de-2017-Dia%CC%81rio-Oficial-da-Unia%CC%83o-Imprensa-Nacional.pdf [último acesso: 06/04/2020].
» https://www.sbahq.org/wp-content/uploads/2018/03/RESOLUC%CC%A7A%CC%83O-2 174-de-14-de-dezembro-de-2017-Dia%CC%81rio-Oficial-da-Unia%CC%83o-Imprensa-Nacional.pdf -
30Carretiero DC, Santiago FE, Motzko-Soares AC, et al. Temperature and toxic Tau in Alzheirmer’s disease: new insights. Temperature. 2015;2:491-8.
Publication Dates
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Publication in this collection
28 Feb 2022 -
Date of issue
Mar-Apr 2022
History
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Received
19 Feb 2020 -
Accepted
27 Feb 2021