Dexmedetomidine, the highly selective alpha 2-adrenergic agonist, produces sedative and pain-relieving effects through its action in the locus ceruleus-spinal cord and causes much less respiratory suppression than other sedatives.[1-3] Dexmedetomidine is known to have better clinical benefits than benzodiazepines because it improves patient’s ability to communicate pain, shortens the duration of intensive care unit (ICU) stay and mechanical ventilation and reduces the risk of delirium, making it the drug of choice for sedative in critically ill patients.[1-6]

Based on these findings, the Society of Critical Care Medicine guidelines describe non-benzodiazepines such as dexmedetomidine and propofol as better sedative agents than benzodiazepines for the treatment of adult critically ill patients.[1] The use of dexmedetomidine along with propofol is expected to rise in intensive care setting. Beside, Ma et al.[7] reported that dexmedetomidine provided the protection of the central nerve against neural cell death or damage resulting from hypoxia and ischemia, signaling further beneficial benefits of this sedative drug in the treatment of critically ill patients with brain damage, if their claim is supported by more evidence.

However, dexmedetomidine was found to cause adverse reactions such as bradycardia in previous studies involving cardiovascular patients, although the incidence of bradycardia was controlled by low intravenous maintenance dose of 0.7 µg/kg/h in another study.[5,8] Thus, they could treat bradycardia by lowering dose of dexmedetomidine without causing systemic hypotension.[5,8] However, when authors were using intravenous dexmedetomidine maintenance dose of 0.2-0.7 µg/kg/h for patients undergoing target temperature management (TTM) at 33℃, bradycardia occurred in 66.0% of the patients, which was much higher than the range of 0-13.8% reported in previous studies. We considered this high incidence of bradycardia is associated with TTM.[8] While the incidence of bradycardia caused by dexmedetomidine during TTM has been rarely studied, we explored the cause of bradycardia during TTM and estimated that common decline in drug metabolism and subsequent sudden increase in serum dexmedetomidine concentration together result in the condition.[9-16]

Clinical application of TTM are likely to expand to encompass a broader range of conditions, including cerebral edema accompanying severe ischemic cerebral artery infarct, sepsis, carbon monoxide poisoning, beyond cardiac arrest accompanying sepsis, promoting increasing use of dexmedetomidine in critically ill patients.[17-19] We therefore aimed to investigate the frequency of bradycardia and associated clinical characteristics in patients given dexmedetomidine during TTM at 33˚C.

In this study, the bradycardia incidence rate of 66.0% (37/56) in the DEX group was much higher, when compared with the range of 0-13.8% calculated for critically ill patients who did not undergo TTM.[8] However, there was no statistically significant relationship between dexmedetomidine and the incidence of bradycardia in multivariate analysis. Nonetheless, the incidence rate of 66% in the DEX group, backed by the high odds (9.737) of having bradycardia, provide meaningful insight into the impact of dexmedetomidine, when compared with a much lower incidence of 16% (2/12) in the MID group. In analysis of factors related to the high incidence of bradycardia, we also estimated the typical decline in drug metabolism during TTM. Dexmedetomidine has a volume of distribution at steady state of 1.33 L/kg or 118 L, distribution half-life of 6 minutes and a short half-life of 2-2.5 hours and high protein binding so that it is quickly eliminated from the body.[9] Because most dexmedetomidine is metabolized in the liver by cytochrom P450, enzyme 2A6 and uridine diphosphate glucuronosyltransferase (UGT), the elimination of the drug can fall by up to 50% in the presence of severe liver failure, calling for low doses for the elderly patients and those with renal failure, low plasma albumin concentration, decreased cardiac output. As the relationship between lower doses and TTM has not been discussed in previous studies, further study is needed to validate the presumed impact of hypothermia conditions.[9-11] Based on literature analysis of the relationship between drug metabolism and TTM, the decline in UGT, cytochrom P450, enzyme decreases drug metabolism and thereby increases concentration, which will eventually cause adverse effects. [12-14] As part of strategic approach to anticipated increases of concentration, reduced doses of sedative drug is recommended during the maintenance period of TTM after bolus injection of the first dose.[12-16] Given the pharmacokinetic features of dexmedetomidine, its concentration appears to increase in hypothermia conditions and subsequently causes bradycardia. Ezzati et al.[20] reported that increased concentration of dexmedetomidine led to cardiocvascular-related adverse effects during TTM in an animal model of hypoxic and ischemic brain damage.

As indicated in Table 3, diagnosis and weight were significantly related to the incidence of bradycardia. In comparison of pathophysiologic conditions used for diagnosis, both groups (CPR and CO) developed myocardia stunning and local sympathomimetic brain damage as a consequence of over secretion of catecholamine from the heart muscle and the edge of the synapse.[21-23] Rivers et al.[24] also claimed the level of catecholamine increased more than 32 times normal in the event of cardiac arrest and more than 90 times normal during CPR after injection of epinephrine. Thus, exogenous and endogenous toxicity of plasma catecholamine can occur in addition to a high concentration in synaptic vesicles, leading to systemic toxicity of catecholamine in patients during and after CPR. Such toxicity of catecholamine appears to occur in the CRP group in this study. Given the fact that TTM is implemented immediately after CPR, the toxicity of catecholamine may have largely contributed to a lower incidence of dexmedetomidine-induced bradycardia, compared with the CO group. The differences between the two groups are also explained by the nature of implications in patients: CO poisoning is tissue toxicity triggered by a combination of lack of oxygen during COHb formation and inactive components in cytochrom oxidase whereas patients resuscitated from CPR have more serious and extensive hypoxic ischemia-reperfusion injury inflicted on the internal organs.[21,22,25] In addition, the primary causes of cardiac arrest are heterogeneous, implying continuous effects on patient conditions even after resuscitation, which is one of the characteristics specific to the CPR group.[23] When combined, these factors may have affected the effects of dexmedetomidine on cardiovascular function, leading to low incidence of bradycardia. Thus, this study suggests the possibility that the incidence of bradycardia may be affected by heterogeneity between groups, meaning that precaution should be taken when designing further study with a greater number of patients undergoing TTM. This study also suggests the need for adjusting the infusion rate of dexmedetomidine in consideration of high incidence of bradycardia in 66% (37/56) patients undergoing TTM and anticipated increases in concentration along with the duration of TTM extends.

As far as weight is concerned, we conclude as follows: the plasma concentration of drug at steady state can be calculated by multiplying infusion rate by clearance (inversely proportional).[11] Therefore, if there are no factors that can increase clearance of an infused drug, the plasma concentration will increase with the rate of infusion. In this study, as the infusion rate of dexmedetomidine was decided in proportion to weight, the plasma concentration of drug is positively correlated with weight when clearance is declined in hypothermia conditions, increasing the risk of bradycardia in overweight patients. In descriptive analysis of 37 patients in the bradycardia group, the infusion rate of dexmedetomidine at the onset of bradycardia was 0.41 ± 0.15 µg/kg/h. Despite the steady infusion of dexmedetomidine at the known safe range of 0.2-0.7 µg/kg/h in the absence of loading dose, the incidence of bradycardia was high. This finding underscores the importance of dose reduction in hypothermia condition to prevent bradycardia.

As presented in Table 4, among the 37 patients who showed bradycardia, 29 patients recovered heart rate by more than 50 beats per min after therapeutic interventions such as dose adjustment and atropine administration. The rest 8 patients failed to recover heart rate by more than 50 beats per min irrespective of therapeutic interventions. However, a total of the 37 patients developed no worse outcomes such as asystole and unstable or lethal bradycardia that required additional cardiac rhythm management. Previous studies have found that declined cellular metabolism in hypothermia conditions decreased demand for cardiac output while cardiac contraction remained intact. This means that increasing heart rate using medication as part of the management of bradycardia, not accompanied by hypoperfusion may result in decreases in cardiac contraction or cardiac output. In less severe forms of bradycardia, cardiac rhythm management is also considered dangerous due to the risk of arrhythmia such as ventricular fibrillation.[15,16] Studies of adverse effects of dexmedetomidine on patients in hypothermia conditions are scarce. Tobias[26] reported a case in which child patients developed bradycardia during TTM at 35-36℃. In the case report, two children with severe traumatic brain damage were given dexmedetomidine but developed bradycardia during TTM when therapeutic hypothermia was additionally added. In these cases, bradycardia characterized by heart rate of 40 beat per min within 24 hours after TTM. However, there were no reduction in blood pressure and cerebral perfusion pressure, and the patients recovered normal heart rate 2 hours only after administration of dexmedetomidine discontinued. Although these cases are not comparable with this study due to the differences in study population and type of study, the results are consistent because the case reports also implies the importance of infusion control when bradycardia occurs when dexmedetomidine and TTM are combined.

This study however has limitations as follows: First, this study was conducted retrospectively by reviewing medical records and is susceptible to selection bias because variables not listed in medical records were excluded. Secondly, in this study, dexmedetomidine was administered by intravenous instillation, and loading dose was not used. Intravenous instillation is less effective than loading dose or cumulative dose, which can be calculated by referring to medical records, to identify the relationship between dexmedetomidine administration and the onset timing of bradycardia. Also, if desired sedation is not achieved by intravenous instillation of dexmedetomidine, a benzodiazepine could be added, but the effects of this addition were not investigated. Thirdly, patients become hemodynamically unstable during the induction period of TTM, regardless of the use of dexmedetomidine. However, it was impossible to identify the causes of unstability based on medical records. In cases of hypotension or increased vasopressor, the effects of dexmedetomidine could not be identified although the sedative agent is deemed to have mpacts on these symptoms and eventually the results of study. Fourthly, sedation of patients admitted to the ICU is initially evaluated with Ramsay and glasgow coma scale at the critical care unit of emergency department in our institution. However, there are usually crowded patients and relative deficits of human resources including doctors and nureses in the emergency department. Therefore, assessment of the symptoms and recordings regarding sedation were insufficiently achieved, which might make the analysis of this study incomplete. A sedation protocol needs to be implemented in emergency department as a requirement for the care of critically ill patients to prevent bradycardia in patients requiring TTM by adjusting doses of dexmedetomidine accurately and objectively. [27] Lastly, this study found a high incidence of bradycardia induced by dexmedetomidine in hypothermia conditions. However, data provided to support for this claim is limited because plasma dexmedetomidine concentration was not measured and the sample size of 12 in the MID group was too small.

In conclusion, this study proposes the following approaches for using dexmedetomidine safely in hypothermia conditions and ensuring sedative and clinical efficacy: First, consistent attention to the risk of bradycardia is required during the period of TTM because the frequency of dexmedetomidine-induced bradycardia is closely affected by diagnosis and weight in patients undergoing TTM. Secondly, for the doses of dexmedetomidine aimed to prevent bradycardia in hypothermia conditions, intravenous instillation of 0.2-0.7 µg/kg/h is recommended as the starting dose, and further reduction in dosage is necessary during the induction and maintenance period of TTM. Thirdly, if bradycardia occurs during the period when the starting dose was used, the rate of infusion can be decreased instead of stopping the infusion. Fourthly, in light of increasing plasma concentration of drug in hypothermia conditions and subsequent risk of developing bradycardia, high doses/high infusion rate of sedatives and the use of loading dose are discouraged. Lastly, it is important to identify pathophysiologic conditions between groups in a large scale study and to decrease infusion rate in accordance with the duration of TTM. Also, protocol-directed sedation is ultimately necessary to improve sedation practices.