Jacobs Journal of Anesthesiology and Research

Dexmedetomidine: An Update of its Pharmacology and Clinical Practice

*Maurizio Marandola
Department Of Cardiorespiratory, Sapienza University, Rome, Italy

*Corresponding Author:
Maurizio Marandola
Department Of Cardiorespiratory, Sapienza University, Rome, Italy
Email:maurizio.marandola@uniroma1.it

Published on: 2017-07-31

Abstract

Surgery and post-operative stress cause an highly risky hyperdynamic state, especially in the cardiovascular patient. In cardiac surgery increased myocardial oxygen demand can have serious sequelae, including death. The effective use of sedative-hypnotic agents and analgesics is an integral part of comfort and safety of the patients. Dexmedetomidine was approved as the most recent agent belonging to this group and was introduced into clinical practice as a short-term sedative.

Keywords

Dexmedetomidine; alpha2 Agonist; Cardiac Surgical Patient; Post-Operative Delirium; Conscious Sedation

Introduction

Perioperative dexmedetomidine use decreased incidence of postoperative complications and delirium, because it provides better hemodynamic stability, decreased sympathetic tone and attenuation of the neuroendocrine response. Dexmedetomidine is widely used for anesthetic premedication, sedation, anxiolysis and analgesia. In cardiovascular anesthesia, it appears to be an attractive alternative to the anesthetic adjunctive agents currently in use.

History

The alpha2 -adrenergic agonists (clonidine, dexmedetomidine) currently used in clinical practice have many desirable effects, including analgesia, anxiolysis, inhibition of central sympathetic outflow and reduction of systemic norepinephrine release, that improve hemodynamic stability, positively affect myocardial oxygen supply and demand, and can provide myocardial protection [1]. The most widely studied alpha2 - agonists is clonidine, a long–acting partial agonist with an alpha2 to alpha1 selectivity ratio of 39:1. Dexmedetomidine is a highly selective, shorter-acting intravenous alpha2 agonist with an alpha2 to alpha1 selectivity ratio of 1600:1 [2]. The use of alpha2 -adrenoceptor agonists as anesthetics is not new. The alpha2 -adrenergic agonists have been used in veterinary anesthesia since the late 1960s. Traditionally, its use has been limited to healthy adult dogs and cats with adequate cardiovascular reserve capacity and no evidence of heart disease, liver or kidney failure, shock or severe debilitation. For a long time Veterinarians have employed xylazine and detomidine to induce analgesia and sedation in animals, and much of our knowledge was gained from this application. Also in veterinary medicine the dexmedetomidine appears to be a very flexible drug. Justin et al. [3] investigated in captive and wild grizzly bears anesthetized with a combination of dexmedetomidine N-methyl-D-aspartate (NMDA) and tranquilizers (tiletamine and zolazepam, respectively). The initial impetus for the use of alpha2 agonists in anesthesia resulted from observations made during anesthesia in patients who were receiving clonidine therapy [4,5]. This was soon followed by a description of the minimum alveolar concentration (MAC) reduction of halothane by clonidine [6]. Martina Aho et al. [7], in 1991, conducted a double blind randomized study in 96 women undergoing abdominal hysterectomy to evaluate the effect of intravenously administered dexmedetomidine on perioperative haemodynamic and isoflurane requirements. The authors demonstrated that in the patients treated with dexmedetomidine (0.6 mcg/kg), the increase in blood pressure and heart rate after tracheal intubation was less than in the patients treated with fentanyl or simple saline solution. Scheinin B et al [8], in 1992, observed an attenuation of sympathoadrenal responses to tracheal intubation after administration of dexmedetomidine before induction anesthesia. Dexmedetomidine was introduced in clinical practice in the United States in 1999 and approved by the Federal Drug Administration (FDA) only as a short-term (<24 hours) sedative for mechanically ventilated adult patients in intensive care unit (ICU) [9] . In Europe it was introduced in clinical practice in 2011 by the European Medicine Agency (EMA) for the sedation in adult patients in ICU with a Richmond Agitation-Sedation Scale (RASS) score between 0-3 [10]. Dexmedetomidine is now being used off-label outside of the ICU in various settings, including sedation and analgesia in the operating room, sedation in diagnostic units and for other applications such as withdrawal/detoxification. It may be useful for the treatment of deleterious cardiovascular effects of acute cocaine intoxication and overdose [11]. Recently, FDA approved the use of dexmedetomidine in treating terminal cancer patients who are suffering from intractable pain, agitation or delirium [12].

Pharmacology

Dexmedetomidine is chemically described as 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride, with a pH range of 4.5-7 (it’s a molecular water soluble and has a pKa of 7.1). Dexmedetomidine is a pharmacologically active D-enantiomer of medetomidine, the methylated derivative of etomidine. Dexmedetomidine follows a linear or zero order kinetics, meaning that a constant amount of the drug is eliminated per hour rather than a constant fraction of the drug per hour. After intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; an onset of action approximately of 15 minutes, a terminal elimination half-life (t1/2) of approximately 2 hours; steady-state volume of distribution (Vss) of approximately 118 liters. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/h when administered by intravenous infusion for up to 24 hours. Clearance is estimated to be 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Total plasma clearance is age independent, but the volume of distribution (Vss) and consequently also the terminal elimination half-life (t1/2) were bigger in children younger than 2 years of age compared with older children [13]. This pharmacokinetic age-related difference leads younger children to need larger initial doses of dexmedetomidine than older ones and adults in order to reach similar steady-state plasma levels, but the maintenance doses are similar. Clinically, this is a well-known phenomenon [14]. However, the characterization of the pharmacokinetics and pharmacodynamics in children is still far from complete and further studies addressing both pharmacokinetic and pharmacodynamic issues at young age are warranted [15]. Dexmedetomidine is highly protein bound (94%). The protein-binding is similar in males and females and it undergoes extensive hepatic metabolism. Biotransformation involves both direct glucuronidation as well as cytochrome P450. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6) of dexmedetomidine to generate 3-hydroxy dexmedetomidine, the glucuronide of 3-hydroxy dexmedetomidine and 3-carboxy dexmedetomidine; N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine and N-methyl O-glucuronide dexmedetomidine. Dexmedetomidine undergoes an almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. There was no observed difference in pharmacokinetics related to gender. In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B or C), clearance values for dexmedetomidine were lower than in healthy ones. The mean clearance values for patients with mild, moderate and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively. Although dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [16]. In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be clinically relevant. The teratogenic effects have not been adequately studied at this time, but the drug does cross the placenta and should be used during pregnancy only if the benefits justify the risk to the fetus. The adverse effects of dexmedetomidine include hypotension, hypertension, nausea, bradycardia, atrial fibrillation and hypoxia [17]. Overdose may cause first degree or second degree atrioventricular block. No study has described the long term use of dexmedetomidine.

Mechanism of Action

Dexmedetomidine (DEX) is an imidazole compound highly selective, specific and potent alpha2 adrenergic agonist. It is chemically related to clonidine, but has a much greater affinity for alpha2 -receptors over alpha1 -receptors. alpha2 receptors have been found in the peripheral and central nervous system, platelets, liver, pancreas, kidney and eye [18]. These receptors appear to possess presynaptic, postsynaptic, extrasynaptic sites of action [19]. Activation of the above mentioned presynaptic receptors leads to alterations in ion channels that result in the inhibition of norepinephrine release. The physiological responses regulated by alpha2 receptors vary depending on their location. Dexmedetomidine has activity at a variety of locations throughout the central nervous system. The sedative and anxiolytic effects are the result of dexmedetomidine binding to receptors in the locus coeruleus of the brain stem. The locus coeruleus is also the site of origin for the descending medullospinal noradrenergic pathway, known to be an important modulator of nociceptive neurotransmission. Cardiovascular effects are due to the activation of both peripheral and central alpha2 receptors and, in larger doses, alpha1 receptors. alpha2 adrenergic agonists have protective effects against myocardial ischemia by increasing the cAMP level and enhancing adenosine-induced coronary vasodilatation effect [20,21]. A biphasic response in blood pressure is typical: we can observe an initial increase in blood pressure after a bolus followed by hypotension and bradycardia with a continued infusion. Stimulation of alpha2 -adrenergic receptors at this site reduces central sympathetic output, resulting in increased firing of inhibitory neurons. The interaction of dexmedetomidine with alpha2 -adrenergic receptors in the dorsal horns of the spinal cord modulates the release of substance P and produces its analgesic effects [22]. The spinal mechanism explain why anesthesiologists have found success in using clonidine as an epidurally administered agent in addition to its primary use as an intravenous drug [23]. The response from other organs containing alpha2 receptors include: decreased salivation, secretion and gastric motility; inhibited renin release; increased glomerular filtration rate; increased secretion of sodium and water in the kidney; decreased intraocular pressure; decreased insulin secretion from the pancreas [24]. The stimulation of alpha2 receptor decreases calcium entry into terminal nerves, which may contribute to its inhibitory effects on neurotransmitter release [25]. In addition, dexmedetomidine has been shown to have anti–inflammatory properties, decreasing mortality and attenuating plasma cytokine concentrations in laboratory animals exposed to endotoxin in a dose-dependent fashion [26]. The mechanism of action is unique and differs from those of currently used sedative agents, including clonidine. 

Dexmedetomidine in Anesthesia and in Intensive Care Units

Surgical stimulation and postoperative stress evoke increased levels of epinephrine and norepinephrine resulting in a state of hypercoagulopathy, thermal instability, hypertension and tachycardia. The hyperdynamic changes predispose to myocardial ischemia, especially in patients with coronary artery disease and a decreased reserve for coronary blood flow. Sedation is commonly used to reduce patients’ discomfort, to improve the mechanical ventilation tolerance in the intensive care unit (ICU), to prevent accidental devices removal and to reduce metabolic demands during respiratory and hemodynamic instability [27]. Continuous sedation have been associated with increased risk of delirium, longer duration of mechanical ventilation, increased length of ICU and hospital stays, long-term risk of neurocognitive impairment, post-traumatic stress disorder and mortality [28]. Dexmedetomidine provides effective sedation during surgical and non- surgical procedures and in the ICU setting, as it has a mechanism of action different from propofol and benzodiazepines. Long-term sedation with benzodiazepines or propofol in ICU has serious adverse effects. Lorazepam is associated with propylene glycol-related acidosis and nephrotoxicity while propofol may cause hypotension, hypertriglyceridemia, pancreatitis and propofol infusion syndrome. Dexmedetomidine is a good alternative for sedation in intensive care units, but it has several side effects. The most common side effects of dexmedetomidine are hypotension and bradycardia, and this limits its use in patients who are dependent on their cardiac output, such as patients in the acute phase of shock [29]. Jacob et al. [30] determined the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation and improving patients’ interaction with nursing care. The PRODEX (Propofol versus Dexmedetomidine) and MIDEX (Midazolam versus Dexmedetomidine) trials demonstrated that dexmedetomidine was not inferior to midazolam or propofol for long-term sedation in mechanically ventilated ICU patients [30]. Dexmedetomidine appeared to shorten mechanical ventilation duration if compared with midazolam but not if compared with propofol; however, the time to extubation was reduced when compared both with midazolam and propofol. Dexmedetomidine enhanced patients’ ability to communicate their pain to the nursing staff and facilitated an earlier extubation. The improved arousability and ability to communicate pain should allow more appropriate use of opioids and facilitate earlier mobilization and functional recovery. Therefore dexmedetomidine has several properties that may additionally benefit those critically ill patients who require sedation. Venn et al. [31] examined the respiratory effects of dexmedetomidine in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit and they concluded that dexmedetomidine had no deleterious clinical effects on respiration when used in doses that provide adequate sedation and effective analgesia in the surgical population requiring intensive care. In single–center retrospective analysis in patients post-operative from cardiac surgery, dexmedetomidine-based sedation often achieved an earlier extubation and a shorten length of hospital stay than propofol-based sedation [32]. Chorney et al.[33] observed no difference in the incidence of bradycardia and hypotension or in the time of mechanical ventilation in patients receiving dexmedetomidine after cardiac surgery compared to patients that received no sedation. Recent guidelines of the Society of Critical Care Medicine recommend using non-benzodiazepine agents, such as propofol or dexmedetomidine especially in patients at risk of delirium not related to alcohol and benzodiazepines use [34]. Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances. Its pathophysiology is highly heterogeneous and not completely understood. Dexmedetomidine provided similar sedation capacity to propofol and was associated with lower opioids requirement; however no differences in extubation times or length of stay were observed. Due to its associated morbidity and mortality, pharmacological and non-pharmacological interventions aimed to prevent the incidence and to reduce time of delirium remain a focal point of investigation in the ICU setting [35- 38]. Maldonado et al. [39] performed a single center study in critically ill post-valvular cardiac surgery patients, comparing open label dexmedetomidine, propofol and midazolam based therapy. They demonstrated that dexmedetomidine perioperatively started led to a significant reduction in the incidence of ICU delirium compared to the propofol and midazolam. The incidence of delirium was 3% in the dexmedetomidine group while it reached the 50% with midazolam and propofol. Pasin et al. [40], in a recent meta-analysis of randomized controlled studies, suggests that dexmedetomidine could help to reduce delirium, agitation and confusion in critically ill patients. A possible mechanism of action is represented by the alpha2 adrenergic-receptor agonist effect in the central nervous system. The authors’ meta-analysis presents some limitations, concluding that large, multicenter, randomized clinical trials would be welcome to confirm these findings. The efficacy and safety of dexmedetomidine for treatment of delirium in cardiac surgery were demonstrated also in a comparative study, with obvious reduction in duration of delirium [41]. 

Dexmedetomidine and Cardiac Surgery

Ji et al. [42] observed significant reduction in in-hospital, 30- day and 1 year mortality in patients undergoing cardiac surgery, who has received dexmedetomidine during the perioperative period. This retrospective study of a total of 1134 patients explored the impact of the alpha2 agonist on cardiac surgical patients from the operative room to the intensive care unit. Perioperative use of dexmedetomidine in addition was associated with improved survival and a significantly reduced incidence of postoperative sepsis. A meta-analysis, conversely, showed that perioperative dexmedetomidine use did not result in a statistically significant improvement in cardiac outcomes in patients undergoing non-cardiac surgery [43].

Cardiac surgery is associated with several complications: postoperative delirium, infection, acute renal failure, adverse cardio-cerebral events, myocardial infarction. Surgical stress is one of the most important factor in the pathogenesis of these complications. Intraoperative intravenous infusion of dexmedetomidine during cardiac surgery decreased intraoperative sympathetic tone with hyperdinamic response control. Protective effect of dexmedetomidine was observed in patient undergoing off-pump coronary artery bypass grafting [44]. Following the first vascular anastomosis grafting the patients in group Dex received a continuous infusion of dexmedetomidine, which was continued in the cardiac surgery intensive care unit for 12 h. Myocardial injures were assessed scheduling the hemodynamic changes, myocardial enzyme levels, myocardial ischemia and arrhythmic events in patients. The results revealed that dexmedetomidine was able to reduce the plasma levels of cTnI and CK-MB during administration, with reduction of post-surgical myocardial ischemia and incidence of arrhythmia. Coronary artery bypass grafting with extracorporeal circulation is a stressful procedure increasing sympathetic activity which could attenuate renal function. A randomized placebo-controlled study tested the correlation between dexmedetomidine and renal function [45]. The authors concluded that the use of intravenous dexmedetomidine, during cardiac surgery, did not alter renal function. It is conceivable that dexmedetomidine attenuates surgical stress-induced increases in circulating epinephrine and norepinephrine and maintains renal blood flow and glomerular filtration. Balkanay et al. [46] by measurements of blood neutrophil gelatinase-associated lipocalin levels (NGAL) have studied the renal damage and have revealed a dose-dependent positive effect of dexmedetomidine on renal functions when used after CABG. In conclusion, dexmedetomidine is predominantly used as a sedative, but the intraoperative administration as an adjuvant anesthetic drug has proved to be satisfactory in cardiac surgery. 

In summary, dexmedetomidine produced rapid and stable sedation in post-surgical ventilated patients while maintaining a high degree of patient arousability and anxiety reduction. In the early follow-up period after CABG, we are faced negative effects of extracorporeal circulation and inflammatory response and dexmedetomidine played a significant role in our postoperative CABG patient management. In our institutional experience, we have found that intravenous infusion of dexmedetomidine at dose of 0.2-0.7 mcg/kg/h produced clinically effective sedation and reduced significantly the analgesic requirements of postsurgical ventilated intensive care unit patients. The weaning from mechanical ventilation has been regular and predictable, besides the hemodynamic parameters were stable and easy to control with a dose dependent effect on heart rate and blood pressure. In conclusion, dexmedetomidine represents a further arrow in our quiver of drugs and it seems to have promising future applications in neuroprotection, cardioprotection and renoprotection.

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