No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans
Abstract
Dexmedetomidine is a potent and highly selective α2-adrenoceptor agonist with a selectivity ratio of 1600:1 (α2:α1). Dexmedetomidine is a highly lipophylic agent that is rapidly distributed to tissues with a distribution half-life (t1/2α) of approximately 6 minutes. It is extensively distributed and rapidly eliminated, with a mean elimination half-life (t1/2) of 2–2.5 hours. This rapid distribution and short elimination kinetics makes dexmedetomidine amenable to frequent titration allowing adjustability of dosage and effects. Generally, dexmedetomidine does not exhibit pharmacokinetic-based interactions; however, dosage modifications of some concomitant medications may be needed to be adjusted due primarily to common pharmacological actions of the two drugs. Dexmedetomidine is eliminated by metabolism to inactive metabolites, primarily glucuronides. Eighty to ninety percent of an administered dose is excreted in the urine and 5%–13% in the faeces.
... In ICU patients, CL has been defined at 31.8-57 l/h (Venn et al., 2002;Zhang et al., 2015). In healthy volunteers, the elimination half-life is 2.1-3.1 h, and in ICU patients, the half-life slightly increases to 2.2-3.7 h (Karol and Maze, 2000;Venn et al., 2002;Zhang et al., 2015). In this context, the presence of hypoalbuminemia decreases or increases half-life times (Iirola et al., 2011a;Zhang et al., 2015). ...
... Numerous factors influencing the DEX dosage have been reported in the literature. Conditions such as hypoalbuminemia, liver dysfunction, reduced cardiac output, and hemodynamic alterations significantly affect both the VD and CL (Karol and Maze, 2000;Dutta et al., 2000;Zhang et al., 2015). Several pharmacokinetic models developed in different populations show that observed inter-individual variability of DEX body disposition is explained by the influence of the aforementioned covariates on pharmacokinetic parameters and patient dose requirements. ...
... Several pharmacokinetic models developed in different populations show that observed inter-individual variability of DEX body disposition is explained by the influence of the aforementioned covariates on pharmacokinetic parameters and patient dose requirements. Other covariates, such as ethnicity and polymorphisms of metabolic enzymes, are less relevant contributors to the described variability (Karol, 1996;Karol and Maze, 2000;Kurnik et al., 2008;Kohli et al., 2012). ...
Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.
... In pre-clinical animal studies, it was found that dexmedetomidine readily crosses the blood-brain and placenta barriers [2,3]. Using non-compartmental analysis, a distribution half-life of about 6 min was found in healthy volunteers [15,19]. The apparent volume of distribution was found to be related to body weight, with a volume of distribution at steady state in healthy volunteers of approximately 1.31-2.46 ...
... The apparent volume of distribution was found to be related to body weight, with a volume of distribution at steady state in healthy volunteers of approximately 1.31-2.46 L/kg (90-194 L) [16,[19][20][21]. In ICU patients, values are highly variable and mean volumes of distribution from 109 to 223 L have been reported [22][23][24]. ...
... A hepatic extraction ratio of 0.7 was found [26]. Less than 1% is excreted unchanged with metabolites being excreted renally (95%) and fecally (4%) [2,3,19]. Direct N-glucuronidation by uridine 5 0 -diphospho-glucuronosyltransferase (UGT2B10, UGT1A4) accounts for about 34% of dexmedetomidine metabolism. ...
Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.
... Dexmedetomidin bindet in erster Linie an Serumalbumin; die Proteinbindung beträgt sowohl bei Männern als auch bei Frauen ca. 94% und zeigte sich unverändert bei renaler Dysfunktion, nahm jedoch bei hepatischer Dysfunktion leicht auf bis zu 82% ab [25]. ...
... Beide Parameter waren tendenziell bei renaler Dysfunktion sogar leicht erhöht, und die terminale Halbwertszeit war bei Probanden mit renaler Dysfunktion geringfügig, aber statistisch signifikant reduziert (113±11 vs. 137±13 min). Ob Änderungen in der Proteinbindung bei renaler Dysfunktion die Ursache für diesen Effekt sein könnten, ist unklar, zumal in anderen Studien keine Änderung der Proteinbindung beobachtet wurde [25]. Dass die Nierenfunktion anscheinend keinen nennenswerten Effekt auf die Pharmakokinetik von Dexmedetomidin hat, hat seinen Grund in der vorwiegend hepatischen Metabolisierung. ...
... 47% reduziert; die terminale Halbwertszeit betrug in diesen Fällen 3,9 h, 5,4 h resp. 7,4 h und war damit gegenüber Normalpatienten (2,5 h) deutlich verlängert [25]. Da die Erhaltungsinfusionsrate für eine definierte Plasmakonzentration direkt proportional zur Clearance ist (I ss =C Ziel •CL), sollte bei hepatischer Dysfunktion die Infusionsrate entsprechend reduziert werden. ...
Mit Dexmedetomidin ist 2011 ein potenter selektiver α2-Adrenozeptor-Agonist zur Sedierung erwachsener, intensivmedizinisch behandelter Patienten neu auf dem europäischen Markt zugelassen worden. Dexmedetomidin zeigt konzentrationsabhängig sowohl sedierende als auch analgetische und anxiolytische Wirkungen. Aktuelle Studien lassen Dexmedetomidin als eine Alternative zu Midazolam für die Langzeitsedierung erscheinen. In dieser Übersichtsarbeit werden die pharmakokinetischen und pharmakodynamischen Eigenschaften von Dexmedetomidin insbesondere bei intensivmedizinischen Patienten, unter besonderer Berücksichtigung des Einflusses von Kovariaten, zusammengefasst. Obwohl Dexmedetomidin nur für Erwachsene zugelassen ist und die Anwendung bei Kindern daher einem ,,off label use“ entspricht, wird auch auf die Pharmakokinetik und -dynamik bei Kindern eingegangen, da dazu ebenfalls zahlreiche Studien vorliegen.
... This observation is supported with the evidence that IV dexmedetomidine has an onset time of 15 minutes, a distribution half-life of 6 minutes, and an elimination half-life of 2.1-3.1 hours. The metabolites of dexmedetomidine are inactive at the α-2 receptors [26][27][28]. Hence, any systemic effect of dexmedetomidine beyond this period would not be expected. ...
... At 15 minutes, the patients receiving systemic dexmedetomidine showed a higher RSS than the control group, while those receiving perineural dexmedetomidine showed the lowest RSS. Intervenous dexmedetomidine, which produces a sedative effect, has its onset effect at 15 minutes [26,27]. However, the results of the RSS may be affected by ethnicity, age, body size, cardiac output, hypoproteinemia, and hepatic metabolism [32]. ...
Background:
The effect of dexmedetomidine as an adjuvant in the adductor canal block (ACB) and sciatic popliteal block (SPB) on the postoperative tramadol-sparing effect following spinal anesthesia has not been evaluated.
Methods:
In this randomized, placebo-controlled study, ninety patients undergoing below knee trauma surgery were randomized to either the control group, using ropivacaine in the ACB + SPB; the block Dex group, using dexmedetomidine + ropivacaine in the ACB + SPB; or the systemic Dex group, using ropivacaine in the ACB + SPB + intravenous dexmedetomidine. The primary outcome was a comparison of postoperative cumulative tramadol patient-controlled analgesia (PCA) consumption at 48 hours. Secondary outcomes included time to first PCA bolus, pain score, neurological assessment, sedation score, and adverse effects at 0, 5, 10, 15, and 60 minutes, as well as 4, 6, 12, 18, 24, 30, 36, 42, and 48 hours after the block.
Results:
The mean ± standard deviation of cumulative tramadol consumption at 48 hours was 64.83 ± 51.17 mg in the control group and 41.33 ± 38.57 mg in the block Dex group (P = 0.008), using Mann-Whitney U-test. Time to first tramadol PCA bolus was earlier in the control group versus the block Dex group (P = 0.04). Other secondary outcomes were comparable.
Conclusions:
Postoperative tramadol consumption was reduced at 48 hours in patients receiving perineural or systemic dexmedetomidine with ACB and SPB in below knee trauma surgery.
... Direct N-glucuronidation by uridine 50-diphosphate-glucuronosyltransferase (UGT2B10, UGT1A4) represents about one-third of dexmedetomidine biotransformation. Furthermore, hydroxylation intervened by cytochrome P450 (CYP) proteins (essentially CYP2A6) is exhibited in liver microsomes [13]. The products of metabolism are hundredfold less powerful as alpha2adrenoceptor agonist and therefore they are considered to be inactive. ...
... Less than 1% of dexmedetomidine is removed unaltered, 90-95% of the results of metabolism are discharged in the urine, and 4-10% in feces [13,14]. The elimination half-life (t1/2) of 2.1-3.1 h, it is accounted in good health volunteers [14]. ...
Patients undergoing neurosurgical procedures or requiring mechanical ventilation at the end of the neurosurgical procedure need analgosedation to reduce the anxiety and discomfort related to the intervention, as well as to minimize ventilator intolerance and desynchronizations. Dexmedetomidine is an alpha2-adrenergic agonist (C13H16HCl), as clonidine but more selective for alpha2-receptor. Dexmedetomidine has become increasingly popular for use in neurosurgical procedures and intensive care units (ICU) due to its proposed peculiarities for the management of systemic and cerebral hemodynamics, and the need for intraoperative cortical mapping.
... Conversely, although there was a tendency toward norepinephrine increase after dexmedetomidine was stopped (from 0.3 to 0.42 μg/kg/min), we still observed a significant difference from baseline (0.69 vs 0.42 μg/kg/min), which we believe cannot be entirely attributed to clinical improvements of patients' conditions. Taken together, our findings indicate that modifications induced by dexmedetomidine persisted after discontinuation and, considering the drug pharmacokinetics, it is unlikely that this was consequence of carryover effects (15). ...
... The enrolment performed during different phases of the disease (both early and established septic shock), the relatively brief observational period, as well as the large variation in norepinephrine dose observed, may reduce the chances of this bias. Considering the pharmacokinetics of dexmedetomidine (distribution half-life of approximately 6 min, mean elimination half-life of roughly 2 hr) and its clinical response (15), it is unlikely that carryover effects occurred despite the study design. Indeed, dexmedetomidine administration lasted 4 hours only without a loading dose, and the last collection time point was chosen 8 hours after dexmedetomidine discontinuation. ...
Objectives:
Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock.
Design:
Prospective open-label crossover study.
Settings:
University hospital, ICU.
Patients:
Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4.
Interventions:
An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period.
Measurements and main results:
Norepinephrine requirements decreased from 0.69 ± 0.72 μg/kg/min before dexmedetomidine to 0.30 ± 0.25 μg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 μg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 μg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 μg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07).
Conclusions:
For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.
... Dexmedetomidine undergoes a complex biotransformation with a small fraction excreted unchanged into urine. The major pathway of biotransformation is glucuronidation, however metabolites are also formed by cytochrome P450 enzymes (mainly 2D6 isoform) [4]. All the metabolites are pharmacologically inactive. ...
... Plasma was placed in a freezer (-80°C). For 22 patients, blood samples were collected just before and at 1,4,8,12,16,20 h after initiation of infusion, and then just before and at 5, 10, 20, 60 min and 2, 4 and 6 h after infusion cessation. For 5 patients a slightly modified protocol was used with samples obtained just before and at 2, 8, 24, 32, 48, 56, 72 and 80 h after initiation of infusion, and then just before and at 5, 10, 15, 30, 60 min and 2, 4, 6 and 12 h after infusion cessation. ...
Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients' health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration.
... 33 Less than 1% is excreted unchanged with metabolites being excreted renally (95%) and fecally (4%). 34 It has an elimination half -life of 2 -3 hours. 24 The most common adverse effects of dexmedetomidine are, due to its mechanism of action, hypotension and bradycardia, as well as dry mouth and nausea. 2 Taking these effects into account, although no definite contraindications exist in regards to dexmedetomidine, relative contraindications to the use of dexmedetomidine have been suggested and include a known sinus node or atrioventricular node dysfunction, and those with limited sympathetic reserve with caution employed in those with comorbid heart disease or when taken with medications with a negative chronotropic effect. ...
Acute agitation occurs in a variety of medical and psychiatric conditions and is the clinical presentation in a significant percentage of urgent psychiatric episodes, requiring prompt and effective intervention. Traditionally, agitation was managed in psychiatric wards using physical restraint. With the advent of tranquilizing neuroleptics, such as chlorpromazine, the pharmacological management of these conditions became possible. Acute agitation, although a potential result of most psychiatric disorders, is often associated with psychotic conditions, mood disorders and neurodegenerative disorders. The authors propose to explore dexmedetomidine as a therapeutic option in states of acute agitation in psychiatric patients in which traditional drugs are not effective. The authors based the work on a non-systematic review of the literature. Keywords used included: dexmedetomidine, acute agitation, rapid tranquilisation, restraint, sedation, psychiatric population and psychiatric disorders. Recently, a significant step forward in methods of treating acute agitation has been achieved through the use of dexmedetomidine in psychiatric patients. It is a selective α2‐receptor agonist being approved for short‐term sedation with the benefit of not having excessive sedation, thus allowing a concomitant psychotherapeutic approach. This proves to be a promising treatment option for those with acute agitation. The amount of studies available on its usefulness in psychiatric mental illness are still scarce. The interventional recommendations in the literature for agitation were developed based on research data, theoretical considerations and clinical experience, however, studies that provide definitive data are needed. It is imperative that the investigation of episodes of acute agitation and their restraint evolve, in order to protect these patients from the consequences of this behaviour and its treatment. Exploring the potential of dexmedetomidine as a tool in the mental health professional’s kit is well deserved as there are few alternatives that reassure the highly agitated patient without excessive sedation.
... Therefore, the effects of benzodiazepines and opioids may be greater in a patient undergoing treatment with dexmedetomidine than without co-administration of dexmedetomidine. Dexmedetomidine is metabolized by the liver via direct glucuronidation and CYP2A6 metabolism followed by clearance in the urine and secondarily in feces [54,55]. Dose adjustments must be considered in patients with liver function impairment and those taking medications that manipulate the activity of CYP2A6, such as amiodarone and phenobarbital. ...
Postoperative delirium (POD) represents a perioperative neurocognitive disorder that has dreaded ramifications on a patient’s recovery from surgery. Dexmedetomidine displays multiple mechanisms of neuroprotection to assist in preventing POD as a part of a comprehensive anesthetic care plan. This review will cover dexmedetomidine’s pharmacological overlap with the current etiological theories behind POD along with pre-clinical and clinical studies on POD prevention with dexmedetomidine. While the body of evidence surrounding the use of dexmedetomidine for POD prevention still requires further development, promising evidence exists for the use of dexmedetomidine in select dosing and circumstances to enhance recovery from surgery.
... Dexmedetomidine, a novel highly selective α2:α1 adrenoreceptor agonist, produces dose dependent sedation, anxiolysis and analgesia without respiratory depression [4]. The intraperitoneal instillation of local anaesthetics have been found to be a simple, safe and effective analgesic in postoperative period following laparoscopic surgeries. ...
Background and Aims: Laparoscopic cholecystectomy has emerged as a gold standard technique for gall bladder stones. The aim of the present study was to compare the analgesic effect of intravenous (IV) vs intraperitoneal (IP) dexmedetomidine as an adjuvant to intraperitoneal (IP) bupivacaine in laparoscopy. Methods: A prospective, randomized, double blind, interventional study was conducted on 100 patients undergoing laparoscopic cholecystectomy where they were divided into following 2 groups: Group A: Patients received IV 1µg/kg dexmedetomidine diluted to 30 ml with normal saline over 10 min and 40 ml of 0.125% bupivacaine IP after removal of gall bladder. Group B: Patients received IV 30 ml of normal saline and 1µg/kg IP dexmedetomidine in 40 ml of 0.125% IP bupivacaine after removal of gall bladder. The primacy outcome was noted as a difference in mean duration for need of first rescue analgesia. The total consumption of analgesic in first 24hours was recorded and compared between the two groups. Results: Both the groups were comparable in terms of demographic profile and intraoperative hemodynamic parameters with no statistical difference. Comparison of time to first analgesic requirement between the two groups showed statistically significant results with unpaired t test The time of first rescue analgesia in Group A was 151.80 min ± 76.624. and in Group B was 94.80min ± 21.499. The total analgesic requirement in 24 hours in Group A was 136.64 ± 31.251 and in Group B was 144.12 ± 21.49. Conclusion: In our study we concluded that intravenous dexmetomidine provided superior analgesia as compared to intraperitoneal dexmetomidine when used as an adjuvant with Bupivacaine intraperitoneally.
... However, this longitudinal study utilizing intravital imaging techniques removes many sources of bias and makes a spurious finding less likely: the stabilizing effect increases with dosage and follows a consistent time series, which suggests a relationship with the pharmacokinetics and metabolism of DEX in mice. In humans, DEX has been found to distribute rapidly to tissues, with a distribution half-life of about 6 min and a mean elimination half-life of 2-2.5 h (Karol & Maze, 2000). The short timespan associated with DEX uptake in tissues by Karol and Maze matches well with the duration of the sedative effect which was observed in this study, although further studies are required to determine the limitations of DEX for stabilizing preclinical microscopy (i.e., build-up or tolerance development in mice). ...
Among intravital imaging instruments, the intravital two-photon fluorescence excitation microscope has the advantage of enabling real-time 3D fluorescence imaging deep into cells and tissues, with reduced photobleaching and photodamage compared with conventional intravital confocal microscopes. However, excessive motion of organs due to involuntary movement such as breathing may result in out-of-focus images and severe fluorescence intensity fluctuations, which hinder meaningful imaging and analysis. The clinically approved alpha-2 adrenergic receptor agonist dexmedetomidine was administered to mice during two-photon fluorescence intravital imaging to alleviate this problem. As dexmedetomidine blocks the release of the neurotransmitter norepinephrine, pain is suppressed, blood pressure is reduced, and a sedation effect is observed. By tracking the quality of focus and stability of detected fluorescence in two-photon fluorescence images of fluorescein isothiocyanate-sensitized liver vasculature in vivo , we demonstrated that intravascular dexmedetomidine can reduce fluorescence fluctuations caused by respiration on a timescale of minutes in mice, improving image quality and resolution. The results indicate that short-term dexmedetomidine treatment is suitable for reducing involuntary motion in preclinical intravital imaging studies. This method may be applicable to other animal models.
... They have shown clinical superiority to placebo in reduction of withdrawal symptoms' severity and treatment completion [25]. As dexmedetomidine has a 6-fold higher affinity for the α2-subunit than clonidine, a hepatic versus renal metabolism, and its elimination half-life is much shorter (2 h versus 6-10 h), it is amenable to frequent titration allowing doses and effects adjustments [26]. Clonidine has similar pharmacologic properties, but its high oral bioavailability, longer half-life, facility of oral method of administration and lower cost provide a convenient and tolerable tapering option for patients on prolonged dexmedetomidine infusions [27]. ...
COVID-19 patients suffering from severe acute respiratory distress syndrome (ARDS) require mechanical ventilation (MV) for respiratory failure. To achieve these ventilatory goals, it has been observed that COVID-19 patients in particular require high regimens and prolonged use of sedatives, analgesics and neuromuscular blocking agents (NMBA). Withdrawal from analgo-sedation may induce a “drug withdrawal syndrome” (DWS), i.e., clinical symptoms of anxiety, tremor, agitation, hallucinations and vomiting, as a result of adrenergic activation and hyperalgesia. We describe the epidemiology, mechanisms leading to this syndrome and our strategies to prevent and treat it.
... The drug is highly bound to plasma proteins (94%) and has a hepatic extraction ratio of 0.7. 3,4 Dexmedetomidine causes minimal sedation, thus allowing patients to cooperate with caregivers. This is a desired property, as current guidelines indicate that overly deep sedation negatively influences the clinical outcomes of patients. ...
Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed‐effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single‐nucleotide polymorphisms were tested. A 2‐compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for <5% of interindividual variability and consequently are of low clinical significance for the purpose of dose adjustment.
... It does not cause respiratory depression; however, hemodynamics must to be closely monitored, as it produces dosedependent decrease in blood pressure and heart rate resulting from its sympatholytic effects [8]. It has minor effects on cognitive function, thus giving the chance for easy communication and cooperation with the patient [9]. ...
... The recent acquisitions and results about this technique are based on the rising use of Dexmedetomidine (DEX), a potent highly selective α2-adrenoceptoragonist [17] with sedative, anxiolytic, analgesic, opioid-sparing [18] and sympatholytic effects. In contrast to other sedative agents, DEX is not associated with respiratory depression; this effect is clinically relevant as demonstrate in a prospective randomized study [19]. ...
Background: It is well demonstrated that awake surgery for brain tumours is the gold standard to achieve the maximal safe resection. On the other hand, many surgeons prefer general anesthesia in order to avoid useless stress for patients. The aim of our paper is to investigate if there are clinical and biochemical findings demonstrating a different stress level in patients who underwent awake craniotomy compared to those who underwent totally asleep surgery. Methods: We compared our awake craniotomy series performed with conscious sedation using Dexmedetomidine to a group of patients treated in general anesthesia settings in terms of patient stress, rated by blood pressure, heart rate, glycaemia, lactate values, post-operative ischemia or bleeding at the MRI. We also compared the duration of surgeries in the two groups and the relations between time and other parameters. Results: We found that preoperative heart rate was higher in the awake group (63.00 (SD13.58) vs. 76.5 (SD 14.34) p value 0.025) together with preoperative systolic blood pressure 122 (SD 12.95 vs. 135.1 SD (11.78) p value 0.044). However there were no clinical, biochemical and radiological differences in post-operative period in the two groups, suggesting the efficacy of Dexmedetomidine in stress control. It is demonstrated a cause-effect relation between the duration of surgery and the raising of blood pressure, suggesting that conscious sedation can reduce useless anesthesiological time in the awake surgery setting. Conclusions: We showed that the two anesthetic settings are similar in terms of stress parameters after surgery. This finding could be confirmed in a prospective study with a higher number of patients.
... The effect of a 2 agonists on hemodynamics is caused by stimulation of a 2 adrenoceptors in the central nervous system [17,18]. It has a very short half-life of distribution, approximately 6 min, and elimination time of 2 hr [19]. ...
Background: Acute hypertension is a common accompaniment during emergence from anesthesia especially in intracranial neurosurgical procedures and may be associated with the development of intracranial hematoma. Although various drugs have been evaluated, management of emergence hypertension in this subset of patients continues to be a challenge for anesthesiologists.
Methodology: Seventy-five patients ASA (I-II) scheduled for supratentorial craniotomy under general anesthesia were randomly allocated to one of three groups at the time of dural closure: Group “dex” received dexmedetomidine infusion in a rate of 1 μg/kg/hr, Group “labetalol” received labetalol infusion in a rate of 0.5 mg/kg/hr, and Group “control” a control group where patients received saline infusion at the same rate of dexmedetomidine and labetalol. Hypertensive episodes were managed with nitroglycerin at a dose starting from 1 μg/kg/min if systolic blood pressure exceeded 25% of its preinduction value. Hemodynamic parameters as well as the number of patients, the total dose of nitroglycerin required in each group and the time to extubation were recorded.
Results: Dexmedetomidine and labetalol had a significant effect in reducing SBP, MAP, DBP, HR during emergence from anesthesia, with more reduction of the SBP, MAP and DBP in the dexmedetomidine group and of the HR in the labetalol group in comparison with the other two groups. The number of patients needing nitroglycerin was 8 representing 32% of patients in dexmedetomidine group, 5 representing 20% of patients in labetalol group and 22 representing 88% of patients in control group (P value = 0.032). Time to emergence from anesthesia was comparable in the three groups.
Conclusion: Both dexmedetomidine and labetalol had favorable effects on hemodynamics at time of emergence from anesthesia in comparison with control group without prolongation of the time of extubation.
... These metabolites are hundredfolds less potent than dexmedetomidine and are considered inactive 60,61 . About 95% of the metabolites and unchanged dexmedetomidine is excreted renally, while the rest fecally 49,62 . Pharmacokinetics of the drug has been investigated in many clinical studies, especially on adults. ...
Dexmedetomidine is an alpha 2-adrenoceptor agonist and has been used as a general anesthetic, sedative, and analgesic for about thirty years. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine, evaluate physiological factors that may affect the pharmacokinetics of dexmedetomidine, and summarize the pharmacodynamics of dexmedetomidine at different plasma levels. The pharmacokinetic parameters reported in previous studies according to non-compartmental analyses or population modeling results are compared. We that the pharmacokinetic profile can be adequately described by a two-compartment model in population pharmacokinetic modeling. Body weight, height, albumin level, cardiac output, disease condition, and other factors were considered to have significant influence on the clearance and/or distribution volume in different population pharmacokinetic models. The pharmacological effects of dexmedetomidine, such as sedation, heart rate reduction, and biphasic change of blood pressure, vary at different plasma levels. These findings provide a reference for individualizing the dose of dexmedetomidine and achieving the desired pharmacological effects in clinical applications.
... [8][9][10][11] However, in AC patients with an unsecured airway, the use of propofol sedation in combination with opioids has been associated with intraoperative airway and/or respiratory complications, and poor patient cooperation during cortical mapping. 9 12-14 Dexmedetomidine is a potent, highly selective α 2 -adrenoceptor agonist [15][16][17] with sedative, anxiolytic, analgesic, opioid-sparing, 18 and sympatholytic effects. 16 In contrast to other sedative agents, dexmedetomidine is not associated with respiratory depression. ...
Background: Awake craniotomy (AC) is performed for the resection of brain tumours in close proximity to areas of eloquent brain function to maximize reduction of tumour mass and minimize neurological injury. This study compares the efficacy and safety of dexmedetomidine vs propofol-remifentanil-based conscious sedation, during AC for supratentorial tumour resection.
Methods: Prospective, randomized, controlled trial including 50 adult patients undergoing AC who were randomly assigned to a dexmedetomidine (DEX group, n=25) or propofol-remifentanil group (P-R group, n=25). The primary outcome was the ability to perform intraoperative brain mapping assessed on a numeric rating scale (NRS). Secondary outcome was the efficacy of sedation measured by the modified Observer's Assessment of Alertness/Sedation (OAA/S) scale. Other outcome measures including haemodynamic and respiratory variables, pain, sedation and anxiety scores, adverse events, and patient satisfaction were also compared.
Results: There were no differences between DEX and P-R groups regarding the ability to perform intraoperative brain mapping [mean NRS score (95% CI): 10.0 (9.9–10.0) vs 9.7 (9.5–10.0), P=0.13] and level of sedation during mapping [mean OAA/S score (95% CI): 4.1 (3.5–4.7) vs 4.3 (3.9–4.7), P=0.51], respectively. Respiratory adverse events were more frequent in the P-R group (20 vs 0%, P=0.021). Heart rate was significantly lower in the DEX group across time (P<0.001); however, the need for treatment of bradycardia was not different between groups.
Conclusions: Quality of intraoperative brain mapping and efficacy of sedation with dexmedetomidine were similar to propofol-remifentanil during AC for supratentorial tumour resection. Dexmedetomidine was associated with fewer respiratory adverse events.
Clinical trial registration: NCT01545297.
... Consistent with a study by Patel [20], in the present study, the end-tidal concentration of sevoflurane after 60 min was lower in the SD group (1.20 ± 0.38) compared to the SN group (1.68 ± 0.48, P < 0.001). According to the previous studies, dexmedetomdine decreased effective end-tidal concentration of isoflurane and effective plasma concentration of propofol for abolishing motor or verbal responses [23]. In case of motor response, end-tidal isoflurane concentration at which 50 % of subjects responded was decreased from 1.048 to 0.722 % when plasma concentration of dexmedetomidine was maintained as 0.3 ng/ml. ...
Background:
Intraoperative dexmedetomidine may decrease postoperative emergence agitation in elderly patients due to its sedative effect. In this study, we evaluated the effect of adjuvant dexmedetomidine on smooth emergence from anaesthesia after orthopaedic surgery in elderly patients.
Methods:
A total 115 patients (ASA I-II, aged over 65 years) were randomly allocated into four groups. Anaesthesia was maintained with either sevoflurane or total intravenous anaesthesia (TIVA) comprising propofol and remifentanil. Patients were also administered either dexmedetomidine (0.4 μg kg(-1) hr(-1); SD and TD) intraoperatively or normal saline (SN or TN) as a control. The bispectral index (BIS) score was maintained from 40-60 intraoperatively. All anaesthetics and dexmedetomidine were discontinued at surgical conclusion, and the recovery times (durations to a BIS = 60, 70, and 80; eye opening; and extubation) were measured. The mean arterial pressure, heart rate, Ricker's agitation-sedation scale (RSAS), visual analogue scale (VAS) for pain, and incidences of emergence agitation and postoperative nausea and vomiting (PONV) were measured in the recovery room.
Results:
Dexmedetomidine significantly decreased the RSAS score in the SD and TD groups, and a calm state postoperatively occurred more frequently in these groups than in the control groups. The heart rate and incidence of emergence agitation were lower in the dexmedetomidine groups. Recovery time was higher in the SD group than in the SN group, and no significant differences occurred between the TN and TD groups. The VAS score was lower in the SD group than in the SN group, and the PONV did not differ regardless of the use of dexmedetomidine.
Conclusions:
Dexmedetomidine may be an effective intraoperative adjuvant for a reducing emergence agitation and smooth emergence from anaesthesia after orthopaedic surgery in elderly patients.
Trial registration:
Current Controlled Trials NCT01851005 .
... The onset of action with this regime is~10-15 min, and peak concentrations are achieved within an hour (Precedex, 2008). Following intravenous administration, dexmedetomidine undergoes a rapid distribution phase with a distribution half-life of~6 min, although context-sensitive half-life increases with duration of infusion (Karol & Maze, 2000). The terminal elimination half-life of dexmedetomidine is~2 h. ...
Dexmedetomidine (an alpha-2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesized that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analyzed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A 'Dex bolus' group (dexmedetomidine bolus prior to MER, 27 cells from 7 patients) was compared with a 'no sedation' group (29 cells from 11 patients). We also performed within-patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analyzed using the Kaneoke-Vitek methodology and local field potential (LFP) oscillatory activity was also interrogated. Dexmedetomidine was associated with a slight increase in firing rate (41.1±9.9 Hz vs. 34.5±10.6 Hz, p = .02) but a significant decrease in burstiness (number of bursts, p = .02; burst index, p < .001; percentage of spike in burst, p = .002) of dorsal but not ventral STN neurons. No associated differences in beta spike oscillations (spike oscillation beta peak, p = .4; signal-to-noise ratio in the beta range for spikes and bursts, p = .3 and p = .5, respectively) and LFP beta power (p = .17) were observed. Since bursting pattern is often used to help identify STN and guide electrode placement, we recommend that high-dose dexmedetomidine should be avoided during DBS surgery. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... Approximately 80-90% is excreted in the urine, and 5-13% is found in the feces. 25 Typically, pharmacokinetic-based interactions are unusual. However, dosage modifications of simultaneously administered sedatives may need to be made because of drug potentiation. ...
The α-2 adrenergic receptor agonists have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity disorder; various pain and panic disorders; symptoms of opioid, benzodiazepine, and alcohol withdrawal; and cigarette craving. (1) However, in more recent years, these drugs have been used as adjuncts for sedation and to reduce anesthetic requirements. This review will provide an historical perspective of this drug class, an understanding of pharmacological mechanisms, and an insight into current applications in clinical anesthesiology.
... It is quickly distributed into tissues with a distribution half-life of ∼6 min. It i s metabolized in the liver to practically inactive products, mainly glucuronides, with a mean elimination half-life of 2-2.5 h [8]. ...
... Otros autores mencionan que se debe a una reducción presináptica de la liberación de noradrenalina o a un efecto vagomimético directo. Disminuye los requerimientos de fármacos hipnóticos, opioides y halogenados hasta en un 30%, siendo dosis dependiente al isofl urano hasta un 90% (13)(14)(15)(16) . ...
RESUMEN La cirugía ortognática es ampliamente utilizada en el mundo debido a que corrige disarmonías dentofaciales, éstos son procedimientos muy precisos. El sangrado transoperatorio, que se presenta en estas cirugías es importante, por tanto, existe la probabilidad de realizar una transfusión sanguínea. Disminuir el sangrado, es una meta en el manejo anestésico. Los 2 agonistas, como la dexmedetomidina, disminuyen los requerimientos de otros fármacos empleados tanto en la inducción como en el manteni-miento anestésico, acción que al parecer está relacionada con el efecto inhibitorio sobre la transmisión central de tipo noradrenérgico. Resultados: Se incluyeron 55 expedientes de pacientes, ambos sexos, sometidos a cirugía ortognática, con intubación nasal, mantenimiento anestésico con isofl urano o sevofl urano más infusión de dexmedetomidina. Se encontró bradicardia del 12%, presión arterial media alrededor de los 70 mmHg, consumo promedio de 43.5 mL de isofl urano y 78 mL de sevofl urano, dexmedetomidina 191.64 g, fentanyl 254.53 g, sangrado de 478 mL. Conclusión: El uso de dexmedetomidina como adyuvante en el manejo anestésico es otra opción, ya que mantiene cifras tensionales adecuadas sin sangrado importante disminuyendo el requerimiento de transfusiones. Palabras clave: Cirugía ortognática, hipotensión controlada, dexmede-tomidina. SUMMARY Orthognathic surgery, is widely used in the world, because correct den-tofacial disharmonies, these are very precise procedures. Intraoperative bleeding, which occurs in these surgeries, is important, therefore, the chances are for a blood transfusion. Decrease bleeding, is a goal in the anesthetic management. The agonist 2 , as the dexmedetomidine, reduce the requirements of other drugs employed both in the induction as the anesthetic maintenance, action which is apparently related to the inhibi-tory effect on the central transmission of type antidepressant. Results: We included 55 records of patients, both sexes, undergoing orthognathic surgery, with nasal intubation, maintenance anesthetic with isofl orane or sevofl orane plus dexmedetomidina infusion. Found bradycardia of 12%, mean blood pressure around the 70 mmHg, average consumption of 43.5 mL of isofl orane and 78 mL of sevofl orane, dexmedetomidine 191.64 g, fentanyl 254.53 g, bleeding of 478 mL. Conclusion: The use of adjuvant dexmedetomidine in the anesthetic management is another option, which maintains tension fi gures suitable, without signifi cant bleeding decreasing transfusion requirement.
... nd renal clearance has no role to play in metabolism or elimination of dexmedetomidine as literary reports confirmed no traces of unchanged dexmedetomidine in urine. These properties will provide another added advantage of dexmedetomidine to be used in RA in patients with deranged renal functions as compared with GA, but not in hepatic dysfunction. [17] CONCLUSION Epidural anaesthesia with ropivacaine and dexmedetomidine can be safely and effectively used in patients undergoing renal surgeries as compared with conventionally used GA technique. Surgical conditions and patient satisfaction scores show only marginal difference in favour of epidural anaesthesia, but sedation scores are bet ...
Background and Aims:
Neuraxial anaesthesia has become popular for the renal surgeries during the last few years. This study was aimed at comparing general anaesthesia (GA) with epidural anaesthesia in patients undergoing renal surgeries.
Methods:
One hundred American Society of Anaesthesiologists (ASA) physical status-I and II adult consenting patients of both gender in the age group of 25-55 years undergoing renal surgeries were randomly assigned to two groups of 50 patients each: Group G and Group E. Group G patients were administered conventional GA while Group E received epidural anaesthesia (EA) with 3 mg/kg of ropivacaine and 1 μg/kg of dexmedetomidine. Besides cardio-respiratory parameters, surgeon's satisfaction, patient's satisfaction and side effects were observed. Parametric data were analysed by ANOVA while non-parametric data were compared with Mann–Whitney U-test and Wilcoxon test. Value of P < 0.05 was considered statistically significant.
Results:
The demographic profile, total anaesthesia time, surgical time and haemodynamic parameters and surgeon's satisfaction scores were comparable in both groups. Patient's satisfaction scores were better in Group E during the post-operative period. Incidence of side-effects such as nausea and vomiting and shivering were higher in Group G (P < 0.001) while the incidence of dry mouth was higher in Group E (P < 0.001).
Conclusion:
Epidural anaesthesia with ropivacaine and dexmedetomidine can be safely and effectively used in patients undergoing renal surgeries.
Background: The relief of pain and suffering is, and always has been, one of the primary concerns of mankind and one of the prime factors that has influenced the course of history of medicine. Transversus abdominis plane (TAP) block is a regional anaesthetic technique which blocks the abdominal neural afferents by introducing local anaesthetic into the neuro-fascial plane between the internal oblique and the transversus abdominis muscle. Aim: To compare the efficacy of Dexmedetomidine and dexamethasone as an adjuvant to 0.2%ropivacaine in ultrasound guided transverses abdominis plane block in infra umbilical surgeries in terms of, 1. Time to initial postoperative pain. 2. Time to initial rescue analgesia. 3. Quality of block.. 4. Total postop analgesic consumption. 5. Patient satisfaction with regard to pain relief. 6. Post-operative nausea and vomiting. Materials And Methods: We included 80 patients of age between 18-60 years of American Society of Anesthesiologists status (ASA)I and II scheduled for elective infraumbilical surgeries in our study. We randomly allotted these patients into two groups namely Group A and Group B of each. Patients in Group APatients who received transversus abdominis plane block with - 18ml Ropivacaine 0.2%+ 2 ml Dexamethasone 8mg. Patients in Group B received transversus abdominis plane block with-18ml Ropivacaine 0.2%+ 2 ml Dexmedetomidine .This TAP block was given soon after the surgery is completed. The duration of block and regression of sensory block, time for rescue analgesia, degree of sedation, hemodynamic parameters, post operative analgesia and adverse effects were noted. Result: The two groups were comparable on the basis of duration of surgery, site of surgery, ASA and BMI. Heart rates and mean arterial pressure were compared and it was found to be significantly lower in group B compared to group A until initial 5 hours. In our study we found that the visual analogue score at rest and on coughing between groups A and B was statistically insignificant. However, the time to first rescue analgesia (330 mins vs 240 mins) and total analgsic consumption in the 24 hours period post operatively was significantly lesser for group A compared to group B. Ramsey sedation score was significantly higher in group B compared to group A until 8 hourspost operatively. Nausea and vomiting in 3 cases of group A , and 2 cases in group B. No other significant side effects were noted. Conclusion: USG-guided TAP block is an effective and safe adjunct for postoperative analgesia in infra umblical surgeries. Addition of dexamethasone as an adjuvant prolongs the duration and reduces post-operative analgesic requirement in patients significantly more than dexmedetomidine whereas dexamethasone provides better control of the heart rate and mean arterial pressure.
Dexmedetomidine is a sedative used in both adults and off‐label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01–19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from −1% to 120% for PRED, and −24% to 60% for IPRED. The model by James et al, which was developed using similar “real‐world” data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model‐informed dosing of hospitalized children.
Background:
Postoperative acute kidney injury (AKI) is a common complication and is associated with increased hospital length of stay and 30 day all-cause mortality. Unfortunately, we have neither a defined strategy to prevent AKI nor an effective treatment. In vitro, animal, and human studies have suggested that dexmedetomidine may have a renoprotective effect. We conducted a retrospective cohort study to evaluate if intraoperative dexmedetomidine was associated with a reduced incidence of AKI.
Methods:
We collected data from 6625 patients who underwent major non-cardiothoracic cancer surgery. Before and after propensity score matching, we compared the incidence of postoperative AKI in patients who received intraoperative dexmedetomidine and those who did not. AKI was defined according to the Kidney Disease Improving Global Outcomes (creatinine alone values) criteria and calculated for postoperative Days 1, 2, and 3.
Results:
Twenty per cent (n=1301) of the patients received dexmedetomidine. The mean [standard deviation] administered dose was 78 [49.4] mcg. Patients treated with dexmedetomidine were matched to those who did not receive the drug. Patients receiving dexmedetomidine had a longer anaesthesia duration than the non-dexmedetomidine group. The incidence of AKI was not significantly different between the groups (dexmedetomidine 8% vs no dexmedetomidine 7%; P=0.333). The 30 day rates of infection, cardiovascular complications, or reoperation attributable to bleeding were higher in patients treated with dexmedetomidine. The 30 day mortality rate was not statistically different between the groups.
Conclusions:
The administration of dexmedetomidine during major non-cardiothoracic cancer surgery is not associated with a reduction in AKI within 72 h after surgery.
Purpose
Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with high protein binding of 94%. Critical illness may affect protein binding and the pharmacokinetic (PK) parameters of many drugs, including DEX. In critically ill patients receiving prolonged infusions of DEX, there is little information documenting the relationship between key pathophysiologic factors and DEX protein binding or PK parameters. The purpose of this study was to characterize the protein binding and PK profile of prolonged DEX infusion in critically ill patients.
Methods
Critically ill, adult intensive care unit patients at a university hospital in Hong Kong were studied. The association between the pathophysiologic changes of critical illness and protein binding was evaluated using a generalized estimating equation. A population pharmacokinetic model to establish the PK profile of DEX was developed, and key pathophysiologic covariate effects of severity of illness, organ dysfunction measures, and altered protein binding on DEX PK parameters in this critically ill population were evaluated.
Findings
A total of 22 critically ill patients and 1 healthy control were included. Mean protein binding of DEX in the critically ill patients was 90.4% (95% CI, 89.1–91.7), which was 4% lower than that in the healthy control. The PK data were adequately described by a 2-compartment model. The estimated population mean (relative standard error [RSE]) values of systemic clearance (CL), volume of distribution of the central compartment (V2), intercompartmental clearance (Q), and Vd in the peripheral compartment (V3) were 38.6 (11.7) L/h, 32.1 (46.1) L, 114.5 (58.3) L/h and 95.1 (30.6) L, respectively. The corresponding estimated interindividual variability expressed as CV% (RSE) was 52.4 (23.8) for CL, 172.9 (19.3) for V2, 123.7 (33.7) for Q, and 106 (39.9) for V3. No significant explanatory pathophysiologic covariates were identified.
Implications
Although a marginally significant reduction of protein binding in critically ill patients was demonstrated, the magnitude of the difference was unlikely to be of clinical significance. Higher alanine aminotransferase concentration was associated with decreased protein binding. No significant pathophysiologic covariates were associated with the observed PK parameters. The high interindividual variability of PK parameters supports the current practice of dose titration to ensure the desired clinical effects of DEX infusion in the intensive care unit setting.
Background
Dexmedetomidine is a potent and highly selective alpha-2 adrenoceptor agonist with sympatholytic, sedative, anxiolytic, and analgesic properties. The aim of the present study is to determine the effect of a dexmedetomidine infusion in liver transplant recipients in the early postoperative period on early and smooth extubation.
Methods
We performed a retrospective chart review of 21 patients undergoing liver transplantation between December 1, 2018, and February 31, 2020. Patients were divided into the dexmedetomidine and midazolam groups. The primary outcome was the extubation time. Secondary outcomes were mean arterial pressure and heart rate before and after extubation. The collected data included the patients’ age, gender, surgery time, Model for End-stage Liver Disease (MELD) score, cold ischemia time, blood transfusion amount, and extubation visual analog scale (VAS) scores.
Results
Extubation time was significantly shorter in the dexmedetomidine group than midazolam group (median [minimum-maximum], 4 [0-6], 8 [4-13] hours, respectively, p = 0.000). Extubation VAS scores were statistically significantly lower in dexmedetomidine group (p = 0.000). Mean arterial pressure values before and after extubation were significantly higher in patients' midazolam group than the dexmedetomidine group (p = 0.003, p = 0.005, respectively).
Conclusions
Dexmedetomidine infusions provided early and smooth extubation with stable hemodynamics in our patients.
Septic shock, known as the most severe complication of sepsis, is a serious medical condition that can lead to death. Clinical symptoms of sepsis include changes in body temperature in the form of hypothermia or hyperthermia, tachypnea or hyperventilation, tachycardia, leukocytosis or leukopenia, and variations in blood pressure, as well as altered state of consciousness. One of the main problems in septic shock is poor response along with reduced vascular reactivity to vasopressors used to increase blood pressure. Therefore, low vascular response associated with reduced sensitivity or lower number of alpha-1 agonist receptors can result in shock and death. In addition to being the state-of-the-art treatment including volume load and vasopressor, use of alpha-2 agonists e.g. dexmedetomidine (DXM) in septic shock can reduce vasopressors needed to restore adequate blood pressure. They can further moderate massive release of endogenous catecholamine. Therefore, the purpose of this study was to investigate the effect of DXM on outcomes of patients with septic shock, especially their needs for vasopressors and impacts on their hemodynamic status. This single-blind randomized controlled trial was performed on a total number of 66 patients with septic shock admitted to the intensive care unit (ICU) of Imam Khomeini Teaching Hospital in the city of Sari, in northern Iran. To this end, DXM (0.6 µg/kg/h) and normal saline (6 mL/kg/h) were infused for 12 h in the study and control groups, respectively. The results revealed that DXM could increase mean arterial pressure (MAP) (P = 0.021), systolic blood pressure (SBP) (P = 0.002), and reduced heart rate (P < 0.001) but diastolic blood pressure (DBP) (P =0.32) and norepinephrine dose requirement didn't change statistically in septic shock patients (P = 0.12).
While they have been used clinically for decades, α-agonists represent the most recent class of drugs to be added to the list of pediatric intensive care unit (PICU) sedatives. Their mechanism of action produces a unique type of sedation which facilitates greater patient cooperation and, possibly, lighter levels of sedation to be tolerated. While two drug options are available, dexmedetomidine has become the most commonly used primary intravenous (IV) PICU sedative, whereas enteral clonidine tends to be reserved for use to either treat iatrogenic withdrawal syndromes from several classes of drugs or to aid in weaning off of dexmedetomidine infusions. Other clinical benefits of α-agonists include reductions in dysrhythmias following cardiac surgical procedures and possibly mitigating the development of ICU delirium. Their limited respiratory-depressing properties make α-agonists an attractive option for maintaining sedation of the behaviorally challenged patient during weaning from mechanical ventilation or for cooperation with invasive therapies in the non-intubated patient. The adverse effect profile of α-agonists is limited in scope, consisting primarily of hypotension and/or bradycardia. These events occur more commonly than reported with other agents but uncommonly require intervention other than reduction in administered doses.
Dexmedetomidine (DMTD), an α2-adrenoceptor agonist, is commonly used for sedation and analgesia in intensive care unit (ICU) patients. The primary plasma metabolites of DMTD are its direct N-glucuronides, namely N3-glucuronide of dexmedetomidine (DG1) and N1-glucuronide of dexmedetomidine (DG2), accounting for 41% of DMTD metabolism in healthy volunteers. Since variations on the extent of N-glucuronidation could be one of the key factors contributing to the high interpatient differences of DMTD pharmacokinetics in ICU patients and its subsequent sedative effect. In order to fully evaluate the N-glucuronidation of DMTD in ICU patients, the current study aimed to develop a LC/MS/MS method to simultaneously quantify DMTD and its two major N-glucuronides, DG1 and DG2, in plasma samples and describe their pharmacokinetics in adult ICU patients. Solid-phase extraction cartridges were used to effectively extract DMTD, DG1 and DG2 from 0.4 mL plasma with the internal standard tolazoline. The method was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients (mean ± SD admission severity of illness APACHE II score 23 ± 5) receiving dexmedetomidine infusion for 667 to 3518 min. Under the optimized LC/MS/MS conditions, no endogenous interference from blank plasma was observed. The linear range was 25-5000 pg/mL for DMTD, 50-5000 pg/mL for DG1, and 56-2800 pg/mL for DG2 with good linearity (r2 ranges: 0.997-0.999, 0.993-0.999, and 0.993-0.998 for DMTD, DG1 and DG2 respectively). The precision, accuracy and the stability of DMTD, DG1, and DG2 at their quality control concentrations complied with Food and Drug Administration bioanalytical criteria. The assay was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients. The range of AUCDG1/AUCDMTD (from 0.40 to 2.20) and AUCDG2/AUCDMTD (from 0.15 to 2.02) suggested large inter-patient differences in the glucuronidation of DMTD. The mean AUC0-∞ ratio between total glucuronides and DMTD in ICU patients receiving infusions (2.09, range 0.55-4.16) appeared lower than the reported value in healthy volunteers receiving bolus intravenous injection (2.86). This description of the pharmacokinetics of DMTD, DG1, and DG2 in ICU patients is novel and suggests that pathophysiological changes in critically ill patients may have potential to decrease the glucuronidation of DMTD.
Background
Sedation is often required for young children during transthoracic echocardiography. Dexmedetomidine and ketamine are two sedatives that are commonly used in children for procedural sedation, but they have some disadvantages when they are used alone.
Aims
The aim of this retrospective study was to analyze the effects and safety of intranasal sedation with a combination of dexmedetomidine and ketamine during transthoracic echocardiography in young children and to analyze risk factors for sedation failure.
Methods
After IRB approval, we retrospectively evaluated data on patients who underwent echocardiography between May 2016 and August 2017 utilizing a combination of dexmedetomidine 2 μg/kg and ketamine 1 mg/kg. We collected information including heart rate, pulse oxygen saturation, sedation onset time, exam time, recovery time, and adverse reactions. Stepwise logistic regression analyses were performed to analyze the risk factors for sedation failure.
Results
Sedation was successful in 2212 patients (96%) and took effect in 15.7 (IQR: 10‐23) min, while sedation failed in 92 patients. Cyanotic heart disease, history of sedation failure, history of congenital heart disease surgery, and fever were independent risk factors for sedation failure. Most of the patients in this study had an American Society of Anesthesiologists (ASA) grade of II to III, but no severe adverse reactions were observed.
Conclusion
Intranasal sedation with a combination of dexmedetomidine and ketamine is effective and appears to have an acceptable safety profile for young children during transthoracic echocardiography.
Background: Dexmedetomidine is a widely used sedative in clinic, which is mainly metabolized by cytochrome P450 2A6 (CYP2A6). Dexmedetomidine was rarely reported for off-label usage of premedication, but lacking relevant pharmacokinetic investigations. Therefore, our study determined the dexmedetomidine pharmacokinetics of CYP2A6*4 allele in Chinese patients pretreated with dexmedetomidine whose mutation frequency of CYP2A6*4 are high, in order to provide clinical references.
Methods: Thirty-one elective surgery patients received premedication with 0.5 μg/kg dexmedetomidine via intravenous pump. Their plasma concentrations at multiple time-points and polymorphism of CYP2A6*4 were determined and statistically analyzed.
Results: 9 patients were *1/*4 or *4/*4, and 22 patients were *1/*1. The main pharmacokinetic parameters were area under curve (AUC) 1396.19±332.47h·ng·l⁻¹, peak blood concentration (Cmax) 495.50±104.90ng·l⁻¹, distribution volume (V) 0.68±0.20 L/kg, clearance (CL) 0.38±0.11 L/h/kg, distribution half-life (t1/2α) 0.05±0.01h, elimination half-life (t1/2β) 2.53±0.04h. No significant pharmacokinetic differences were found among CYP2A6*1/*1, *1/*4, and *4/*4 patients.
Conclusions: In Chinese patients pretreated with dexmedetomidine, T1/2β was consistent with that published, but T1/2α, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.
This is a unique question‐and‐answer chapter for surgical residents and trainees, concentrating on the analgesia and anesthesia. Dexmedetomidine is a sedative, analgesic, and anxiolytic that is an agonist on the central alpha‐2 adrenergic receptors. It does not cause respiratory depression, and can be used in patients who are not intubated. Dexmedetomidine provides anesthesia without decreasing respiratory drive. It works through the central nervous system (CNS), as an alpha‐2 receptor agonist. The manifestations of local analgesia toxicity start with tachycardia and hypertension. As blood levels continue to rise, symptoms can continue to progress to myocardial depression, hypertension, and decreased cardiac output. Ketamine is classified as a dissociative anesthetic. It produces amnesia and analgesia. Propofol can be used in patients with neurologic injury. It can decrease intracranial pressure, cerebral blood flow, and cerebral metabolism.
Aim. This study aimed to evaluate the pharmacodynamics of dexmedetomidine in elderly cardiac patients.
Material and Methods. Twelve patients of 60 years or older and need for analgesia after surgery or as a result of critical health conditions were included into our study. Dexmedetomidine was administered intravenously as a continuous infusion without the initial dose. At the beginning the infusion was started at the rate of 0.7 µg/kg/h and then it was continued in the range of 0.17–1.39 µg/kg/h according to desired level of sedation. Information about heart rate, systolic, diastolic and mean arterial blood pressure, bispectral index and cardiac index were collected a few minutes before, during and in 12 hours after infusion of dexmedetomidine.
Results. The hemodynamic data as well as BIS level were collected from 12 patients. The duration of dexmedetomidine infusion was less than 9 hours. For each patient the reduction in blood pressure and heart rate compared to the value before dexmedetomidine infusion was observed. We did not observe bradycardia in any patient. Appropriate sedation level was achieved using only dexmedetomidine and ranged from 60 to 80. In only 2 cases it was necessary to give a single dose of another sedative.
Conclusions. To conclude, in the patients’ population involved in the study, which included older cardiac patients dexmedetomidne has been shown as a sedative agent which enabled to achieve desire level of sedation in the recommended ranges without episodes of bradycardia, however hypotension events were noted.
What is known and objective:
The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals.
Method:
Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations.
Results and discussion:
The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V1 = 60.6 L, V2 = 222 L, Cl1 = 0.825 L/min and Cl2 = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P < .05), there were no differences in the context-sensitive half-life and the revival time of anaesthesia between the 2 groups.
What is new and conclusion:
The pharmacokinetics of dexmedetomidine were best described by a two-compartment model in our study. The pharmacokinetic parameters of dexmedetomidine in patients with end-stage renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further studies of dexmedetomidine pharmacokinetics are recommended to optimize its clinical use.
Background and Objective
Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients.
Methods
Thirty-nine children aged 1–9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1–2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models.
Results
Data of 36 patients (age 1–9 years, weight 10–27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3–41.1) l/h, central volume of distribution 84.3 (70.3–91.4) l, intercompartmental clearance 82.8 (63.6–136.6) l/h, peripheral volume of distribution 114 (95–149) l, and terminal half-life 4.4 (3.6–5.3) h. Age did not show any influence on weight-adjusted parameters.
Conclusions
Chinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians.
Trial Registration
ChiCTR-OPC-14005659.
Using locoregional anesthesia, due to the surgery duration and the patient type, it's common the administration of sedation, this aims to produce comfort to the patient and reducing risks such as: respiratory depression, produce amnesia and induce sleep, reducing anxiety and stress during the surgical act. The risks are related to the drugs used, by the following mechanisms: dose dependent and synergy between different drugs, which are used in higher percentage: combinations of opioids, benzodiazepines and hypnotic as propofol, also the dexmedetomidine, an α2 adrenergic receptor, powerful and highly selective agonist drug, with analgesic and sedative properties but no respiratory effects. Methodology: 82 patients randomized trial included in 2 groups, they were managed with dexmedetomidine or fentanyl and lidocaine, epidural via, measuring degree of sedation with Wilson scale, Bromage, heart rate, medium blood pressure and oxygen saturation. Results: The obtained degree of sedation was higher in the group of dexmedetomidine p < 0.05, obtained similar levels of Bromage, with mayor hemodynamic stability than patients with fentanyl. Conclusion: The epidural dexmedetomidine provides a degree of useful sedation in patients undergoing loco regional anesthesia, without risk of respiratory depression.
We describe the anaesthetic management of a patient requiring intra-operative MRI and awake neurological testing during neurosurgical resection of a frontal tumour. This tumour involved her motor and speech areas. The anaesthetic drugs administered during awake craniotomy should be safe and allow appropriate changes in the level of sedation, so that the patient is adequately sedated during periods of intense surgical stimulus, yet awake, comfortable and cooperative during functional testing and tumour resection. We report the novel and successful use of a sedative - dexmedetomidine in combination with a narcotic, remifentanil. There has not been much experience with this combination locally. Dexmedetomidine, a selective alpha-2 agonist with sedative, analgesic and anaesthetic-sparing effect does not suppress ventilation. Patients are sedated, but can be easily roused verbally. Remifentanil is a useful choice in this surgery as it can be rapidly titrated according to level of surgical intensity and has a reliable context sensitive half life. Potential problems associated with awake craniotomy such as impaired ventilation during sedation, nausea, vomiting and seizures are discussed. These anaesthetic challenges are compounded by the challenges posed by the iMRI environment. Emphasis is placed on patient selection and preparation peri-operatively. This is crucial to the success of the operation.
Dexmedetomidine is a selective alpha-2 adrenoceptor agonist that is used preoperatively to produce sedation and reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs.
To explore the effects of mild hypoalbuminemia on pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery.
A prospective cohort study.
University-affiliated teaching hospital.
The study was performed in 30 consecutive patients undergoing major abdominal or thoracic surgery. They were aged 18 to 65 years and graded as American Society of Anesthesiologists physical status I and II. All patients were scheduled to require more than 6 hours of postoperative sedation and mechanical ventilation. Nine of the patients had low plasma albumin levels (<35 g/L but >24 g/L; male/female, 6/3) after the operation, who were assigned to hypoalbuminemia group, and the remainder with normoalbuminemia (>35 g/L; male/female, 15/6) were assigned to normoalbuminemia group.
All patients were administered a loading dose of dexmedetomidine 1.0 μg/kg infused over 10 minutes after admitted into intensive care unit and a maintenance dose of 0.4 μg/kg per hour followed for 6 hours.
Plasma dexmedetomidine levels were determined by high performance liquid chromatography - mass spectrum. Sedation was evaluated using Ramsay sedation score. Heart rate and arterial pressures were monitored. Adverse events were recorded.
Compared with patients with normoalbuminemia, maximum plasma concentration of dexmedetomidine decreased by 21.2% in patients with hypoalbuminemia (P < .01). Its volume of distribution at steady state increased by 40.5%; elimination half-life decreased by 33.5% (P < .01). However, heart rates, arterial pressures, and Ramsay sedation scores did not differ significantly between the 2 groups. No serious adverse events occurred in either the patients with hypoalbuminemia or normoalbuminemia.
Sedation and adverse reactions of dexmedetomidine infusion did not differ significantly between patients with mild hypoalbuminemia and normoalbuminemia, although its volume of distribution at steady state increased and elimination half-life shortened in patients with hypoalbuminemia. This suggests that dexmedetomidine infusion can safely be used in mild hypoalbuminemia patients after major abdominal or thoracic surgery.
Copyright © 2015. Published by Elsevier Inc.
Liver transplantation is a complex surgical procedure requiring comprehensive and intensive multidisciplinary involvement in the perioperative period. Over the years there has been significant evolution of the surgical technique and the perioperative management that resulted in improved outcomes. The anesthesiologist and intensivist play a crucial role throughout the perioperative period and adequate analgesic delivery is of outmost importance during this period. Providing adequate pain control may prove to be challenging and there are unique considerations in patients undergoing liver transplantations. In addition to relieving mental suffering associated with pain, appropriate pain control is essential to prevent the profound physiologic consequences of inadequate analgesia. This chapter aims to address and discuss in detail the analgesic issues in liver transplantation and liver resection.
Objective:
To describe fentanyl pharmacokinetics during isoflurane anesthesia and on recovery from anesthesia with concurrent administration of acepromazine, dexmedetomidine or saline in dogs.
Study design:
Experimental blinded, randomized, crossover study.
Animals:
Seven adult hound dogs.
Methods:
Dogs were administered intravenous (IV) fentanyl as a bolus (5 μg kg(-1)) followed by an infusion (5 μg kg(-1) hour(-1)) for 120 minutes during isoflurane anesthesia and emergence from anesthesia, and for 60 minutes after extubation during recovery from anesthesia. At the time of extubation, dexmedetomidine (2.5 μg kg(-1)), acepromazine (0.05 mg kg(-1)) or saline were administered IV. Venous blood was sampled during the maintenance and recovery periods. Fentanyl plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry and population pharmacokinetic analyses were performed.
Results:
Mean fentanyl plasma concentrations were 1.6-4.5 ng mL(-1) during isoflurane anesthesia and 1.6-2.0 ng mL(-1) during recovery from anesthesia. Recovery from isoflurane anesthesia without sedation was associated with an increase in the volume of the central compartment from 0.80 to 1.02 L kg(-1). After administration of acepromazine, systemic clearance of fentanyl increased from 31.5 to 40.3 mL minute(-1) kg(-1) and the volume of the central compartment increased from 0.70 to 0.94 L kg(-1). Administration of dexmedetomidine did not significantly change fentanyl pharmacokinetics. Inter-individual variability for fentanyl parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4%.
Conclusions and clinical relevance:
The dose rates of fentanyl used in this study achieved previously established analgesic plasma concentrations for the duration of the infusion. Despite alterations in fentanyl pharmacokinetics, differences in fentanyl plasma concentrations among treatments during recovery from anesthesia were small and were unlikely to be of clinical significance.
Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications.
Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach.
A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations.
This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.
Most critically ill patients undergoing mechanical ventilation require the administration of at least two different sedative
agents for a median of 3 (interquartile range 2–6) days to optimize patient comfort and safety, facilitate patient-ventilator
synchrony and optimize oxygenation.1,2 With an increasing number of safety concerns associated with the administration of sedatives, the likelihood of patients
experiencing an adverse drug event during their ICU admission is high.3 While many adverse effects are common pharmacologic manifestations of an agent (e.g., dexmedetomidine-associated bradycardia)
and therefore frequently reversible, others are idiosyncratic (e.g., propofol-related infusion syndrome), unexpected, and
may be associated with substantial morbidity and mortality.4,5
X-ray diffraction data were used to determine the absolute configuration of dexmedetomidine, a new member of a class of drugs with 4-arylalkyl-1H-imidazole structure. When the anomalous effect of the parent compound proved to be too small for determination of the absolute configuration the tosyl derivative, with the same configuration, was synthesised and used as a reference. Stability of the stereogenic center was verified by HPLC technique. The absolute configuration of the compounds is S. Complete crystal structures are reported for both compounds. Co radiation was used for measurements.
Dexmedetomidine–propofol pharmacodynamic interaction was evaluated in nine healthy subjects in a crossover design. Dexmedetomidine/placebo was infused using a computer-controlled infusion pump (CCIP) to maintain a pseudo-steady-state plasma concentration of 0.66 ± 0.080 or 0 ng/mL, respectively. Forty-five minutes after the dexmedetomidine/placebo infusion was started, propofol was infused using a second CCIP to achieve a stepwise logarithmically ascending propofol concentration (1.00 to 13.8 μg/mL) profile. Each propofol step lasted 10 min. Blood was sampled for plasma concentration determination, and pharmacodynamic endpoint assessments were made during the study. Propofol and dexmedetomidine/placebo infusions were terminated when three endpoints (subjects were too sedated to hold a syringe, followed by loss of eyelash reflex, followed by loss of motor response to electrical stimulation) were achieved sequentially. The concentration of propofol associated with 50% probability of achieving a pharmacodynamic endpoint in the absence of dexmedetomidine (EC50; placebo treatment) was 6.63 μg/mL for motor response to electrical stimulation and ranged from 1.14 to 1.98 μg/mL for the ability to hold a syringe, eyelash reflex, and sedation scores. The apparent EC50 values of propofol (EC50APP; concentration of propofol at which the probability of achieving a pharmacodynamic endpoint is 50% in the presence of dexmedetomidine concentrations observed in the current study; dexmedetomidine treatment) were 0.273, 0.544–0.643, and 3.89 μg/mL for the ability to hold a syringe, sedation scores, and motor response, respectively. Dexmedetomidine reduced propofol concentrations required for sedation and suppression of motor response. Therefore, the propofol dose required for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:172–181, 2001
The effects of dexmedetomidine, a selective α2-adrenoceptor agonist, and its levo enantiomer (MPV-1441), on in vitro microsomal P450-dependent drug-metabolizing activities as well as on in vivo aminopyrine elimination and hexobarbital sleeping time were studied. Both enantiomers inhibited the oxidative metabolism of several model substrates and testosterone in rat liver microsomal incubations. Microsomal activities derived from control animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of dexmedetomidine than those from rats treated with 3-methylcholanthrene. Enzyme activities in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the elimination of aminopyrine was dose-dependent; elimination was marginally retarded with doses up to 100 μg/kg (from 17 to 23 min.; both enantiomers). Higher doses of the levo enantiomer prolonged aminopyrine half-life to 78 (1 mg/kg) and 162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg of the levo enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg had no effect (23 versus 20 min.). These studies indicate that both enantiomers of medetomidine are inhibitors of microsomal drug metabolism in vitro, but significant effects on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses, which do not allow the use of dexmedetomidine because of excessive sedative effect.
The effects of dexmedetomidine, an alpha 2-adrenoceptor agonist, on vigilance, thiopental anesthetic requirements, and the hemodynamic, catecholamine, and hormonal responses to surgery were investigated in healthy (ASA physical status 1) women scheduled for dilatation and curettage (D & C) of the uterus. Fifteen minutes before induction they received single iv doses of either dexmedetomidine (0.5 micrograms/kg; n = 19) or saline (n = 20) in a double-blind fashion. Anesthesia was induced with thiopental and maintained with N2O/O2 (70/30%) and thiopental. Dexmedetomidine was well tolerated and no serious drug-related subjective side-effects or adverse events were observed. The most prominent subjective effects were fatigue and decreased salivation. The total amount of thiopental needed to perform D & C of the uterus was reduced approximately 30% (from 456 +/- 141 mg [mean +/- SD] after saline to 316 +/- 79 mg after dexmedetomidine). This was mostly due to a smaller induction dose in the group receiving dexmedetomidine. Dexmedetomidine appeared to improve the recovery from anesthesia as measured by visual analogue scales (VAS) on fatigue and nausea. The plasma concentration of norepinephrine was decreased by 56% after dexmedetomidine implying decreased sympathetic nervous activity. Systolic and diastolic blood pressure were moderately reduced after dexmedetomidine administration. The authors conclude that dexmedetomidine preanesthetic medication decreases thiopental anesthetic requirements and improves the recuperation from anesthesia with no serious hemodynamic or other adverse effects. Further studies in patients undergoing more stressful surgery are indicated.
The effect of dexmedetomidine DEX on cytochrome P4502D6 (CYP2D6)-dependent dextromethorphan O-demethylase (DEXTROase) activity was studied using native human liver microsomes. DEX (0.01-4.0 microM inhibited DEXTROase activity (IC50 = 1.8 +/- 0.25 microM; mean +/- SD; N = 5 livers) and was less potent than quinidine (QND), prototypical and clinically relevant CYP2D6 inhibitor (IC50 = 0.22 +/- 0.02 microM; mean Ki = 0.07 microM). Similar results were obtained with human B-lymphoblast microsomes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 microM; QND, IC50 0.15 microM). Formal kinetic analyses indicated that DEX was a reversible mixed (competitive/noncompetitive) inhibitor of DEXTROase activity in human liver microsomes, where Kies > Ki and alpha > 1 (Ki = 0.4 +/- 0.2 microM; Kies = 2.3 +/- 0.9 microM; alpha = 8.1 +/- 6.8; N = 3 livers). In addition, DEX elicited a Type IIb difference spectrum (lambda max approximately 436 nm; lambda min approximately 414 nm) when added to cDNA-expressed CYP2D6 under aerobic (oxidized) conditions. These data indicated that DEX was able to bind reversibly to the heme (ferric) iron of CYP2D6. It is postulated that binding occurs via the 4(5)-substituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (Ks) of 0.4 microM that was identical to the Ki obtained with native human liver microsomes.
Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs. Dexmedetomidine pharmacokinetics were characterized in healthy subjects after intravenous administration by means of a computer-controlled infusion pump. A series of seven stepwise increasing pseudo-steady-state plasma concentrations were targeted. The influence of cardiac output on the pharmacokinetics was investigated by use of a compartmental modeling approach in which the elimination clearance was characterized as being either cardiac output independent or dependent. At dexmedetomidine concentrations of 0, 0.6, and 1.2 ng/mL, mean (SD) estimated cardiac outputs were 5. 6 (0.85), 5.1 (0.67), and 4.5 (0.83) L/min, and mean (SD) clearances were 40 (10), 38 (9.0), and 35 (8.5) L/h, respectively. Dexmedetomidine V(SS) and elimination half-life were 72 (19) L and 1. 9 (0.62) h, respectively. The approximately 3 to 19% decrease in cardiac output observed within the anticipated therapeutic range of 0.3 to 1.2 ng/mL was similar to that observed for clonidine. The decrease in cardiac output with increasing plasma concentrations of dexmedetomidine resulted in a corresponding decrease in drug elimination clearance of < or =12% within the therapeutic range; however, this decrease in dexmedetomidine clearance is likely not clinically relevant.
Open Label, Parallel Study to Evaluate the In¯uence of Age on the Pharmacokinetics of Dexmedetomidine in Healthy Volunteers
- Ke Karol
- I Phase
- Single
- Center
Karol MD & Rynkiewicz KE. A Phase I, Single Center, Open Label, Parallel Study to Evaluate the In¯uence of Age on the Pharmacokinetics of Dexmedetomidine in Healthy Volunteers, 1998 Abbott Laboratories. Internal Report.
Double-Blind, Randomized, Comparative Study Evaluating the Eect of Two Doses of Dexmedetomidine Versus Placebo in Adult Patients Undergoing Elective Coronary Artery Bypass Graft Surgery
- J Karol Md & Jennings
- Phase
- Multicenter
Karol MD & Jennings J. A Phase III Multicenter, Double-Blind, Randomized, Comparative Study Evaluating the Eect of Two Doses of Dexmedetomidine Versus Placebo in Adult Patients Undergoing Elective Coronary Artery Bypass Graft Surgery, 1998 Abbott Laboratories. Internal Report.
Pharmacokinetics of Dexmedetomidine in Normal Healthy Subjects and Subjects with Various Degree of Hepatic Impairment
- Wong
Wong S & Rynkiewicz KE. Pharmacokinetics of Dexmedetomidine in Normal Healthy Subjects and Subjects with Various Degree of Hepatic Impairment, 1998 Abbott Laboratories. Internal Report.
Phase I Study of the Metabolism and Excretion of [ 3 H]Dexmedetomidine . HCl in Normal Male Subjects
- Mayer
Mayer MD & Machinist JM. Phase I Study of the Metabolism and Excretion of [ 3 H]Dexmedetomidine. HCl in Normal Male Subjects, 1997 Abbott Laboratories. Internal Report.
Identi®cation of Cytochrome P450 Isoforms Involved in the Oxidative Metabolism of Dexmedetomidine and the Eect of Dexmedetomidine on Cytochrome P450-mediated Monooxygenase Activities
- D Hickman
- Kumar
- Gn
Hickman D & Kumar GN. Identi®cation of Cytochrome P450 Isoforms Involved in the Oxidative Metabolism of Dexmedetomidine and the Eect of Dexmedetomidine on Cytochrome P450-mediated Monooxygenase Activities, 1998 Abbott Laboratories. Internal Report.
Protein Binding of [ 3 H] Dexmedetomidine in the Plasma from Subjects with Various Liver Function
- Jm Machinist
Machinist JM. Protein Binding of [ 3 H] Dexmedetomidine in the Plasma from Subjects with Various Liver Function, 1998 Abbott Laboratories. Internal Report.
In Vitro Protein Binding of [ 3 H] Dexmedetomidine in the Plasma of Humans with Renal Impairment
- Kukulka
Kukulka MJ & Machinist J. In Vitro Protein Binding of [ 3 H] Dexmedetomidine in the Plasma of Humans with Renal Impairment, 1996 Abbott Laboratories. Internal Report.
Dexmedetomidine Hydrochloride lnjection, Package insert
- Precedex
Precedex, Dexmedetomidine Hydrochloride lnjection, Package insert, PDR, 2000.