Erkki Kentala

Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background:Dexmedetomidine, a selective &agr;2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating &agr;2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic &agr;2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. Methods:The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. Results:The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, −27% from baseline [95% confidence interval, −31 to −23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate–pressure product (−23% [−28 to −18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (−3% [−12 to +6%] from low dexmedetomidine, P > 0.05; −29% [−39 to −18%] from baseline, P < 0.001) or statistically significantly affect the rate–pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. Conclusions:In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.

Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients

BACKGROUND Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach. METHODS Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models. RESULTS The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration. CONCLUSIONS The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

Correlation properties and complexity of perioperative RR-interval dynamics in coronary artery bypass surgery patients.

Background Dynamic measures of heart rate variability (HRV) may uncover abnormalities that are not easily detectable with traditional time and frequency domain measures. The purpose of this study was to characterize changes in RR-interval dynamics in the immediate postoperative phase of coronary artery bypass graft (CABG) surgery using traditional and selected newer dynamic measures of HRV. Methods Continuous 24-h electrocardiograph recordings were performed in 40 elective CABG surgery patients up to 72 h postoperatively. In one half of the patients, Holter recordings were initiated 12–40 h before the surgery. Time and frequency domain measures of HRV were assessed. The dynamic measures included a quantitative and visual analysis of Poincaré plots, measurement of short- and intermediate-term fractal-like scaling exponents (&agr;1 and &agr;2), the slope (&bgr;) of the power-law regression line of RR-interval dynamics, and approximate entropy. Results The SD of RR intervals (P < 0.001) and the ultra-low-, very-low-, low-, and high-frequency power (P < 0.01, P < 0.001, P < 0.001, P < 0.01, respectively) measures in the first postoperative 24 h decreased from the preoperative values. Analysis of Poincaré plots revealed increased randomness in beat-to-beat heart rate behavior demonstrated by an increase in the ratio between short-term and long-term HRV (P < 0.001) after CABG. Average scaling exponent &agr;1 of the 3 postoperative days decreased significantly after CABG (from 1.22 ± 0.15 to 0.85 ± 0.20, P < 0.001), indicating increased randomness of short-term heart rate dynamics (i.e., loss of fractal-like heart rate dynamics). Reduced scaling exponent &agr;1 of the first postoperative 24 h was the best HRV measure in differentiating between the patients that had normal (≤ 48 h, n = 33) or prolonged (> 48 h, n = 7) intensive care unit stay (0.85 ± 0.17 vs. 0.68 ± 0.18;P < 0.05). In stepwise multivariate logistic regression analysis including typical clinical predictors, &agr;1 was the most significant independent predictor (P < 0.05) of long intensive care unit stay. None of the preoperative HRV measures were able to predict prolonged intensive care unit stays. Conclusions In the selected group of patients studied, a decrease in overall HRV was associated with altered nonlinear heart rate dynamics after CABG surgery. Current results suggest that a more random short-term heart rate behavior may be associated with a complicated clinical course. Analysis of fractal-like dynamics of heart rate may provide new perspectives in detecting abnormal cardiovascular function after CABG.

Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients

IntroductionOnly limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.MethodsThirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.ResultsThe following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.ConclusionsThe results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.Trial RegistrationClinicalTrials.gov: NCT00747721

Assessing the depth of dexmedetomidine‐induced sedation with electroencephalogram (EEG)‐based spectral entropy

Background:  Adequate sedation of critically ill patients improves the outcome of intensive care. Maintaining an optimal level of sedation in the intensive care unit (ICU) is difficult because of a lack of appropriate monitoring methods to guide drug dosing. Dexmedetomidine, a selective α2‐adrenoceptor agonist, has recently been introduced for the sedation of ICU patients. This study investigated the utility of electroencephalogram (EEG)‐based spectral entropy monitoring (with M‐ENTROPY™, GE Healthcare, Helsinki, Finland) for the assessment of dexmedetomidine‐induced sedation.

The breakdown of fractal heart rate dynamics predicts prolonged postoperative myocardial ischemia.

UNLABELLED Patients with myocardial ischemia after noncardiac surgery have a three- to ninefold increased risk of adverse cardiac events. In this study we tested the hypothesis that altered preoperative heart rate variability (HRV) predicts postoperative prolonged myocardial ischemia (>10 min) in elderly surgical patients. Thirty-two patients, age 60 yr or older, admitted to hospital for surgical repair of a traumatic hip fracture with preoperative night and daytime Holter recordings were included. Holter monitoring was initiated at arrival at hospital and continued until the third postoperative morning. Conventional HRV measures along with analysis of short-term fractal scaling exponent (alpha(1)) of RR intervals were assessed for night (from 2 AM to 5 AM) and day (7 AM to 12 AM) periods in each patient. Preoperative alpha(1) was significantly lower (i.e., increased randomness in HRV) during the nighttime compared with daytime (mean +/- SEM; 0.92 +/- 0.08 versus 1.03 +/- 0.06; P = 0.002) in patients with postoperative myocardial ischemia. Patients without ischemia had no such difference. In stepwise multivariate logistic regression analysis, increased preoperative night-day difference of alpha(1) was the only independent predictor of postoperative prolonged ischemia. The odds ratio for an increase of 0.16 U in night-day difference of alpha(1) (corresponding to interquartile range) was 7.7 (95% confidence interval, 1.9-51.4; P = 0.0018). Breakdown of fractal-like heart rate dynamics is predictive for postoperative prolonged myocardial ischemia in elderly patients having emergency surgery for traumatic hip fracture. IMPLICATIONS Night and daytime Holter recordings before surgical repair of traumatic hip fracture were analyzed with linear and nonlinear heart rate variability methods. Preoperatively increased randomness in heart rate variability was predictive for postoperative, silent prolonged myocardial ischemia. Prolonged myocardial ischemia increases the risk for adverse cardiac events.

Relation of heart rate dynamics to the occurrence of myocardial ischemia after coronary artery bypass grafting

Postoperative myocardial ischemia is a common finding after coronary artery bypass grafting (CABG) and is associated with an adverse short-term clinical outcome. The reasons and pathophysiologic background for the occurrence of ischemia after CABG are not well established. We tested the hypothesis that altered heart rate (HR) behavior precedes the onset of myocardial ischemic episodes in patients after CABG. Time-domain HR variability measurements, along with analysis of Poincaré plots and fractal scaling analysis were assessed in 40 CABG patients from 48-hour postoperative Holter recordings. Twenty patients experienced 195 ischemic episodes during the postoperative course. In the univariate analysis of HR variability measurements of the first postoperative day (POD), the increased ratio between the short-term (SD1) and long-term (SD2) HR variability analyzed from the Poincaré plot and the decreased short- and intermediate-term fractal scaling exponents alpha(1) and alpha(2) were significantly associated with ischemia during the study period (p <0.01, p <0.05, and p <0.05, respectively). In the multivariate model, the increased SD1/SD2 ratio of the first POD was the most powerful independent predictor of all possible confounding variables for the occurrence of postoperative ischemia (corresponding to a change of 0.15 U; odds ratio 2.2 and 95% confidence interval 1.2 to 5.7; p <0.01). Altered HR dynamics have been associated with myocardial ischemic episodes in patients after CABG, suggesting that the autonomic nervous system has an important role in the pathogenesis of myocardial ischemia in the postoperative phase of CABG.

Effects of nitric oxide synthase inhibition on dexmedetomidine-induced vasoconstriction in healthy human volunteers

BACKGROUND This study aimed to assess the contribution of endothelial nitric oxide synthesis to the net responses of human peripheral blood vessels in vivo to the selective alpha(2)-adrenoceptor agonist dexmedetomidine. METHODS Two groups of healthy young men were studied. In the first experiment, after brachial plexus block, the responses of digital arteries to systemically administered dexmedetomidine (target plasma concentration 1.2 ng ml(-1)) were studied using a photoplethysmograph (n=10) during i.a. infusions of saline and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (8 micromol min(-1)). In a separate experiment, after pre-treatment with acetylsalicylic acid, responses to increasing doses of dexmedetomidine (0.01-164 ng min(-1)) in the presence and absence of L-NMMA were compared in dorsal hand veins (DHV) (n=10) using linear variable differential transformers. RESULTS L-NMMA significantly augmented dexmedetomidine-induced vasoconstriction of digital arteries as assessed by an increase in light transmission through a finger and by a decrease in finger temperature. The mean (95% confidence interval) extent of the additional effect of L-NMMA over the constrictor effect of dexmedetomidine alone was 19% (14-24) (P<0.0001). In DHV, L-NMMA had variable effects on the dexmedetomidine-constriction dose-response curve. In three subjects, the curve was shifted significantly to the left (with a >10-fold difference in ED(50)), but ED(50) was only marginally affected by L-NMMA in the other subjects (difference in ED(50) <five-fold). CONCLUSIONS The endothelial NOS enzyme has a significant role in opposing the vasoconstrictor action of dexmedetomidine at drug concentrations within the therapeutic range.

Unrecognised obstructive sleep apnoea is common in severe peripheral arterial disease

Patients needing surgery for peripheral arterial disease (PAD) represent a severe form of atherosclerosis with an overall 5-yr mortality of 30% after revascularisation. The aetiology for poor post-operative clinical outcome in these high-risk patients is not fully established. Obstructive sleep apnoea (OSA) is associated with atherosclerosis and is an independent risk factor for fatal and nonfatal cardiac events. Here, we determine the prevalence of undiagnosed OSA in a homogenous group of PAD patients undergoing subinguinal surgical revascularisation. 82 consecutive patients (mean age 67±9 yrs, 52 males) with sinus rhythm and without congestive heart failure or previously diagnosed OSA were enrolled for pre-operative polysomnography and echocardiography. OSA was present in 70 (85%) patients (95% CI 75–93%), of whom 24 (34%) had severe OSA. OSA was mostly asymptomatic, and age- and sex-adjusted multivariate regression analysis showed no relation to obesity, metabolic syndrome or any manifestation of atherosclerosis, other than PAD. Left ventricular ejection fraction (p = 0.002) and high-density lipoprotein/total cholesterol ratio (p = 0.03) were the only independent predictors for the severity of OSA. Thus, prevalence of OSA is unexpectedly high in patients with PAD and is not related to classical risk factors of sleep apnoea.

Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods.

ObjectiveCardiac output (CO) has traditionally been measured using invasive techniques, which involve an element of risk. Thus, a reliable less-invasive method for determining CO would be very valuable for research use. We tested whether simple analysis of the arterial pulse waveform, not requiring large-vessel catheterisation or expensive equipment, could provide an estimate of CO that is accurate enough for pharmacological studies.MethodsWe measured CO in 11 healthy male subjects who received low and high doses of dexmedetomidine (α2-adrenoceptor agonist), using pulse contour analysis, echocardiography and pulmonary thermodilution techniques.ResultsAt baseline, these methods gave the following mean (SD) values of CO: 6.18 (1.59), 5.22 (1.35) and 7.03 (1.54) l/min, respectively. High-dose dexmedetomidine reduced CO to 4.50 (0.68), 3.65 (0.65) and 4.80 (0.89) l/min, corresponding to −25 (14) %, −28 (12) % and −30 (14) % reductions from baseline, respectively. The pulse contour method described these dexmedetomidine-induced changes in CO very similarly to the thermodilution and echocardiographic methods. The limits of agreement [bias (2SD)] were 0.55 (2.55) and −0.10 (2.04) l/min, respectively.ConclusionThe minimally invasive pulse contour analysis technique might be suitable for pharmacological studies for the detection of major drug-induced reductions in CO.