Antero Kallio

The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.

UNLABELLED We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia. IMPLICATIONS The alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.

Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting

Background Alpha2 ‐Adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific alpha2 ‐adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting. Methods Eighty patients scheduled for elective coronary artery bypass grafting received, in a double‐blind manner, either a saline placebo or a dexmedetomidine infusion, initially 50 ng [center dot] kg‐1 [center dot] min‐1 for 30 min before induction of anesthesia with fentanyl, and then 7 ng [center dot] kg‐1 [center dot] min‐1 until the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs. Results Compared with placebo, dexmedetomidine decreased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia (3 vs. 24 mmHg) and surgery (2 vs. 14 mmHg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine decreased the incidence of intraoperative (2 vs. 13 patients) and postoperative (5 vs. 16 patients) tachycardia. Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increments of enflurane (4.4 vs. 5.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl‐induced muscle rigidity (15 vs. 33 patients) and postoperative shivering (13 vs. 23 patients). Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.

Dexmedetomidine, an α2-Adrenoceptor Agonist, Reduces Anesthetic Requirements for Patients Undergoing Minor Gynecologic Surgery

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 Intravenously Administered Dexmedetomidine on Perioperative Hemodynamics and Isoflurane Requirements in Patients Undergoing Abdominal Hysterectomy

The effects of two doses of dexmedetomidine (0.3 or 0.6 micrograms.kg-1), fentanyl 2.0 micrograms.kg-1, or saline as a single intravenous bolus administered 10 min prior to the induction of anesthesia were assessed in double-blind, randomized study in 96 women undergoing abdominal hysterectomy. In each patient, anesthesia was induced with thiopental 4.0 mg.kg-1, and after the effect of succinylcholine had dissipated, isoflurane 0.3% end-tidal concentration in 70% nitrous oxide was begun to maintain anesthesia. The isoflurane concentration was adjusted to maintain blood pressure and heart rate within 20% of preoperative values, and fentanyl was given if the end-tidal isoflurane concentration exceeded 1.5%. In all groups, blood pressure and heart rate increased after tracheal intubation. However, the increase in blood pressure and heart rate was significantly less in the higher dexmedetomidine (0.6 micrograms.kg-1) group than in the saline group (P less than 0.01). Also, the postintubation increase in heart rate was significantly less (P less than 0.05) in the dexmedetomidine 0.6 micrograms.kg-1 group (increase of 18 +/- 3 beats per min) compared to the fentanyl group (increase of 26 +/- 3 beats per min). In patients receiving dexmedetomidine 0.3 micrograms.kg-1, the increase in blood pressure or heart rate did not differ from that of the saline group. The mean end-tidal isoflurane concentration was significantly less in the women receiving the higher dose of dexmedetomidine (0.35%) than in those receiving saline (0.47%) or fentanyl (0.48%), although the reduction was not clinically important.(ABSTRACT TRUNCATED AT 250 WORDS)

A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence

Abstract: The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, γ-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment.

Plasma 3, 4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4- hydroxyphenylglycol (MHPG) are insensitive indicators of α2-adrenoceptor mediated regulation of norepinephrine release in healthy human volunteers

The usefulness of the plasma concentrations of two major metabolites of norepinephrine (NE), 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG), as indicators of neuronal NE release was investigated. The potent alpha 2-adrenoceptor agonist, dexmedetomidine, induced only about 15% maximal reductions in the metabolite concentrations, in spite of almost total inhibition of neuronal NE release, as evidenced by 90% reductions in plasma NE concentrations. Similarly, administration of the alpha 2-adrenoceptor antagonist atipamezole was followed by only small increases in plasma DHPG and no change in MHPG levels, in spite of almost six-fold, albeit short-lasting, increases in plasma NE. In contrast, a single dose of the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide reduced plasma DHPG levels by 78% and MHPG levels by 51%. It is concluded that the plasma concentrations of DHPG and MHPG are largely determined by intraneuronal, MAO-A-dependent metabolism of NE, and do not accurately reflect acute alterations in neuronal NE release. The concentration of NE in venous plasma is clearly a more sensitive indicator of alpha 2-adrenoceptor-mediated regulation of NE release.

Dexmedetomidine premedication for minor gynecologic surgery.

The effects of four different doses (0.167, 0.33, 0.67, and 1.0 μg/kg) of dexmedetomidine, a novel α2-adrenoceptor agonist, on anesthetic requirements, hemodynamics, and plasma catecholamine levels were investigated in a single-blind fashion in 20 healthy (ASA physical status I) women scheduled for uterine dilatation and curettage. The drug was administered intravenously 15 min before anesthesia induction with thiopental. Nitrous oxide/oxygen (70%/ 30%) was used for maintenance. Dexmedetomidine was well tolerated, and no serious drug-related subjective side effects or adverse events were observed. The most prominent subjective effects were tiredness and decreased salivation. The total amount of thiopental needed to perform uterine dilatation and curettage was decreased dose-dependently from 400 ± 166 mg (mean ± SD) after 0.167 μg/kg of dexmedetomidine to 180 ± 65 mg after 1.0 μg/kg of dexmedetomidine (P = 0.028). Blood pressure, heart rate, and plasma norepinephrine levels were reduced after dexmedetomidine. The optimal dose of dexmedetomidine for single-dose intravenous premedication studies in minor surgery appears to be in the range of 0.33--0.67 μg/kg.

Comparison of intramuscular dexmedetomidine and midazolam premedication for elective abdominal hysterectomy

The purpose of this study was to compare the periop-erative effects of the intramuscular (IM) α2 agonist, dexmedetomidine (DEX), and midazolam (MID) premedication. The study comprised 192 women (64 per group) scheduled for abdominal hysterectomy. The doses of the study drugs were chosen to obtain equal sedative effects. The three groups were: 1) IM DEX (2.5 μ/kg) and intravenous (IV) placebo (DexPla group), 2) IM DEX and IV fentanyl (FENT) (1.5 μg/kg) (DexFent group), and 3) IM MID (0.08 mg/kg) and IV FENT (MidFent group). IM drugs were administered 45–90 min before induction of anesthesia. Preoperative sedation and anxiolysis after DEX was comparable to that after MID. The maximum arterial blood pressure response to endotracheal intubation was blunted in the DexFent group, while in the two other groups blood pressure increased 30–34 mm Hg after endotracheal intubation. The mean isoflurane concentration during surgery was 0.14% in the DexFent group, 0.24% in the DexPla group, and 0.34% in the MidFent group (P < 0.001). During surgery, bradycardia (heart rate < 40 bpm) was observed in 6.2% of DEX patients, and no MID patients, whereas postoperatively 14.1% of DEX patients and 1.6% of MID patients had bradycardia. Fewer patients suffered from postoperative shivering after DEX (10%) than after MID (52%). We conclude that DEX has many desirable effects, but side effects such as bradycardia may limit its routine use in ASA physical status 111 patients.

Comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with atipamezole

STUDY OBJECTIVE To evaluate the effects of dexmedetomidine, an alpha-2 agonist, as an intravenous sedative drug and the effects of atipamezole, an alpha-2 antagonist, on recovery. DESIGN Randomized, double-blind study with three parallel groups. An open dose-finding study preceded it to optimize the atipamezole dose. SETTING Outpatient operating room at the gynecologic and obstetric university hospital in Helsinki, Finland. PATIENTS Seventy-two healthy women scheduled for legal termination of pregnancy. INTERVENTIONS Patients were assigned to one of three groups of 24 patients each to receive either dexmedetomidine 2 micrograms/kg and atipamezole 50 micrograms/kg; dexmetomidine 2 micrograms/kg and saline; or midazolam 0.15 mg/kg and saline. In addition to paracervical block, each patient received two different study drugs: study drug 1 was a sedative agent (either dexmedetomidine or midazolam), administered before the procedure. If the sedation was not deep enough and the patient reacted to the procedure, a low dose of propofol was administered. Study drug 2 was a reversing agent or a placebo, administered following the procedure. MEASUREMENTS AND MAIN RESULTS The mean time to regain consciousness was shorter in the dexmedetomidine-atipamezole and the dexmedetomidine-saline groups compared with the midazolam group. Postoperative sedation, tested both by subjective and objective assessments, decreased more quickly in the dexmedetomidine-atipamezole group compared with the dexmedetomidine-saline and the midazolam groups. CONCLUSION Atipamezole is an effective antagonist for reversing psychomotor impairment following dexmedetomidine sedation.

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine—a novel α2‐adrenergic receptor agonist under development for preanesthetic use—were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5,1.0, and 1.5 µg/kg) and placebo were administered to six subjects in a single‐blind, multiple crossover study. Dexmedetomidine induced dose‐related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose‐dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose‐related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half‐life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6‐hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic‐pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this α2‐agonist.