Van A. Doze

Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia

The pharmacokinetic and pharmacodynamic properties of propofol were studied in 50 surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0–20 mg/min, and intermittent supplemental boluses, 10–20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 ± 0.65 1/min (mean · SD), the volume of distribution at steady state was 159 ± 57 I, and the elimination half-life was 116 ± 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 ± 0.42 vs. 2.19 ± 0.64 1/min), whereas women (vs. men) had greater clearance rates (33 ± 8 vs. 26 ± 7 1 · kg−1 · min−1) and volumes of distribution (2.50 ± 0.81 vs. 2.05 ± 0.65 1/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 ± 40 vs. 108 ± 29 min). Patients required an average blood propofol concentration of 4.05 ± 1.01 μg/ml for major surgery and 2.97 ± 1.07 μg/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 μg/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38–0.43 μg/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.

Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha2 Adrenergic Receptor

The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the alpha2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was dtrmined before and after either dexmedtomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 μg/kg or vehicle ip. There was a dose-dependent decrease in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedtomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether alpha2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg ip, a highly selective alpha2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by lexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg ip, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg ip, an A, adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whethr postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chlorothyl0-n-ethyl-2-bromobnzylamine (DSP-4) or reserpine and alpha-mthyl-para-tyrosine and MAC was dtrmined before and after each dose of dexmedtomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine depleted rats. These data indicate that the reduction of MAC caused b dexmedetomidine is mediated through alpha2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic alpha2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic alpha2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.

Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors.

Dexmedetomidine, a highly selective and potent alpha-2 adrenoceptor agonist, reduces halothane anesthetic requirements by over 90% in rats. The present study examined whether dexmedetomidine produces a hypnotic-anesthetic action in rats. Dexmedetomidine induced a hypnotic-anesthetic state in rats characterized by loss of righting reflex at doses greater than or equal to 0.1 mg/kg. This response was dose-dependent between 0.1 and 3 mg/kg. Alpha-2 adrenoceptor antagonists that cross the blood-brain barrier (antipamezole and idazoxan) decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. In contrast, the alpha-2 antagonist, L-659,066, which does not penetrate into the CNS did not affect dexmedetomidine-induced hypnosis. Antagonists for the other adrenoceptors not only failed to reduce the hypnotic-anesthetic action of dexmedetomidine but in some cases even potentiated this effect. Thus, prazosin, an alpha-1 adrenoceptor antagonist, significantly enhanced the hypnotic-anesthetic property of dexmedetomidine. Antagonists with beta-2 receptor blocking properties also enhanced dexmedetomidine-induced hypnosis. Selective beta-1 receptor antagonists did not affect the hypnotic action of dexmedetomidine. These results suggest that dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors.

Propofol-Nitrous Oxide Versus Thiopental-isoflurane-nitrous Oxide for General Anesthesia

One hundred and twenty patients undergoing elective operations were randomly assigned to receive anesthesia with cither thiopental, 4 mg/kg-isoflurane, 0.2–3%-nitrous oxide, 60–70% (control) or propofol, 2 mg/kg-propofol infusion, 1–20 mg/min-nitrous oxide, 60–70% (propofol). Although anesthetic conditions were similar during the operation, differences were noted in the recovery characteristics. For non-major (superficial) surgical procedures, the times to awakening, responsiveness, orientation, and ambulation were significantly shorter in the propofol group (4 ± 3, 5 ± 4, 6 ± 4, and 104 + 36 min) than in the control group (8 ±7,9 ±7, 11 ±9, and 142 ± 61 min, respectively). In addition, less nausea and vomiting (20 vs. 45%) and significantly less psychomotor impairment was noted in the non-major propofol (vs. control) group. Following major abdominal operations, recovery characteristics did not differ between propofol and control groups. Delayed emergence (>20 min), significant psychometric impairment, and a high overall incidence of postoperative side effects (55–60%) were noted in both drug treatment groups. The authors conclude that propofol-nitrous oxide compares favorably to thiopental-isoflurane-nitrous oxide for maintenance of anesthesia during short outpatient procedures. However, for major abdominal operations, propofol anesthesia docs not appear to offer any clinically significant advantages over a standard inhalational anesthetic technique.

Comparison of propofol with methohexital for outpatient anesthesia

Propofol is an intravenous anesthetic currently available for clinical investigative use. The intraoperative and postoperative effects of propofol were compared to methohexital when used as an adjuvant to nitrous oxide for outpatient anesthesia. Sixty healthy young women were randomly assigned to receive either methohexital, 1.5 mg/kg intravenously (IV), or propofol, 2.5 mg/kg IV, for induction of anesthesia. Both drugs produced transient cardiovascular and respiratory depression after induction. Maintenance of anesthesia consisted of either methohexital, 6 ± 2 mg/min, or propofol, 7 ± 2 mg/min (mean ± SD) by continuous infusion in combination with nitrous oxide, 70% in oxygen. Use of a propofol infusion was associated with lower blood pressures and heart rates during maintenance. Propofol was associated with fewer side effects (e.g., hiccoughing, nausea, and vomiting) intra- and postoperatively. Recovery times for awakening, orientation, and ambulation were consistently shorter with propofol. We conclude that propofol is a useful alternative to methohexital for induction and maintenance of outpatient anesthesia.

Outpatient Premedication: Use of Midazolam and Opioid Analgesics

The perioperative effects of administering sedative and analgesic drugs prior to outpatient surgery were evaluated. One hundred fifty adult outpatients were randomly assigned to one of six study groups according to a double-blind protocol design. Patients were given placebo (saline) or midazolam (5 mg im) 30-60 min prior to surgery, and then either placebo, oxymorphone (1 mg iv), or fentanyl (100 micrograms iv) 3-5 min prior to a standardized anesthetic technique. Preoperatively, midazolam premedication was associated with a significantly lower anxiety level (37 +/- 29 mm vs. 50 +/- 32 mm, P less than 0.05), higher sedation level (254 +/- 136 mm vs. 145 +/- 109 mm, P less than 0.01), worsening of psychomotor skill (5 +/- 5 vs. 2 +/- 2 dots missed, P less than 0.01; midazolam vs. placebo), and impaired recall abilities. In addition, use of midazolam did not prolong the discharge time. Compared to control patients, those who received fentanyl had a decreased incidence of intraoperative airway difficulties such as coughing (28% vs. 0%, P less than 0.01). Although use of opioids increased the incidence of postoperative nausea (42% vs. 18%, P less than 0.01) and vomiting (23% vs. 2%, P less than 0.01; opioid vs. no opioid), average recovery times were not affected by opioid administration. Oxymorphone use was associated with a lower incidence of pain at home compared with that following fentanyl (46% vs. 74%, P less than 0.05). Finally, preoperative administration of both midazolam and fentanyl or oxymorphone prior to a standardized methohexital-nitrous oxide anesthetic technique did not adversely affect recovery after outpatient surgery.

Pertussis Toxin and 4-Amino pyridine Differentially Affect the Hypnotic–Anesthetic Action of Dexmedetomidine and Pentobarbital

Dexmedetomidine, a highly selective and potent agonist at alpha-2 adrenoceptors, produces a hypnotic-anesthetic action in rats. The mechanism for this response may involve an inhibitory G-protein and increased conductance through a potassium channel. To investigate this, the effects of pertussis toxin, a specific inactivator of inhibitory G-proteins, and 4-aminopyridine, a blocker of potassium channels, on the hypnotic-anesthetic response to dexmedetomidine were studied in rats. Pertussis toxin and 4-aminopyridine both decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. To preclude the possibility that pertussis toxin and 4-aminopyridine attenuated the hypnotic-anesthetic action of dexmedetomidine via indirect central nervous system excitation, the effects of pertussis toxin and 4-aminopyridine on the hypnotic-anesthetic action of pentobarbital also were assessed. Pentobarbital-induced hypnosis was not attenuated by either treatment. These results suggest that the receptor-effector mechanism for the hypnotic-anesthetic action of dexmedetomidine involves an inhibitory G-protein and increased conductance through a potassium channel.