Pharmacokinetic-Pharmacodynamic Modeling of the New Steroid Hypnotic Eltanolone in Healthy Volunteers

Background: In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers.

Methods: Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 micro gram [centered dot] ml sup -1 [centered dot] min sup -1 and a targeted concentration of 2-2.5 micro gram/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model.

Results: The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 micro gram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min sup -1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening.     

Hämodynamische Wirkungen von 3 unterschiedlichen Dosierungen des Induktionshypnotikums Eltanolon bei koronarchirurgischen Patienten

Eltanolone is a new steroid anaesthetic agent that is a 5-β reduced derivative of progesterone. In the present study we investigated the haemodynamic effects of eltanolone or thiopentone in patients scheduled for coronary artery bypass grafting. Methods. After obtaining approval of the institutional ethics committee and informed patient consent, 40 patients (age 45–70 years, ASA III and IV, ejection fraction >50%, cardiac index >2.5?l/min per m²) were randomly assigned to four groups, each containing 10 patients: After premedication with 2?mg flunitrazepam, anaesthesia was induced with 3?mg/kg thiopentone in group 1, 0.5?mg/kg eltanolone in group 2, 0.75?mg/kg eltanolone in group 3, 1.0?mg/kg eltanolone in group 4. Each patient additionally received 3?μg/kg fentanyl after induction and 0.1?mg/kg pancuronium. Heart rate, mean arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure and cardiac output were recorded in the awake state, 2?min after induction of anaesthesia, and 1 and 5?min after intubation. Cardiac index and systemic vascular resistance were calculated. Results. Two minutes after induction, mean arterial pressure was significantly lower than the baseline (P<0.05) in each group. Mean arterial pressure changes were more prominent in the case of eltanolone, but intergroup tests did not reveal significant differences between the four groups. There was a fall in cardiac index in all groups, and these changes reached the level of significance only in the thiopentone patients. The most obvious difference between eltanolone and thiopentone was systemic vascular resistance. It dropped significantly 2?min after induction with eltanolone at all dosages. In contrast, there was an increase in systemic vascular resistance following induction of anaesthesia with thiopentone. Intergroup tests also showed significantly (P<0.05) lower systemic vascular resistance 1 and 5?min after intubation with eltanolone compared to thiopentone. Discussion. Mean arterial pressure reduction induced by eltanolone is most likely the result of the combination of a decrease in cardiac contractility and peripheral vasodilatation. In contrast, mean arterial pressure reduction in the case of thiopentone seems to be exclusively related to the negative inotropic properties of the drug. Results of a dosage finding study [5] with eltanolone revealed an AD₅₀ of 0.33?mg/kg. In our study 0.5?mg/kg eltanolone brought all the patients to sleep within 2 minutes. The haemodynamic results do not show any significant difference up to twofold dosage. Therefore, the therapeutic margin seems to be large. Because of considerable interindividual variability additional studies in larger collectives are required for definitive evaluation of the drug.     

Concentration-Effect Relationships of Eltanolone Given as a Bolus Dose or Constant Rate Intravenous Infusion to Healthy Male Volunteers

Background: The primary purpose of this study was to evaluate concentration-effect relationships of the new steroid anesthetic eltanolone during recovery from a bolus dose and constant rate intravenous infusion in healthy male volunteers.

Methods: Ten subjects received a bolus dose of 0.75 mg/kg eltanolone over 20 s. A 2-h constant rate intravenous infusion of eltanolone was given to five subjects at a rate of 2 mg *symbol* kg sup -1 *symbol* h sup -1 and to another five subjects at a rate of 3.5 mg *symbol* kg sup -1 *symbol* h sup -1. Recovery performance was assessed as the time required to reach different end-points and by means of three different psychomotor tests.

Results: A low interindividual variability was found in the serum concentration of eltanolone at the pharmacodynamic end-points during recovery. The Cp50 value for "eye opening" was 382 micro gram/l (95% confidence interval, 285-489) after a bolus dose corresponding to a median time of 16 min (range 8-25). After eltanolone infusion, the Cp50 value for "eye opening" was 507 micro gram/l (95% confidence interval, 425-605) and the corresponding median time was 21 min (range 8-25) in the low-dose group and 49 min (range 31-66) in the high-dose group. The Cp50 values at the same effect end-points in the bolus group were less than those in the infusion groups, probably because of insufficient equilibration time between serum and the effect compartment.     

Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop.

BACKGROUND: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the mu-opioid receptor agonist morphine. METHODS: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 microg/kg, followed by 30 microg x kg(-1) x h(-1)). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD. RESULTS: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l x min(-1) x mmHg(-1) (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l x min(-1) x mmHg(-1), not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l x min(-1) x mmHg(-1) (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l x min(-1) x mmHg(-1) (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l x min(-1) x %(-1), respectively; P < 0.05). The ventilatory response to sustained hypoxia (i/e., 15 min) did not differ between men and women. CONCLUSIONS: The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.     

A comparison of minidose lidocaine-fentanyl spinal anesthesia and local anesthesia/propofol infusion for outpatient knee arthroscopy

Traditional methods of spinal anesthesia have proven problematic in the outpatient setting. Minidose lidocaine-fentanyl spinal anesthesia (SAB(MLF)) may be the adaptation necessary to reestablish spinal anesthesia in this venue. One hundred patients scheduled for outpatient knee arthroscopy were randomized to receive either local anesthesia plus a titrated IV propofol infusion (LA/PI) or SAB(MLF) using 20 mg lidocaine 0.5% + 20 microg fentanyl. Patients received midazolam 0.02-0.03 mg/kg IV and fentanyl 0.75-1.0 microg/kg IV upon arrival in the operating room before lumbar puncture or propofol infusion. The propofol infusion was begun at 50-75 microg. kg(-)(1). min(-)(1) and titrated to maintain patient comfort. Boluses (200-400 microg/kg) were given as needed. Local anesthesia included 30 mL lidocaine 1% with epinephrine 1:200,000 intraarticularly plus 10 mL at the portal sites. Three patients (6%) in the LA/PI group versus none in the SAB(MLF) group required general anesthesia. Airway support was required in 54% of the LA/PI patients and in none of the SAB(MLF) patients. Total operating room time (43 vs 45 min), time to home readiness (43 vs 45 min), actual discharge times (73.5 min in both groups), and the incidence of discharge >90 min (22% vs 24%) were the same for both LA/PI and SAB(MLF) groups. LA/PI and SAB(MLF) groups differed in terms of postoperative pruritus (8% vs 68%), pain (44% vs 20%), nausea (8% vs 22%), and ability to void before discharge (56% vs 32%). One patient in each group had mild difficulty initiating voiding at home, but neither required medical attention. In both groups, 90% of patients were either "satisfied" or "very satisfied" with their anesthetic. The two techniques provided comparable patient satisfaction and efficiencies both intraoperatively and in postoperative recovery and discharge. The efficiencies of these techniques were not dependent on special provisions of the physical plant or the practice model. IMPLICATIONS: Both local anesthesia supplemented by a titrated IV propofol infusion and minidose lidocaine-fentanyl spinal anesthesia for outpatient knee arthroscopy provide high patient satisfaction with equally rapid recovery and discharge.     

Research on the effect of atenolol on lidocaine pharmacokinetics in rats

The aim was to determine the influence of atenolol on lidocaine pharmacokinetics in rats for one hour interval of time (average of a dental intervention). The study was carried out on 2 groups of Wistar rats treated with saline solution (0.5 ml/kg), respectively with atenolol (1.5 mg/kg), administered orally 24 hours and 3 hours before intraperitoneal administration of lidocaine (1.5 mg/kg). Blood samples were collected before and 5, 10, 20, 30, 60 minutes after lidocaine administration. Lidocaine plasma concentrations were determined by HPLC. Some pharmacokinetic parameters of lidocaine were statistically significant higher (p < 0.05, ANOVA) for the rats treated with atenolol compared with control group: Cmax (196.97 +/- 2.15 ng/ml vs. 125.29 +/- 2.90 ng/ml), AUD (7734.07 +/- 129.06 ng/ ml x min vs. 4478.57 +/- 296.61 ng/ml x min), AUC1 after 5 minutes (314.23 +/- 6.59 ng/ml x min vs. 190.71 +/- 19.75 ng/ml x min). Tmax was 20 minutes, similar for both groups. CONCLUSION: local anesthesia with lidocaine might be enhanced in the presence of atenolol compared to controls.     

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 l, 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 l/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 l.kg-1.min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 l/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 micrograms/ml for major surgery and 2.97 +/- 1.07 micrograms/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 microgram/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 microgram/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.     

Are women more sensitive to a pre‐curarization dose of rocuronium than men?

Background: There is increasing evidence that there are gender-related differences in the pharmacodynamics of neuromuscular blocking drugs. However, it is not known whether gender influences the pharmacodynamics of a pre-curarizing dose.
Methods: In the first part, we measured the neuromuscular blockade after administration of rocuronium 0.03 mg/kg (10% of ED₉₅) after induction of anaesthesia in 20 patients (10 female and 10 male patients) by electromyography. In the second part, 40 female and 40 male patients were observed for signs and symptoms of muscle weakness 2.5 min after injection of rocuronium 0.03 mg/kg before loss of consciousness. Succinylcholine-associated post-operative myalgia (POM) was also assessed.
Results: Median twitch heights were comparable between the two groups: 95.5 (range: 85–97; female) vs. 96.0 (range: 85–99; male), (NS). Train-of-four ratios were 97.5 (range: 64–100; female) vs. 99.0 (range: 52–100; male) (NS). Signs and symptoms of muscle weakness were observed in 64 (80%) patients, but there were no gender-related differences. The incidence and severity of POM did not differ significantly between the study groups.
Conclusions: Pre-curarization with rocuronium 0.03 mg/kg affected men and women equally. Nor was the incidence and the severity of muscle weakness affected by gender.     

Einfluss des Geschlechts auf den Verlauf der neuromuskulären Blockade nach Rocuronium

BACKGROUND: We studied 40 patients (20 female and 20 male) undergoing elective surgery under general anaesthesia to evaluate the effect of gender on the pharmacodynamics of rocuronium. METHODS: Using electromyography (EMG) we determined the maximal neuromuscular block and time course of action of 0.45 mg/kg rocuronium (1.5 x ED95). RESULTS: Age and body mass index were comparable between females and males (38 (+/- 8) vs. 37 (+/- 10) years and 24.2 (+/- 2.9) vs. 25.2 (+/- 1.7) kg/m2. However, significant differences in weight and height were found between females and males (65.7 +/- 9.3 kg vs. 77.5 +/- 5.5 kg; p < 0.01 and 178 +/- 6.8 cm vs. 164 +/- 6.7 cm; p < 0.01). Onset time was shorter in females (168 +/- 65 s vs. 211 +/- 56 s; p < 0.05). Maximal neuromuscular blockade after 0.45 mg/kg rocuronium was 94 (+/- 3) % in females and 89 (+/- 6) % in males; p < 0.01. Clinical duration was increased in females (23 +/- 5 min vs. 17 +/- 5 min; p < 0.05), while the recovery index was comparable between both groups (9 +/- 4 min in females and 9 +/- 3 min in males; n.s.). CONCLUSION: Compared to men neuromuscular blockade after 0.45 mg/kg rocuronium was more pronounced in women. The onset time was shortened and the clinical duration increased in female patients.     

Population Pharmacodynamics and Pharmacokinetics of Remifentanil as a Supplement to Nitrous Oxide Anesthesia for Elective Abdominal Surgery

Background: Remifentanil blood concentrations necessary for adequate intraoperative anesthesia have not been defined. The goal of this study was to determine the blood concentrations of remifentanil needed for anesthesia with 66% nitrous oxide during intraabdominal surgery. In addition, the pharmacokinetics of remifentanil and the effects of covariates on both the pharmacodynamics and the pharmacokinetics were determined.

Methods: Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and remifentanil. Remifentanil was administered by a computer-controlled infusion pump that rapidly attained, and then maintained, constant remifentanil blood concentrations. If the patient showed signs of inadequate anesthesia (autonomic or somatic response), the target concentration was increased by 1 or 2 ng/ml. If no response occurred during a 15-min period, the concentration was decreased by 1 or 2 ng/ml. Remifentanil pharmacodynamics and pharmacokinetics were estimated using NONMEM.

Results: The remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery (Cb50) with 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. The Cb50 values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively. Remifentanil pharmacokinetics were best described by a two-compartment model with lean body mass as a significant covariate, where V1 = 0.129(lean body mass-50) + 3.79 l, V (2) = 6.87 l, CL1 = 0.0389(lean body mass-50) + 2.34 l/min and CL2 = 1.14 l/min.     

The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopic surgery

We compared esmolol and remifentanil infusions with respect to their effect on intraoperative hemodynamic stability and early recovery after outpatient laparoscopic surgery when administered as IV adjuvants during desflurane anesthesia. After premedication with midazolam 2 mg IV, anesthesia was induced with propofol 2 mg. kg(-1) IV in combination with either esmolol 1 mg. kg(-1) IV (n = 27) or remifentanil 1 microg. kg(-1) IV (n = 26) and succinylcholine 1 mg. kg(-1) IV according to a randomized, double-blinded protocol. Anesthesia was initially maintained with desflurane 2.5% (subsequently titrated to maintain an electroencephalogram-bispectral index value of 60) and nitrous oxide 65% in oxygen. Before skin incision, an infusion of either esmolol (5 microg. kg(-1). min(-1)) or remifentanil (0.05 microg. kg(-1). min(-1)) was started and titrated to maintain the heart rate within 25% of the baseline value. Mivacurium, 0.04 mg/kg IV, bolus doses were administered to maintain a stable peak inspiratory pressure. Esmolol (12.8 +/- 13.1 microg. kg(-1). min(-1)) and remifentanil (0.04 +/- 0.02 microg. kg(-1). min(-1)) infusions were equally effective in maintaining a stable heart rate during these laparoscopic procedures. Although the mivacurium requirement was larger in the Esmolol group (7 +/- 5 vs 3 +/- 4 mg), the Esmolol group reported a smaller incidence of postoperative nausea and vomiting (4% vs 35%). Both drugs were associated with frequent "postanesthesia care unit bypass" rates (78-81%), short times to "home readiness" (119-120 min), excellent patient satisfaction (81-85%), and rapid resumption of normal activities (2.6-3.2 d). Fast-tracked patients were ready for discharge home significantly earlier (112 +/- 46 vs 151 +/- 50 min). We concluded that esmolol infusion is an acceptable alternative to remifentanil infusion for maintaining hemodynamic stability during desflurane-based fast-track anesthesia for outpatient gynecologic laparoscopic surgery.     

Lidocaine pharmacokinetics in children during general anesthesia

In spite of the increasing use of intravenous lidocaine in the operating room, no pharmacokinetic data exist for intravenous lidocaine in children. We studied ten children, ages 0.5-3 yr, and eight adults to determine lidocaine pharmacokinetics during anesthesia with halothane, nitrous oxide, and oxygen. After induction of anesthesia, tracheal intubation, and insertion of venous and arterial catheters, lidocaine, 1 mg/kg, was infused intravenously over 30 sec. Arterial samples were drawn at 0.5, 1, 2, 4, 5, 10, 15, 30, 60, 90, and 120 min. Plasma was separated and analyzed for lidocaine, using gas chromatography. Plasma concentration vs time data were fitted to a two-compartment model. Using standard formulas, we derived the following data: Children: distribution half-life (t 1/2 alpha) 3.2 min, elimination half-life (t 1/2 beta) 58 min, volume of the central compartment (V1) 0.22 L/kg, volume of distribution (Vd area) 1.1 L/kg, and total plasma clearance (Cl) 11.1 ml X kg-1 X min-1. Adults: t 1/2 alpha 3.6 min, t 1/2 beta 43 min, V1 0.16 L/kg, Vd area 0.71 L/kg, and Cl 9.8 ml X kg-1 X min-1. No significant differences were found between children and adults for all parameters analyzed. We conclude that children older than 6 months of age distribute and eliminate intravenous lidocaine in the same manner as adults.     

A deeper level of ketamine anesthesia does not affect functional residual capacity and ventilation distribution in healthy preschool children

BACKGROUND: Ketamine is commonly used in children in the emergency setting and while undergoing diagnostic and therapeutic interventions because of its combination of hypnotic and analgesic properties. Although studies comparing various levels of ketamine anesthesia are lacking, previous work suggests that lung mechanics might only be minimally affected by ketamine. METHODS: After approval from the Ethics Committee, anesthesia was induced with 2 mg.kg(-1) racemic ketamine followed by a continuous infusion of ketamine 2 mg.kg(-1) h(-1) (level I) in 26 children (2-6 years of age), and after 5 min, the first set of measurements was performed. Then, a second bolus of ketamine 2 mg.kg(-1) followed by ketamine 4 mg.kg(-1) h(-1) was administered (level II) and after 5 min, the second set of measurements was performed. Functional residual capacity (FRC) and lung clearance index (LCI) were calculated using a multibreath analysis by a blinded observer. RESULTS: Functional residual capacity and LCI did not change between the two levels (FRC 25.6 [4.3] ml.kg(-1) vs 25.5 [4.2] ml.kg(-1), P=0.769, LCI 10.5 [1.2] vs 10.3 [1.1], P=0.403). The minute ventilation was similar between the two levels of anesthesia. The University of Michigan Sedation Scale increased from 3 (3) to 4 (3-4) at the second level of ketamine anesthesia. CONCLUSIONS: A deeper level of anesthesia induced by ketamine does not affect FRC, ventilation distribution or minute ventilation suggesting that the depth of ketamine anesthesia has a minimal effect on pulmonary function.     

Midazolam premedication delays recovery from propofol-induced sevoflurane anesthesia in children 1–3 yr

PURPOSE: To study the effect of midazolam premedication on the recovery characteristics of sevoflurane anesthesia induced with propofol in pediatric outpatients. METHODS: Sixty children, one to three years, presenting for ambulatory adenoidectomy were randomly assigned , in a double-blind fashion, to receive either 0.5 mg x kg(-1) midazolam (Group M) or placebo (Group P) p.o. 30 min before anesthesia. Anesthesia was induced with 10 microg x kg(-1) atropine, 10 microg x kg(-1) alfentanil, and 3-4 mg x kg(-1) propofol i.v.. Tracheal intubation was facilitated with 0.2 mg x kg(-1) mivacurium. Anesthesia was maintained with nitrous oxide/oxygen (FiO2 0.3) and sevoflurane with controlled ventilation. Recovery characteristics were compared using the modified Aldrete scoring system, the Pain/Discomfort scale and measuring specific recovery end-points (emergence, full Aldrete score, discharge). A postoperative questionnaire was used to evaluate the children's well-being at home until 24 hr after discharge. RESULTS: Emergence from anesthesia (22 +/- 9 vs 16 +/- 6 min (mean +/- SD), P = 0.005) and achieving full Aldrete scores (30 +/- 11 vs 24 +/- 16 min, P = 0.006) were delayed in patients receiving midazolam. Children in the placebo group were given postoperative analgesia sooner than those in the midazolam group (18 +/- 11 vs 23 +/- 8 min, P = 0.009). More children premedicated with midazolam suffered from arousal distress (20% vs 3%, P = 0.04) and scored higher on the Pain/Discomfort scale (P = 0.004) at 20 min after arrival in the recovery room. Discharge was not affected by premedication and well-being at home was similar in the groups. CONCLUSIONS: Oral premedication with midazolam delays early recovery but not discharge after ambulatory sevoflurane anesthesia induced with propofol in children one to three years. Midazolam did not improve the quality of recovery.     

Response of human growth hormone to anesthesia induction with propofol

Although there are distinct differences in both pharmacokinetics and chemical structure, propofol has sedative effects similar to those of benzodiazepines. Both diazepam and thiopental, commonly used agents for inducing anaesthesia, show some typical neuroendocrine effects such as liberation of human growth hormone (hGH) in addition to their well-known influences on the cardiovascular system. It was our aim to examine the endocrine response of hGH after induction of anaesthesia with propofol and to compare any possible effects with those of diazepam and thiopental. The study was performed on 30 non-premedicated patients, who underwent plastic-surgery (mean age: x = 35 +/- 8.3 years, mean body weight: x = 68.9 +/- 23.2 kg). No signs of endocrine disturbances were found in the patients prior to the study. Patients were divided in a random fashion into 3 groups of 10 persons each: In group 1 propofol was given in a bolus injection (2 mg/kg) and then by infusion for a period of 10 min (0.2 mg/kg/min). In group 2 diazepam (0.3 mg/kg) and in group 3 thiopental (5 mg/kg) were administered as a bolus to induce anesthesia. All patients were intubated immediately after induction of anesthesia and then relaxed using vecuronium (1 mg/kg). Ventilation was performed mechanically during the entire operative period (N2O/O2 - FiO2:0.33, tidal volume 10 ml/kg, respiratory rate: 14/min). To maintain anesthesia halothane (0.5-1.0 vol.-%) and meperidine (0.75 mg/kg) were added 15 min after induction.(ABSTRACT TRUNCATED AT 250 WORDS)     

患者硬膜外注射不同浓度左旋布比卡因的药代动力学

目的 探讨患者硬膜外注射不同浓度左旋布比卡因的药代动力学.方法 择期行结肠癌根治术、经腹或腹会阴直肠癌根治术患者20例,ASA Ⅰ或Ⅱ级,年龄35～59岁,随机分为0.75%左旋布比卡因组(Ⅰ组)和0.5%左旋布比卡因组(Ⅱ组),每组10例.麻醉方法为腰段硬膜外阻滞联合全麻.经L1,2硬膜外穿刺成功后,分别经2 min注入0.75%或0.5%左旋布比卡因2 mg/kg.硬膜外注药结束后30 min内记录感觉和运动阻滞效果,记录不良反应发生情况.于注药后即刻、注药后10、20、30、45、60、90、120、210、300、420、540、660和840 min时取中心静脉血3 ml,采用高效液相色谱法测定血浆左旋布比卡因浓度,绘制血浆左旋布比卡因浓度-时间曲线,计算2组药代动力学参数.结果 2组血浆左旋布比卡因浓度-时间曲线均符合二房室开放模型;2组药代动力学参数比较差异均无统计学意义(P＞0.05).结论 0.75%和0.5%左旋布比卡因2mg/kg腰段硬膜外阻滞安全性高,血浆药物浓度-时间曲线均符合二房室开放模型,两者药代动力学特性无差异.     

Pharmacokinetics of sufentanil in obese patients.

The pharmacokinetics of sufentanil were determined in eight obese (94.1 +/- 14 kg, mean +/- SD) and eight control patients (70.1 +/- 13 kg) anesthetized for neurosurgery. After induction of anesthesia, 4 micrograms/kg of sufentanil was administered in a single intravenous bolus. Multiple arterial samples were obtained at timed intervals over 6 h, and plasma concentrations of sufentanil were measured by radioimmunoassay. Calculation of pharmacokinetic variables from the derived compartmental models demonstrated an increased volume of distribution of sufentanil in the obese (9098 +/- 2793 mL/kg ideal body weight, mean +/- SD) when compared with a control group (5073 +/- 1673 mL/kg ideal body weight) (P less than 0.01) and a prolonged elimination half-life (208 +/- 82 min vs 135 +/- 42 min, P less than 0.05). The total volume of distribution correlated linearly with the degree of obesity, as expressed in percent ideal body weight (r = 0.67). In contrast, plasma clearance was similar in both obese and control groups (32.9 +/- 12.5 vs 26.4 +/- 5.7 mL/kg ideal body weight). The high lipid solubility of sufentanil probably explains the altered pharmacokinetics of this opioid in obese patients.     

Scopolamine prevents dreams during general anesthesia

BACKGROUND: Dreaming during anesthesia is not a well-understood phenomenon. Anticholinergic drugs are used in anesthesia as premedication, but their use to decrease the incidence of dreams and psychological adverse reactions after anesthesia is not well established. The authors therefore studied the efficacy of intramuscular atropine and scopolamine for the prevention of dreams during general anesthesia with propofol and nitrous oxide. METHODS: Healthy women undergoing minor gynecologic surgery were randomly assigned to receive 2.5 microg/kg scopolamine or 10 microg/kg atropine intramuscularly (n = 50/group). In both groups, anesthesia was induced and maintained with propofol as a 2.5-mg/kg bolus, followed by 12 mg x kg(-1) x h(-1) as a continuous infusion and 70% nitrous oxide in oxygen. Two interviews regarding dreaming activity and characteristics were conducted at 20 min and 6 h after surgery. RESULTS: None of the patients in the scopolamine group and 47% of the patients in the atropine group reported the occurrence of dreams 20 min after recovery. The results were similar at 6 h: 6% of the scopolamine group and 43% of the atropine group reported dream activity. No differences in sedation or anesthetic requirements were found. CONCLUSIONS: Previous studies in animals and humans suggest that dreams are affected by drugs acting on the central cholinergic system. The current results suggest that intramuscular scopolamine prevents dreams or dream recall in healthy young women undergoing short elective surgery with propofol-nitrous oxide anesthesia.     

Effect of renal failure and cirrhosis on the pharmacokinetics and neuromuscular effects of rapacuronium administered by bolus followed by infusion

BACKGROUND: Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion. METHODS: During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling. RESULTS: Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium. CONCLUSION: Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs: VII. Verapamil and thiopental

To assess the role of basal anesthesia in the negative inotropic properties of verapamil, the effect of thiopental (30 mg/kg followed by 3.5 mg.kg-1.min-1) on verapamil pharmacokinetics (200 micrograms/kg iv; n = 6) and its pharmacodynamics (3 and 6 micrograms.kg-1.min-1; n = 11) in chronically instrumented dogs was studied. In the presence of thiopental, verapamil pharmacokinetics remained essentially unchanged. In contrast, anesthesia altered verapamil hemodynamic properties. In the conscious animal verapamil infusions increased heart rate (14 +/- 3 and 27 +/- 4 beats/min, respectively), cardiac output (0.22 +/- 0.07 and 0.24 +/- 0.08, l/min, respectively) and PR interval (14 +/- 2 and 25 +/- 6 ms, respectively) and slightly decreased dP/dt (-315 +/- 114 and -419 +/- 106 mmHg/s, respectively). Systemic vascular resistance (SVR) decreased at the low dose (-2.7 +/- 0.7 mmHg.1.min-1), and stroke volume decreased at the high dose (-4.4 +/- 0.6 ml). Yet the presence of thiopental resulted in an accentuation of verapamil-induced tachycardia (27 +/- 7 and 31 +/- 6 beats/min, respectively), and a decrease in stroke volume (-5.3 +/- 2.0 and -6.3 +/- 2.1 ml, respectively). At 3 micrograms.kg-1.min-1 verapamil did not increase PR interval, cardiac output, or vasodilation. Finally, at 6 micrograms.kg-1.min-1 verapamil did not decrease dP/dt and increased renal blood flow (21.8 +/- 6.4 ml/min). These data provide evidence that the negative inotropic properties of verapamil are more pronounced in the presence of thiopental. However, the role of basal anesthesia appears to be limited.