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This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh-cross ponies (weighing 135-300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20-40 μg/kg/min). Blood samples (

Summary Three possible factors predisposing to Althesin hypersensitivity, namely total dose, method of administration, either by bolus dose or infusion, and pregnancy have been studied in patients receiving the drug for the first time. Of 137 patients given Althesin, four exhibited clinical signs of mild hypersensitivity, while C3 conversion alone, indicative of a subclinical reaction, was seen in a further six patients. No reactions were observed in two control groups in whom anaesthesia was induced with thiopentone. Neither the total dose nor method of administration appeared consistently to influence the incidence of reactions, but eight of the ten patients producing an altered response to Althesin were pregnant.

Background The relative potency of the steroid anaesthetic agent eltanolone has been compared with respect to induction of anaesthesia in ASA I and II young (1840: years) and elderly (>65 years) patients. Results: Anaesthesia was adequately induced in 12/40 elderly and 7/40 young patients. The lowest effective induction dose was 0.2 mg/kg in elderly and 0.3 mg/kg in young patients. This gave a relative potency of 0.28 (95% CI 0.12–52; P=0.0039). The cardiovascular effects associated with induction were small; other side-effects included involuntary movement and hypertonus, and respiratory upsets (apnoea, hiccups and coughing). Conclusion: The effective induction dose of eltanolone was significantly lower in the elderly patients; but the drug safety profile was similar in both age groups of patients. Method:113 temazepam premedicated patients (60 elderly) were evaluated in an open randomised study. They were allocated to receive doses between 0.05 and 0.75 mg/kg given i.v. over 30 s. The first 33 patients formed a pilot phase; the formal study comprised 80 patients. The primary efficacy variable was loss of verbal contact within 120 s and an effect lasting more than 4 min. All patients breathed 100% oxygen throughout the study period. Safety data (heart rate, blood pressure, respiratory apnoea, involuntary movements, hypertonus and other adverse effects) were noted.

We have studied the effects of ketorolac, bupivacaine and low-dose heparin on three thrombelastographic (TEG) variables (r, alpha, MA) in vitro. Blood samples were obtained from 12 healthy volunteers and 88 ASA I-II elective surgical patients. Clinically relevant concentrations of ketorolac (4.1 micrograms ml-1) and bupivacaine (2.7 micrograms ml-1) had little or no effect on the TEG variables. However, low concentrations of heparin (0.07-0.28 u. ml-1) had marked effects on all three TEG variables. Thus the interpretation of TEG abnormalities during anaesthesia and surgery may be confounded by the presence of heparin, but not by clinical concentrations of ketorolac or bupivacaine.

This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh-cross ponies (weighing 135-300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20-40 μg/kg/min). Blood samples (2 mL) were collected prior to, during and after the infusion, and on assuming standing position. Anaesthesia was uneventful; with the duration of infusion 31-89 min. Blood propofol concentrations during the infusion ranged between 1.52 and 7.65 μg/mL; pseudo-steady state concentrations 3.64-6.78 μg/mL, and concentrations on assuming standing position 0.75-1.40 μg/mL. Propofol clearance and volume of distribution were 31.4 (SD 6.1) mL/min/kg and 220.7 (132.0) mL/kg, respectively. The propofol analyser allows titration of propofol to a given concentration; and may be useful for anaesthesia in animals where kinetics are unknown; in disease states; and where intercurrent therapies affect propofol disposition.

We conducted a pharmaco-economic analysis of the prospective peri-operative studies of beta-blocker and statin administration for major elective non-cardiac surgery, using the Discovery Health claims costs for 2004. This analysis shows that acute peri-operative beta-blockade and statin therapy could result in a cost saving through a reduction in major perioperative cardiovascular complications in patients with an expected peri-operative major cardiovascular complication rate exceeding 10% following elective major non-cardiac surgery. The validity of these findings is dependent on whether the incidence of cardiovascular complications following major noncardiac surgery reported in the international literature is found to be similar in South Africa.

The pharmacokinetics and thermal antinociceptive effects of buprenorphine after intravenous (i.v.) or oral transmucosal (OTM) administration were studied in six adult cats. Plasma buprenorphine concentrations were measured using radioimmunoassay in a crossover study after a dose of 20 microg/kg given by the i.v. or OTM route. Oral pH was measured. Blood for drug analyses was collected before, and at 1, 2, 4, 6, 10, 15, 30, and 60 min and at 2, 4, 6, 8, 12, and 24 h after treatment. Thermal thresholds were measured before treatment, then following treatment every 30 min to 6 h, every 1 hour to 12 h and at 24 hours postadministration. Plasma buprenorphine concentration effect relationships were analyzed using a log-linear effect model. Oral pH was 9 in each cat. Peak plasma buprenorphine concentration was lower and occurred later in the OTM group but median bioavailability was 116.3%. Thermal thresholds increased significantly between 30 and 360 min in both groups. Peak effect was at 90 min and there was no difference at any time between the two groups. There was distinct hysteresis between plasma drug concentration and effect in both groups. Overall, OTM administration of buprenorphine is as effective as i.v. treatment and offers a simple, noninvasive method of administration which produces thermal antinociception for up to 6 h in cats.

Knowledge about UK doctors' career intentions and pathways is essential for understanding future workforce requirements. The aim of this study was to report career choices for and career progression in anaesthesia in the UK.Postal questionnaire surveys were undertaken of qualifiers from all UK medical schools in nine qualification years since 1974.74% (24623/33417) and 73% (20709/28468) of doctors responded at 1 and 3 yr after qualification. At 1 and 3 yr after qualification, on average, 8% of doctors chose anaesthesia. Between 1974 and 2002 the percentage of doctors choosing anaesthesia, 1 yr after qualification, increased from 5 to 12%. A majority of doctors who chose anaesthesia 1 and 3 yr after qualification were working in anaesthesia 10 yr after qualification. In addition to doctors' enthusiasm for the specialty, career choices for anaesthesia were positively influenced by their perception of working hours, conditions of work, and career and promotion prospects.Anaesthesia has become increasingly popular as a career choice in the UK. Training numbers could be increased in the short term to speed up the process of providing a consultant-delivered service.

Data allowing rational use of analgesics in cats are limited. Pharmacokinetics and pharmacodynamics of fentanyl were studied in cats. Plasma fentanyl concentrations were measured using radioimmunoassay in a crossover study in six cats after 10 microg/kg (i.v.) or by application of fentanyl in pluronic lecithin organogel (PLO) to the inner ear pinna. On a separate occasion thermal thresholds were measured after i.v. fentanyl (10 microg/kg) or saline. Plasma fentanyl concentrations reached 4.7-8.31 ng/mL 2 min after i.v. administration and were undetectable after 95 min. Fentanyl was not detected in plasma at any time after PLO use. Thermal thresholds did not change following saline administration but were increased above baseline from 5 to 110 min after i.v. fentanyl. In this model a plasma concentration of1.07 ng/mL was required to provide analgesia. Plasma concentrations were measured in additional cats after intranasal or oral dosing (2 microg/kg) and after 30 microg/kg in PLO gel. After oral and nasal dosing, Cmax values were 0.96 and 1.48 ng/mL at 5 and 2 min, respectively. Plasma fentanyl was not detected after application of the higher dose of fentanyl in PLO.

Little is known about the effect of chronic beta-adrenoceptor antagonist therapy during the peri-operative period in patients undergoing non-cardiac surgery. We conducted a literature review to identify studies examining the relationship between chronic therapy and adverse peri-operative outcome. Eighteen studies were identified in which it was possible to ascertain the incidence of adverse cardiac outcomes in those patients who were and were not receiving chronic beta-blocker therapy. None of the studies demonstrated a protective effect of chronic beta-blockade. The results of these studies were then combined and a cumulative odds ratio calculated for the likelihood of myocardial infarction, cardiac death and major cardiac complications. Patients receiving chronic beta-blocker therapy were more likely to suffer a myocardial infarction (p0.05). These findings differ from the published effects of acute beta-blockade. Reasons for this discrepancy are considered.

The molecular basis of i.v. general anaesthetic activity was investigated using comparative molecular field analysis (CoMFA).The free plasma concentrations that abolish movement to a noxious stimulus for 14 structurally diverse i.v. anaesthetics were obtained from the literature. The compounds were randomly divided into a training set (n=10) to derive the activity model, and a separate test set (n=4) used to assess its predictive capability. The anaesthetic structures were aligned so as to maximize their similarities in molecular shape and electrostatic potential to conformers of the most active agent in the group, eltanolone. The conformers and alignments that showed the maximum similarity (calculated using combined Carbo indices) were retained, and used to derive the CoMFA models.The final model explained 94.0% of the variance in the observed activities of the training set (n=10, P0.0001) and was a good predictor of test set activity (n=4, r(2)=0.799). In contrast, a model based on non-polar solubility (LogP) explained only 78.3% of the variance in the observed activities of the training set (n=10, P=0.0007) and was a poor predictor for the test set (n=4, r(2)=0.272). Further analysis of the CoMFA results identified the spatial distribution of key areas where steric and electrostatic interactions are important in determining the activity of the 14 anaesthetics considered.A single activity model can be formulated for i.v. general anaesthetics and preliminary pharmacophoric maps derived, which describe the molecular basis of their in vivo potency.

Two hundred and seventy-five non-cardiac surgical patients were recruited to determine risk factors associated with the development of postoperative cardiovascular complications during the first year after surgery. Patients underwent ambulatory electrocardiography pre- and postoperatively. There were 34 adverse events over the whole study period. Twenty-four occurred within 6 months and the remaining 10 occurred between 6 and 12 months postoperatively. Silent myocardial ischaemia was associated with adverse outcome over both the first 6 months [OR 4.44 (95% CI 1.77-11.13)] and the whole study period [OR 2.81 (1.26-6.07)]. Other risk factors were: vascular surgery [OR 17.09 (2.67-351.44)], history of angina [OR 6.29 (2.21-17.62)], concurrent treatment with calcium entry blockers [OR 2.68 (1.03-6.93)] and smoking [OR 4.93 (2.00-12.02)]. None of these was a useful predictor of long-term outcome (between 6 and 12 months postsurgery). These results are at variance with other published data, but we conclude that monitoring for peri-operative silent myocardial ischaemia does not aid the prediction of long-term cardiovascular complications.

We investigated the use of measurements of serum concentrations of the cardiac proteins troponins I and T as biochemical markers of myocardial cell damage in 80 patients undergoing vascular or major orthopaedic surgery. Holter electrocardiographic monitoring was carried out before surgery and for 3 days after surgery. Blood samples for troponins I and T and creatine kinase-MB isoenzyme were taken on each of these 4 days. Outcome was assessed at 3 months using a patient questionnaire, general practitioner follow-up and case notes review. Silent postoperative myocardial ischaemia was detected in 21 patients; increases in troponins I and T and creatine kinase-MB occurred in four, six and 17 of these patients, respectively. Eight patients suffered major postoperative complications (cardiac death, myocardial ischaemia, congestive cardiac failure, unstable angina and cerebrovascular accident) and 21 minor complications (poorly controlled hypertension needing increased or new additional treatment, palpitations, increased tiredness or shortness of breath in the absence of known respiratory disease). There were no associations between postoperative ischaemia and cardiac protein concentrations. The relative odds for the associations of major adverse outcome at 3 months after surgery and postoperative ischaemia or increased serum concentrations of the three proteins were 5.39 [95% confidence intervals 1.16-27.67] for postoperative ischaemia; 5.64 [1.07-31.00] for creatine kinase-MB isoenzyme; 17.00 [2.20-116.54] for troponin T and 13.20 [1.12-135.00] for troponin I. We found troponin T to be the only prospective marker for both major and minor cardiovascular complications (relative odds 10.65 [1.26-252.88]).

One hundred and twenty-seven patients undergoing major lower limb joint replacement surgery were studied to determine the incidence of silent myocardial ischemia and to ascertain any link between pre-operative cardiac risk factors, silent myocardial ischaemia and postoperative morbidity. Patients underwent ambulatory ECG monitoring for 4 days (on the pre-operative night and for 3 days postoperatively). Postoperative cardiorespiratory symptomatology and morbidity was assessed by questionnaire at 3 months. Eighty-seven patients had risk factors for silent myocardial ischaemia; 42 patients (30 with risk factors) had peri-operative silent myocardial ischaemia. The median ischaemic loads (range) were 1.04 (0.32-13.31) min.h-1 pre-operatively and 5.53 (0.26-56.39), 6.69 (0.04-42.71) and 1.23 (0.1-53.74) min.h-1 on postoperative days 1-3, respectively. Risk factors did not predict the occurrence of silent myocardial ischaemia or an increased ischaemic load pre-operatively or overall postoperatively. New symptoms (chest pain, palpitations, breathlessness or fatigue) were associated with both silent myocardial ischaemia and ischaemic load (p0.05). Thus cardiac risk factors do not predict the occurrence of silent myocardial ischaemia or adverse outcome. Peri-operative silent myocardial ischaemia was associated with increased postoperative fatigue.

To examine the physiologic and pharmacokinetic effects of a technique of total intravenous anesthesia in ponies.6 healthy ponies.Ponies were premedicated with acepromazine (0.03 mg/kg of body weight, IV) and xylazine (1.0 mg/kg, IV). Two minutes later, anesthesia was induced with ketamine (2.0 mg/kg, IV) followed by climazolam (0.2 mg/kg, IV). Anesthesia was maintained for 120 minutes by an infusion of climazolam (0.4 mg/kg/h) and ketamine (6.0 mg/kg/h). Oxygen (5 L/min) was supplemented. 20 minutes after the infusion was stopped sarmazenil (0.04 mg/kg, IV) was administered. Cardiovascular and respiratory function measurements were taken before and after premedication, and during anesthesia. Plasma cortsol, ACTH, and catecholamine concentrations were used to assess adrenal and pituitary gland function Ketamine and climazolam kinetics were calculated, on the basis of plasma drug concentrations.There were no significant changes from pre-xylazine values in heart rate, respiratory rate, arterial blood pressure, cardiac index, systemic vascular resistance, or arterial PO2, PCO2, and pH. Plasma cortisol concentration decreased during anesthesia, but plasma ACTH and catecholamine concentrations did not change. Recovery was fairly smooth, but some excitement and ataxia were noted in 2 ponies.Ketamine-climazolan infusion appeared suitable for maintenance of anesthesia in ponies, although recovery was not ideal in 2 of 6 ponies.

Anaesthetists often provide anaesthesia by continuous infusion of intravenous drugs, using open-loop control systems. Such systems include syringe pumps and volumetric pumps.

We have studied the effects of stepwise increasing infusion rates of propofol 200-500 micrograms kg-1 min-1 on blood concentrations of propofol and the disposition and clearance of a bolus dose of indocyanine green (ICG) 0.5 mg kg-1 in 10 acutely instrumented dogs. Drug concentrations and ICG clearance were measured 30 min after each change of infusion rate and after reverting for 60 min to the basal propofol infusion rate. Increasing infusion rates resulted in significant prolongation of the elimination half-life of ICG and decrease in ICG clearance at the largest infusion rate (500 micrograms kg-1 min-1) compared with the basal rate. Similarly, there were greater than predicted blood concentrations of propofol at the largest infusion rate. When the infusion rate reverted to 200 micrograms kg-1 min-1, and continued for 60 min, there was a significant difference between the initial blood concentration of propofol at this basal infusion rate and this latter value (P0.01). These changes reflect the persistent myocardial depression observed during the recovery phase.

Pharmacokinetic variables of propofol were investigated in 6 mixed-breed dogs, and the effect of medetomidine (10 micrograms/kg of body weight) on these kinetics was investigated using a two-way crossover design. On 2 occasions, dogs received either a bolus dose of propofol sufficient to allow endotracheal intubation, followed by an infusion of propofol (0.4 mg/kg/min) for 120 minutes, or medetomidine (10 micrograms/kg, IM), 15 minutes prior to induction of anesthesia as described, followed by infusion of propofol (0.2 mg/kg/min). Dogs given medetomidine received atipamezole (50 micrograms/kg, IM) at the end of the 120-minute propofol infusion. Blood propofol concentration was measured, using high-performance liquid chromatography with fluorescence detection. Mean elimination half-life, blood clearance, mean residence time, and mean volume of distribution at steady state, were 486.2 minutes, 34.4 ml/kg/min, 301.8 minutes, and 6.04 L/kg, respectively, in the absence of medetomidine, and 136.9 minutes, 36.2 ml/kg/min, 215.1 minutes, and 3.38 L/kg, respectively, in the presence of medetomidine. Mean time to walking without ataxia was 174 minutes in the nonpremedicated dogs (with a median blood propofol concentration of 2.2 micrograms/ml) and was 160 minutes in the premedicated dogs in which median blood propofol concentration was 1.03 microgram/ml.

Thoracic bio-impedance cardiography was used to study the haemodynamic changes in 28 patients undergoing transurethral prostatectomy (TURP) under either general or spinal anaesthesia. Cardiac output and mean arterial pressure fell with induction of general anaesthesia, whilst mean arterial pressure and systemic vascular resistance fell with induction of spinal anaesthesia. The transthoracic fluid index fell during resection under general anaesthesia, but no significant haemodynamic changes were seen during resection under either anaesthetic. This study suggests that resection has no specific adverse haemodynamic consequences. Spinal anaesthesia may produce less haemodynamic disturbance than general anaesthesia in patients undergoing TURP and formal comparison of the 2 techniques seems necessary.

General anaesthesia is the reversible depression of central nervous system function. There is still no agreement over what constitutes depth of anaesthesia, and the clinical anaesthetist must thus titrate drug input according to clinical signs (heart rate, blood pressure, somatic movement, autonomic responses). The potency of inhalational agents may be expressed in terms of the MAC (minimum alveolar concentration); comparable end-points (including blood concentrations) have been proposed for the intravenous agents. Kinetic infusion regimens can be constructed for the intravenous agents to achieve the ED95 concentrations required to provide clinically adequate anaesthesia. However, because of individual differences in drug kinetics and: dynamics, as well as the influences of disease states and intercurrent therapy, the clinician will titrate the dose according to response. Administration of volatile or intravenous anaesthetics by fixed regimens may result in either overdosage or the risk of patient awareness. The choice of anaesthetic drug is usually based on the nonhypnotic side effects of the different agents — including their central and regional cardiovascular effects, the speed and completeness of recovery, and the need to provide intraoperative analgesia. In addition, special techniques and drugs are often needed for neurosurgical, cardiothoracic and obstetric anaesthesia. All anaesthetic agents (inhalation and intravenous) have other side effects (such as cardio-respiratory depression and organ toxicity related to the liver or kidney). Both halothane and enflurane may be responsible for postoperative hepatic dysfunction, while the metabolism of enflurane can also result in nephrotoxicity in patients with pre-existing renal dysfunction. Isoflurane has been reported to cause ‘coronary steal’ in patients with ischaemic heart disease through its coronary vasodilator properties. Of the intravenous agents available for maintenance anaesthesia, large doses of thiopental result in prolonged recovery time, while ketamine may cause hallucinations. Benzodiazepines obtund these effects of ketamine, but are also accompanied by delayed recovery. At present, the combination of propofol and alfentanil offers the best pharmacological properties for maintenance of anaesthesia; however, caution is needed in the patient with ischaemic heart disease, hypertension or hypovolaemia.

Propofol (2,6, di-isopropylphenol) was given by continuous intravenous infusion to provide sedation following coronary artery bypass surgery. The need for additional sedation, analgesia and hypotensive agents was assessed at two propofol infusion rates (10 or 25 micrograms/kg/min). Both rates provided clinically satisfactory conditions. There were no differences in the requirements for analgesia or vasodilators between the groups. The higher infusion rate of 25 micrograms/kg/min was associated with a lower requirement for additional sedation but a more frequent need to stop the infusion temporarily to prevent hypotension.

The reduction of elevated fasting plasma glucose levels to near normal by repeated intravenous bolus insulin doses, given according to a simple algorithm, has been studied in 17 Type I and 23 Type II, healthy diabetic patients. Using a formula based on the patient's plasma glucose, height and bodyweight with insulin boluses given every 30 min if the plasma glucose remained above 6 mmol/1, plasma glucose levels were reduced to less than 7.5 mmol/1 in 28 (70%) patients by 60 min at which time the mean (+/- 1 SD) plasma glucose level in the Type I diabetic patients had reduced from 18.2 +/- 4.9 to 8.9 +/- 3.5 mmol/1 and in the Type II diabetic patients from 12.3 +/- 3.1 to 5.9 +/- 1.4 mmol/1. None of the patients had symptomatic hypoglycaemia although in one Type I patient the plasma glucose level fell to 2.2 mmol/1. The rate of fall of glucose in the less insulin sensitive patients was not increased by giving more insulin. The regimen allows a reproducible and prompt glycaemic reduction in fasting diabetic patients.

The disposition of alfentanil has been investigated in 10 anaesthetized patients with chronic renal failure undergoing kidney transplantation and compared with eight age matched anaesthetized patients with normal renal function. Plasma samples were collected to 660 min following intravenous administration of alfentanil 3–5 mg (50 μg kg−1). Drug concentrations were measured by RIA; and alfentanil binding to plasma proteins by equilibrium dialysis against 0·1 M phosphate buffer, pH 7·4. Alfentanil binding to plasma proteins was 87·6% (s.d. 2·0) in the patients with chronic renal failure, and 89·7% (1·2) in patients with normal renal function (P = 0·025). There was no correlation between alfentanil binding and plasma albumin, total plasma proteins, plasma urea or plasma creatinine concentrations. In both groups, the drug concentration-time profile decayed in a curvilinear manner; in the chronic renal failure patients, restoration of function did not influence the decay profile. Elimination half life, mean residence time and apparent volume of distribution at steady state were not different in the two groups of patients (mean values: 142·4 and 120·2 min; 128·5 and 136·0 min; and 40·5 and 27·6 L, respectively in chronic renal failure patients and patients with normal renal function). Total drug clearance and Vd area were significantly increased in the chronic renal failure patients: 341·9 vs 211·8 mL min−1; and 69·3 and 35·5 L. There were no differences in intrinsic clearance or apparent volume of distribution at steady state for unbound drug between the two patient groups.

Summary A variety of methods are currently available for the management of the diabetic patient in the peri-operative period. A questionnaire about current clinical practice was sent to all anaesthetists in the Oxford region. The majority reported that minor surgery in both insulin treated and noninsulin treated diabetic patients warranted no intervention other than avoidance of meals and medication before surgery, and that, for major surgery, a glucose-insulin-potassium infusion should be used. Fifty one out of 71 respondents in the junior staff grades preferred this latter approach for intermediate surgical procedures in insulin treated patients compared with 27 out of 69 of the consultant staff. Most anaesthetists aimed for blood glucose levels of 7–13 mmolilitre in the peri-operative period. The literature is also reviewed.

A technique is described for the determination of equipotent rates of infusion of intravenous hypnotic agents. Two end points have been defined; the rates needed to suppress the initial response to the surgical incision in 50% (ED50) and 95% (ED95) of patients receiving continuous infusion anaesthesia to supplement 67% nitrous oxide in oxygen. For patients aged 20-60 years, and premedicated with morphine 0.15 mg/kg intramuscularly, the ED50 values for Althesin (as alphaxalone) and methohexitone by infusion were 13.7 and 48.8 micrograms/kg/minute respectively. The ED95 values were 18.1 and 75.9 micrograms/kg/minute. For patients of a similar age premedicated with diazepam 10 mg orally, the ED50 values for Althesin and methohexitone were 18.5 and 66.0 micrograms/kg/minute respectively; while the ED95 values were 24.2 and 80.8 micrograms/kg/minute.

In order to avoid Cremophor-related reactions and reduce the incidence of pain on injection, diisopropylphenol (ICI 35,868; propofol) has been reformulated as an emulsion. One hundred and fifteen patients received an induction dose of propofol in the new formulation. The dose required to induce anaesthesia in 95% of healthy, unpremedicated patients was 2.5 mg/kg. Induction was associated with a degree of cardiovascular and respiratory depression. There were no adverse reactions although there were a number of minor side-effects. The incidence of pain on injection was low (3%) and the overall quality of induction was assessed as good or adequate in 92% of patients.

Existing methods for the measurement of plasma or tissue alphaxalone concentrations by gas chromatography are not wholly satisfactory because of the problems of interfering peaks and detector contamination by the silylation reagent. This paper describes an alternative gas chromatographic method using the nitrogen selective alkali flame ionization detector. Plasma samples from patients given Althesin (alphaxalone-alphadolone acetate) were extracted with light petroleum. O-Methyl oximes were formed using methoxyamine hydrochloride, and the O-methyloxime-3-acetate prepared by heating the extract with acetic anhydride-pyridine. Gas liquid chromatography was carried out on a column of 3% OV 17 on Celite 545 (mesh 80–100), initial temperature 235 °C and increasing by 1 °C min−1. Comparison has been made of the O-methyl oxime acetates with trimethylsilyl ethers using both gas chromatography and gas chromatography-mass spectrometry. The results of the two methods were not significantly different. The coefficient of variation for the O-methyloxime-3-acetates at a plasma concentration of 1·09 μl−1 was 6·9%. This method has an improved sensitivity and selectivity over the existing method, and allows determination of the plasma alphaxalone concentrations found in patients receiving Althesin-supplemented anaesthesia.

Gas chromatography-mass spectrometry has been used to study the metabolism of Althesin (alphaxalone and alphadolone acetate) in man. Two metabolites, 20α-reduced alphaxalone and alphadolone, as well as the two parent steroids, have been detected in the plasma during and after an infusion of Althesin. The main urinary metabolites were alphaxalone and 20α-reduced alphaxalone, with smaller amounts of alphadolone, all of which were excreted mainly as the glucuronide conjugates. No alphadolone acetate was detected in the urine. In 3 patients in whom bile was collected over the 1st 24 h post-operation from an indwelling T-tube, it has not been possible using the methods described to detect in bile the presence of the parent steroids, or any of their probable metabolites.

The disposition kinetics of propofol have been determined in 12 patients (6 female) receiving 2.5 mg/kg for induction of anaesthesia which was maintained using 1.5% halothane and 67% nitrous oxide in oxygen. Patients were premedicated with oral diazepam 10 mg and were undergoing body surface surgery. Peripheral venous samples were collected up to 8 h after injection of the drug. Whole blood propofol concentrations were determined by high pressure liquid chromatography using fluorescence detection. Data analysis indicates a 3 compartment model, with a terminal half-life of 286 (s.e.m. +/- 36) min, clearance of 1803 +/- 125 ml/min, and volume of distribution of 755 +/- 109 litres. These values are significantly different from those reported previously by Adam et al., (1983) for the Cremophor formulation of the drug. Seven of the patients showed significant secondary peaks of the blood concentration associated with recovery from anaesthesia.

The cardiovascular effects of induction of anesthesia with minaxolone, a new water soluble steroid agent, have been studied in 12 normotensive patients and 5 patients with treated hypertension. The arterial pressure, heart rate and ECG were continuously recorded before and during induction of anesthesia with Minaxolone 0.5 mg kg-1. Cardiac output measurements were made in the awake patient, at 3 minutes after the induction of anesthesia and 2 minutes after an increment of the drug. In both groups of patients, induction of anesthesia led to a decrease in systolic arterial pressure and a smaller decrease in diastolic arterial pressures. This was coupled with an increase in the heart rate. The decrease in cardiac output was similar in both the normal and treated hypertensive patients. Administration of an increment of minaxolone (0.1 mg kg-1) did not produce further significant changes in the cardiovascular variables. The results of this study show that the changes in hemodynamic variables with minaxolone are comparable with those seen following induction of anesthesia with other intravenous agents, with the one difference in that there was only minimal change in the diastolic arterial pressure.

The influence of age has been studied on equipotent rates of continuous infusions of two intravenous hypnotic agents. Two end points have been defined; ED50: the rate needed to suppress the initial response to the surgical incision in 50% of patients, and ED95: the corresponding rate in 95% of patients receiving continuous infusion anaesthesia to supplement 67% nitrous oxide in oxygen. All 210 patients included in the study were premedicated with morphine 0.15 mg kg-1. For patients aged 20-40 years (young group), the ED50 values for Althesin (as alphaxalone) and methohexitone were 14.6 micrograms kg-1 min-1 and 59.9 micrograms kg-1 min-1. The ED95 values were 21.0 micrograms kg-1 min-1 and 92.1 micrograms kg-1 min-1. For patients aged 55-80 years (old group), the ED50 values for Althesin and methohexitone were 11.0 micrograms kg-1 min-1 and 44.2 micrograms kg-1 m in-1, while the corresponding ED95 values were 16.4 micrograms kg-1 min-1 and 76.2 micrograms kg-1 min-1.

Althesin (alphaxalone: alphadolone acetate) and the new water-soluble steroid intravenous anaesthetic agent minaxolone have been administered by continuous infusion to supplement nitrous oxide: oxygen anaesthesia in 20 patients. Plasma drug concentrations were estimated in blood samples taken during and following cessation of the infusion. In both group (Althesin: n = 11, minaxolone: n = 9), there was no evidence of drug accumulation within the plasma. The decay in the plasma drug concentrations after the infusion could be fitted to a bi-exponential equation, indicating that the steroids were distributed according to an open two-compartment pharmacokinetic model. The prolonged recovery following minaxolone may be related to its water-solubility, and to a larger volume of distribution of the drug. Studies gas chromatography: mass spectrometry to analyse samples of blood and urine have confirmed than Althesin and minaloxone both undergo biotransformation in the body. Hepatic conjugation to glucuronic acid is of importance in the excretion of the lipophilic agent, Althesin.

The disposition kinetics of propofol have been determined in 12 patients (six female) receiving propofol 2.5 mg kg-1 for induction of anaesthesia, which was maintained with 67% nitrous oxide in oxygen and 1-1.5% halothane. Peripheral blood samples were collected at selected times up to 8 h after the injection of the drug, and whole blood propofol concentrations determined by HPLC with fluorescence detection. Drug concentration-time data were analysed by the non-linear regression program ELSFIT. This showed the data to be describable by a tri-exponential equation, corresponding to a three-compartment model. There were no differences in the derived kinetic indices for the male and female patients, with the exception of a greater Vdss:V gamma ratio in the males. The terminal half-life in the male patients was 262 min (SEM 44), and in the female patients 309 min (60). Vdss was 329 litre (67) and 313 litre (69) in male and female patients, respectively. The clearance in both groups was 1.8 litre min-1. Seven out of 12 patients showed significant secondary peaks in blood propofol concentration associated with recovery from anaesthesia.

The disposition kinetics of the two steroid components of the anaesthetic agent Althesin have been determined in seven male patients undergoing peripheral vascular reconstructive surgery. The blood decay profiles for both alphaxalone and alphadolone can be described by an open two-compartment model, with a mean alpha phase half life of 1.9 min, and a mean beta phase half life of 34 min. The systemic clearances of alphaxalone and alphadolone were 1.52 l min-1 and 1.09 l min-1 respectively (p less than 0.01). The remaining derived kinetic parameters showed no difference for the two steroids except for a greater fraction of the alphadolone administered being present in the peripheral compartment at steady-state conditions (p less than 0.05). The relative contributions of metabolic loss to total loss of drug from the body were 0.56 and 0.85 at 10 min and 60 min respectively for alphaxalone, and 0.42 and 0.80 respectively for alphadolone (p less than 0.01 and p less than 0.05). Although alphadolone exists as the acetate in the proprietary formulation, rapid hydrolysis to the native steroid seems to occur in man. The exact site of this hydrolysis remains uncertain at present.

In a non-double-blind, prospective, randomized study, the intra-operative electrocardiograms of 128 mildly hypertensive surgical patients were examined in order to determine the incidence of myocardial ischemia during anesthesia. No patient had been receiving chronic antihypertensive therapy prior to the study, but a single small oral dose of a beta-adrenergic blocking agent (labetalol, atenolol, or oxprenolol) was given to 89 of them along with premedication. Forty-four per cent of the untreated control patients and 61% of the patients pretreated with a beta-adrenergic blocking agent had normal preoperative electrocardiograms and no risk factors for coronary artery disease other than hypertension (this difference between groups was not statistically significant). During tracheal intubation and/or emergence from anesthesia, a brief, self-limited episode of myocardial ischemia was detected in 11 of 39 untreated control patients, and in two of 89 patients pretreated with a beta-adrenergic blocking agent (P less than 0.001). Tachycardia always accompanied the ischemic events, but a conspicuous increase in blood pressure did not. The authors conclude that mild hypertension, when untreated prior to the induction of anesthesia, is associated with a high incidence of myocardial ischemia; and that a single small oral dose of a beta-adrenergic blocking agent, given with pre-medication, can significantly reduce that risk.

Eighty women (40 for elective Caesarean section and 40 for elective gynaecological surgery) were randomly assigned to one of five treatment groups and received pre-operatively either no medication; magnesium trisilicate mixture (BP) 30 ml; metoclopramide 10 mg intramuscularly; ranitidine 150 mg orally on the night prior to, and the morning of, surgery; or metoclopramide 10 mg intramuscularly in combination with oral ranitidine 150 mg (the latter again given on the night prior, and the morning, of surgery). The effect of these medications on intragastric pH, volume and serum gastrin-17 was measured. No patient receiving ranitidine had a pH of less than 4. Magnesium trisilicate mixture resulted in the largest intragastric pH change although one woman in this group had a pH of 1.7. The largest intragastric volumes were seen in the patients who had received magnesium trisilicate mixture, whilst the patients who had received metoclopramide in combination with ranitidine had the smallest intragastric volumes. Magnesium trisilicate mixture and metoclopramide resulted in no change in serum gastrin levels. However, in the subjects who had received ranitidine on the night prior to surgery, the fasting serum gastrin was significantly higher (p less than 0.01) than the values in the remaining subjects, the mean (SEM) values being 60.3 (6.3) pg/ml in those not receiving ranitidine and 111.3 (19.5) pg/ml in those who had been given ranitidine.