The Leiden anaesthesia simulator.

We describe an anaesthesia simulator capable of simulating all possible situations during anaesthesia. The Leiden anaesthesia simulator (LAS) may be used with most commercially available anaesthesia equipment and monitors, which are connected to the simulated patient as they are to a patient. A commercially available intubation manikin attached to an electromechanical lung model represents the patient. The lung allows both spontaneous and mechanical ventilation. Compliance, resistance, tidal volume and ventilatory frequency may be altered by a controlling computer. Carbon dioxide production and oxygen uptake are simulated. Physiological signals (ECG, arterial, pulmonary arterial and central venous pressure waveforms) generated by a signal generator under software control provide input to the monitors. All types of ECG disturbances may be simulated. There are facilities for simulating non-invasive arterial pressure measurement and pulse oximetry. A series of physiological models is being developed to control interactions between the cardiovascular and respiratory variables. During a simulation session, a pre-defined scenario is presented to the trainee. The task of the trainee is to diagnose and treat the problem as if in real life. The simulator experiences on the LAS were judged as highly realistic by 28 subjects. This simulator is currently being used for teaching and training of anaesthetists, trainees and anaesthesia personnel and for research.

Does training on an anaesthesia simulator lead to improvement in performance?

We have used the Leiden anaesthesia simulator, which makes use of a standard anaesthesia machine and monitors, and realistically simulates the anaesthesia work place. After obtaining informed consent, 28 anaesthetists and anaesthesia trainees in one hospital took part in the study. All participants were exposed to a pre-scripted simulated "control" scenario of anaphylactic shock (phase 1). The sessions were videotaped and the performances of individual participants were evaluated using a standardized scoring scheme. During phase 2, the participants were allocated randomly to undergo training in the management of either anaphylactic shock (group A, n = 13) or malignant hyperthermia (group B, n = 15) on the simulator. After 4 months, each participant underwent a blinded evaluation session with a pre-scripted "test" scenario of malignant hyperthermia (phase 3). These sessions were also videotaped and evaluated as for phase 1. The participants in group B responded more quickly, treated better and deviated less from the accepted procedure during phase 3 than those in group A. The total performance of participants in group B during phase 3 was significantly better than those in group A. We conclude that training on an anaesthesia simulator does improve the performance of anaesthetists in dealing with emergencies during anaesthesia.

Pharmacokinetics of alfentanil administered at a variable rate during three types of surgery.

To determine if the pharmacokinetics of alfentanil varied with the type of surgery (site of operation and intensity of surgical stimulation) or with the mode of administration, three groups of patients were given a variable-rate infusion of alfentanil (supplemented with bolus injections) as an adjunct to nitrous oxide-oxygen anaesthesia for breast surgery, lower abdominal surgery, or upper abdominal surgery. A two-compartment pharmacokinetic model adequately characterized the plasma concentration profiles of alfentanil for 31 of 34 patients. Mean distribution half-life (6 min), elimination half-life (87 min), initial volume of distribution (10 litres), steady state volume of distribution (31 litres), total body clearance (308 ml min-1), and distribution clearance (656 ml min-1) did not vary with the type of surgery. The pharmacokinetics could not be determined for three patients undergoing upper abdominal surgery, probably because of nonstationarity. Comparison of our data with those obtained after a single bolus injection or a constant-rate infusion indicates that the pharmacokinetics of alfentanil do not vary with the mode of administration.

The effect of age on the systemic absorption, disposition and pharmacodynamics of bupivacaine after epidural administration.

The influence of age on the systemic absorption and disposition of bupivacaine following epidural administration in 20 male patients (22 to 81 years) was examined using a stable isotope method to determine whether pharmacokinetics play a role in age-related pharmacodynamic changes seen with the drug. After epidural bupivacaine administration a deuterium-labelled analogue was administered intravenously. Bi- and triexponential functions were fitted to plasma concentration-time data of deuterium-labelled bupivacaine. The systemic absorption was described by 2 parallel first-order absorption processes. The upper level of analgesia and the duration of analgesia at dermatome T-12 increased with age (r = 0.68, p less than 0.001; r = 0.56, p less than 0.01, respectively). The time to maximal caudad spread of analgesia and the time to onset of motor block decreased with age (r = -0.76, p less than 0.0001; r = -0.72, p less than 0.001, respectively). Age did not influence systemic absorption or disposition of bupivacaine. We conclude that the changes in the clinical profile of bupivacaine with age are not due to altered pharmacokinetics, but may be related to changes in the pharmacodynamics of the drug.

Reported significant observations during anaesthesia: a prospective analysis over an 18-month period.

We describe a prospective analysis, in one hospital, of reported significant observations involving unsafe practices and working conditions during anaesthesia. Of the 549 significant observations reported voluntarily during a period of 18 months, 82% involved occurrences which were considered preventable and 27% could have been fatal if they had not been recognized and corrected. Ninety-three percent of incidents did not lead to a negative outcome. Human error was responsible for 411 (75%) reports. Lack of vigilance and failure to check were the most frequently reported factors associated with human error. Significant observations involving errors in drugs administration were the most frequent. Forty-five percent of all reported significant observations were made during maintenance of anaesthesia.

Age does not influence the serum protein binding of bupivacaine.

The serum protein binding of bupivacaine was studied in 74 subjects, 39 males and 35 females, aged 20-90 years, without evidence of acute or chronic inflammatory disease or malignancy. Subjects were drug free for at least 1 month. The free fractions of bupivacaine did not change with age in either males or females. This is in keeping with the lack of effect of age on AAG concentrations. Free fractions of bupivacaine were slightly higher in females as compared with males. The previously observed decline in clearance of bupivacaine with age probably reflects a concomitant decline in the metabolic activity of hepatic enzymes.

Pharmacokinetics and EEG effects of flumazenil in volunteers.

The effect of intravenous flumazenil 10 mg on the electroencephalogram (EEG) was investigated in 7 volunteers in a placebo-controlled, randomised, double-blind, crossover study. The EEG was recorded between Fp1-M1 and Fp2-M2 and analysed using an aperiodic analysis technique. Two volunteers were excluded from the study because of significant asymmetry between baseline EEG recordings of the left and right hemisphere, in the remainder there were no changes in the beta-frequency range (12 to 30 Hz) or in other ranges of the EEG during or after flumazenil or placebo administration, with regard to the parameters total number of waves per second or total amplitude per second. There were no changes in heart rate, respiratory rate or blood pressure after administration of flumazenil or placebo. Three volunteers reported feelings of 'pressure to move' during the initial 2 min of the flumazenil infusion. The pharmacokinetics of flumazenil were investigated in the same volunteers. Flumazenil 10 mg was administered intravenously over 10 min; the data from 1 volunteer were excluded from this analysis because of blood sampling problems. The plasma concentration-time data of the remaining 6 volunteers were characterised by a biexponential function. The pharmacokinetic parameters were (mean +/- SD): initial volume of distribution, 16 +/- 5.7L; volume of distribution at steady-state, 64.8 +/- 12.5L; total body clearance, 53.8 +/- 1.2 L/h; distribution half-life, 4.1 +/- 1.3 min; and elimination half-life, 70.2 +/- 9.9 min. The authors conclude that flumazenil has no significant EEG effects. The rapid distribution and elimination of flumazenil may explain its previously reported short duration of action after intravenous anaesthesia with high doses of midazolam.

Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers by aperiodic EEG analysis.

The CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and Fp2-M2. The EEG parameter total number of waves between 12 and 30 Hz (TNW12-30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that 'steady-state' concentrations of 10 and 20 micrograms/L were obtained. Doses of midazolam 15, 30 and 60 mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 micrograms/L (session B) or 20 micrograms/L (session C), respectively. Venous blood samples were taken until 8 h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW12-30. Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (+/- SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW12-30 (EC50) were 276 +/- 64, 624 +/- 187 and 1086 +/- 379 micrograms/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t1/2ke0), estimated by a nonparametric method, were 2.2 +/- 1.2, 3.3 +/- 3.3 and 2.9 +/- 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 +/- 1.0 micrograms/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.

The effect of age on systemic absorption and systemic disposition of bupivacaine after subarachnoid administration.

In order to evaluate the role of the pharmacokinetics of the age-related changes in the clinical profile of spinal anesthesia with bupivacaine, we studied the influence of age on the systemic absorption and systemic disposition of bupivacaine after subarachnoid administration in 20 male patients (22-81 yr), ASA Physical Status 1 or 2, by a stable isotope method. After subarachnoid administration of 3 ml 0.5% bupivacaine in 8% glucose, a deuterium-labeled analog (13.4 mg) was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of unlabeled and deuterium-labeled bupivacaine were determined with a combination of gas chromatography and mass fragmentography. Biexponential functions were fitted to the plasma concentration-time data of the deuterium-labeled bupivacaine. The systemic absorption was evaluated by means of deconvolution. Mono- and biexponential functions were fitted to the data of fraction absorbed versus time. The maximal height of analgesia and the duration of analgesia at T12 increased with age (r = 0.715, P less than 0.001; r = 0.640, P less than 0.01, respectively). In 18 patients the systemic absorption of bupivacaine was best described by a biexponential equation. The half-life of the slow systemic absorption process (r = -0.478; P less than 0.05) and the mean absorption time (r = -0.551; P less than 0.02) decreased with age. The total plasma clearance decreased with age (r = -0.650, P less than 0.002), whereas the mean residence time and terminal half-life increased with age (r = 0.597, P less than 0.01; r = 0.503, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of midazolam and propofol in combination with alfentanil for total intravenous anesthesia.

Hemodynamic function during induction of anesthesia, the alfentanil and naloxone requirements, and the speed of recovery from total intravenous anesthesia with alfentanil/midazolam (group M, n = 10) or alfentanil/propofol (group P, n = 10) were compared in patients undergoing lower limb surgery. Twenty patients were randomly assigned to receive either 2 mg/kg propofol in 5 min followed by 9 mg.kg-1.h-1 for 30 min and 4.5 mg.kg-1.h-1 until skin closure, or 0.42 mg/kg midazolam in 5 min followed by 0.125 mg.kg-1.h-1 until skin closure. Simultaneously, a variable-rate infusion of alfentanil was given. Patients were ventilated with 30% oxygen in air. In both groups blood pressure and heart rate decreased significantly (P less than 0.02) and to a similar extent during induction. The total dose of alfentanil was similar in both groups. No patient in group P and nine patients in group M needed naloxone (average dose 130 +/- 70 micrograms, P less than 0.001). Recovery, as judged by psychomotor tests (90% score was reached at 1 h in the P group and at about 4 h in the M group, P less than 0.001), sedative scores, and orientation in time and place, was shorter in group P than in group M. The conclusion is reached that propofol is superior to midazolam in total intravenous anesthesia with alfentanil.

Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling.

The effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis. The EEG was recorded between Fp1-M1 and Fp2-M2. Following a 15-minute baseline EEG registration, midazolam 15 mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the beta frequency range (12 to 30 Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes. The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30 Hz (TNW12-30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (Emax) model was used to characterise the effect compartment midazolam concentration-TNW12-30 data. The plasma drug concentration corresponding to half the maximum increase in TNW12-30 (EC50) was 290 +/- 98 micrograms/L.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of age on serum concentrations of albumin and alpha 1-acid glycoprotein.

1. Human serum albumin (HSA) concentrations and alpha 1-acid glycoprotein (AAG) concentrations were measured in 68 subjects, 35 males and 33 females, aged 20-90 years without evidence of acute or chronic inflammatory disease or malignancy. Subjects were drug free for at least 1 month. HSA and AAG concentrations were measured using rate nephelometry. 2. Age had no effect on alpha 1-acid glycoprotein concentration, whereas plasma albumin levels decreased as a function of age in both sexes. We observed no differences between males and females in the plasma concentrations of HSA and AAG. 3. These data show that in healthy subjects the HSA concentration decreases with increasing age, whereas age, uncomplicated by disease does not influence AAG concentration.

Accidents, near accidents and complications during anaesthesia. A retrospective analysis of a 10-year period in a teaching hospital.

A retrospective analysis is presented of all reports of faults, accidents, near accidents and complications associated with anaesthesia in one hospital from 1978 to 1987. 113,074 anaesthetics were administered in that period, of which 97,496 were for noncardiac procedures. There were 148 reports; 39 were of dental damage. Peri-operative cardiac arrests during noncardiac surgery were reported 29 times. Sixteen of these were fatal. Anaesthesia was thought to have played an important role in 13 cardiac arrests (1 per 7500 anaesthetics) and six were not successfully resuscitated (1 per 16,250 anaesthetics). There were 12 reports of postoperative peripheral neuropathies (1 per 9422 anaesthetics). Failure to check, lack of vigilance and inattention or carelessness were the most frequently associated factors with the rest of the reports.

Pulmonary shunting after cardiopulmonary bypass.

The effect of cardiopulmonary bypass (CPB) on pulmonary function was investigated in 32 adult patients, including 23 patients undergoing coronary artery bypass grafting and nine patients undergoing heart-valve replacement. Clinical indicators for pulmonary insufficiency, such as chest X-ray, gas exchange and lung function tests were measured. Transthoracic electrical impedances were measured, and the mean specific thoracic impedance (RHO) was calculated. (RHO is an accurate indicator for the intrathoracic fluid content; low RHO values correspond with high intrathoracic fluid content.) Significant postoperative decreases in RHO were paralleled by a significant impairment of gas exchange. Chest X-rays demonstrated accumulation of intrathoracic fluid. Lung function tests showed significant postoperative decreases in lung volumes and vital capacity. These findings are consistent with the concept that CPB provokes an inflammatory reaction in the lung. The non-invasive RHO measurement proved to be simple and in good agreement with clinical indicators. This method may be a real asset in the prevention and treatment of pulmonary dysfunction after CPB. The possibility of calibrating RHO with respect to absolute values of intrathoracic fluid content should be investigated.

Threshold serum concentrations of bupivacaine associated with early CNS toxicity and pharmacokinetics of bupivacaine in young versus old rhesus monkeys.

Effects of aging on the onset of early signs of central nervous system (CNS) toxicity, associated total and free arterial threshold serum concentration, and the disposition of bupivacaine were studied in eight younger (11-15 years) and eight older (16-28 years) rhesus monkeys. Bupivacaine was infused at a rate of 0.15 mg/kg minute until unceasing movements of the eye, oscillating from side to side and up and down (nonpositional nystagmus). This was regarded as an objective sign of early CNS toxicity. Most animals showed drowsiness and sedation by the end of the infusion. CNS toxicity occurred significantly faster (p less than 0.025) in the younger (13.7 +/- 2.5 minutes) than in the older (17.1 +/- 2.6 minutes) animal group. A significant correlation was found between the onset time of CNS toxicity and age. The coefficient of determination (R2) for this correlation was 0.48. Also, the dose associated with the onset of CNS toxicity was significantly smaller in the younger (2.06 +/- 0.38 mg/kg) than in the older (2.60 +/- 0.39 mg/kg) animals. However, the total and free arterial threshold serum concentration of bupivacaine was similar in both groups. Age did not influence the disposition of bupivacaine.

Antagonism of midazolam sedation by flumazenil: a placebo-controlled study in patients recovering from intravenous anaesthesia with high doses of midazolam.

Twenty adult surgical patients were anaesthetized with high-dose midazolam and alfentanil by infusion, vecuronium, and intubated and ventilated with 50% N2O in O2. The midazolam and alfentanil infusions were stopped at the end of surgery. Residual neuromuscular blockade and ventilatory depression were antagonized and the patients extubated. In the recovery room, patients were randomly allocated to receive either flumazenil 1 mg of placebo i.v. Before, and until 2 h after injection, patients were asked to perform psychomotor tests. In addition, sedation, comprehension and orientation were scored. The flumazenil (n = 10) and the placebo (n = 10) groups were comparable. Prior to injection all patients were heavily sedated. After flumazenil all were awake within 2-3 min, but fell asleep again 15-60 min later. The improvement in test scores was sustained for a longer time. After placebo, patients awoke in 1-2 h. At 60 and 120 min, test scores in the two groups were similar. Heart rate, blood pressure and respiration rate did not change. No side-effects were observed or reported. It is concluded that flumazenil is an effective and safe antagonist of high dose midazolam, with a rapid onset but a short duration of action.

Pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration in surgical patients: simultaneous investigation of absorption and disposition kinetics using stable isotopes.

The pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration were studied in 12 surgical patients using a stable isotope method. After subarachnoid administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of the unlabelled and the deuterium-labelled local anesthetics were determined using a combination of capillary gas chromatography and mass fragmentography. Bi-exponential functions were fitted to the plasma concentration-time data of the deuterium-labelled local anesthetics. The progression of the absorption was evaluated using deconvolution. Mono- and bi-exponential functions were then fitted to the fraction absorbed versus time data. The distribution and elimination half-lives of the deuterium-labelled analogues were 25 +/- 13 min (mean +/- SD) and 121 +/- 31 min for lidocaine and 19 +/- 10 min and 131 +/- 33 min for bupivacaine. The volumes of the central compartment and steady-state volumes of distribution were: lidocaine 57 +/- 10 l and 105 +/- 25 l, bupivacaine 25 +/- 6 l and 63 +/- 22 l. Total plasma clearance values averaged 0.97 +/- 0.21 l/min for lidocaine and 0.56 +/- 0.14 l/min for bupivacaine. The absorption of lidocaine could be described by a single first order absorption process, characterized by a half-life of 71 +/- 17 min in five out of six patients. The absorption of bupivacaine could be described adequately assuming two parallel first order absorption processes in all six patients. The half-lives, characterizing the fast and slow absorption processes of bupivacaine, were 50 +/- 27 min and 408 +/- 275 min, respectively. The fractions of the dose, absorbed in the fast and slow processes, were 0.35 +/- 0.17 and 0.61 +/- 0.16, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)