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Biomedical subjects

J W Sear

Publications and source records attributed to J W Sear.

At least 19 recordsLinked to original sources
PubMed1992

Effects of different hepatic pathologies on disposition of alfentanil in anaesthetized patients.

We have studied the influence of different hepatic pathologies on the disposition of alfentanil in 23 unpremedicated patients (six healthy control subjects, six patients with liver dysfunction of alcoholic aetiology and 11 patients with non-alcohol related liver disease). All patients received a bolus of alfentanil 500 micrograms i.v. as supplement to 67% nitrous oxide and isoflurane in oxygen anaesthesia. Plasma drug concentrations were measured in venous blood samples at intervals up to 24 h by radio-immunoassay and protein binding was determined by equilibrium dialysis. Kinetic estimates were determined using non-compartmental analysis. Patients with non-alcoholic liver disease had lesser plasma clearance (114.8 (range 66.8-213.5) ml min-1) than the alcoholic group (158.8 (100.0-220.7) ml min-1) or controls (187.4 (125.2-269.5) ml min-1). In all three groups, there was considerable intersubject variability, with a bimodal distribution in the non-alcoholic group. This group also had a smaller apparent volume of distribution at steady state. Mean residence time was prolonged in the alcoholic group compared with controls (284.9 (217.8-362.2) min vs 226.8 (201.2-250) min). Protein binding was decreased in the alcoholic group compared with controls (84.9 (SD 4.2)% vs 89.3 (2.1)%); this was attributable to a lesser plasma alpha 1-acid glycoprotein concentration (0.55 (0.18) g litre-1 vs 0.89 (0.21) g litre-1). Free drug clearance was reduced in both liver dysfunction groups compared with controls.

Adult↗
PubMed1992

Effect of graded infusion rates of propofol on regional and global left ventricular function in the dog.

We have studied the effects of graded infusion rates of propofol (0.2-0.5 mg kg-1 min-1) on left ventricular global and regional function, in eight acutely instrumented dogs. Global function was assessed by measurement of aortic and left ventricular pressure, LV dP/dtmax, aortic blood acceleration and stroke volume. Regional function was assessed by measurement of systolic shortening and the end-systolic pressure-length relationship. The response of the coronary circulation to short periods of occlusion was also assessed. Administration of propofol significantly reduced left ventricular preload, as indicated by reductions in end-diastolic pressure and length; contractility was depressed, the depression being greater in the apex than in the base of the left ventricle. High infusion rates impaired relaxation. Regulation of coronary blood flow was not disrupted. Reductions in preload and contractility contributed to the propofol-induced hypotension. After 60 min, recovery from the greatest infusion rate was incomplete.

Animals↗
PubMed1992

Pregnanolone: a new steroid intravenous anaesthetic. Dose-finding study.

The intravenous steroid anaesthetic pregnanolone has been investigated as an induction agent in 60 fit adults premedicated with morphine and atropine. The drug was given in a stepwise fashion starting with 0.5 mg.kg-1; following a successful induction, the next patient received 15% less, while the subsequent patient received 15% more if anaesthesia was not achieved. Taking loss of eyelash reflex as the end point, 31 patients were satisfactorily induced; the AD50 in these patients was 0.44 mg.kg-1 (95% CI 0.41-0.47). A further 23 patients were induced satisfactorily as assessed by cessation of counting. Induction was trouble free with minimal changes in heart rate and arterial blood pressure, a low incidence of apnoea and few involuntary movements; pain on injection was not a feature. Loss of eyelash reflex is not a good end point for assessment of loss of consciousness following pregnanolone.

Adult↗
PubMed1992

Thoracic electrical bioimpedance measurement of cardiac output and cardiovascular responses to the induction of anaesthesia and to laryngoscopy and intubation.

Noninvasive methods of determining cardiac output (by thoracic electrical bioimpedance) and arterial pressure (by intermittent oscillometry) were used to record minute-by-minute changes in heart rate, mean arterial pressure, stroke volume, cardiac output and systemic vascular resistance following induction of general anaesthesia and laryngoscopy and intubation in 60 healthy female patients who were either unpremedicated, or premedicated with temazepam or papaveretum-hyoscine. Anaesthesia was induced with a sleep dose (3-5 mg.kg-1) of thiopentone and maintained with 70% nitrous oxide in oxygen with 0.5-1% enflurane. Tracheal intubation was facilitated by administration of vecuronium 0.1 mg.kg-1. Mean arterial pressure and cardiac output decreased maximally 5 min after induction in all premedication groups by mean estimates of 21-25% and 14-22% respectively. Heart rate increased initially one minute after induction, but decreased to less than the baseline value 5 min after induction. Systemic vascular resistance was unchanged. The stimulus of laryngoscopy and tracheal intubation was accompanied by a significant pressor response and tachycardia one minute after intubation (with mean increases in mean arterial pressure and heart rate of 29-34% and 22-33% respectively). The increase in mean arterial pressure was secondary to an increase in systemic vascular resistance (36-57%), and was accompanied by a decrease in stroke volume (-25 to -31%). These changes were significant in all three groups. Cardiac output decreased only in unpremedicated patients. There were wide variations in the different haemodynamic indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Practical treatment recommendations for the safe use of anaesthetics.

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 cardiorespiratory 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1992

Propofol to provide sedation after coronary artery bypass surgery. A comparison of two fixed rate infusion regimens.

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.

Adult↗
PubMed1991

Preoperative silent myocardial ischaemia: incidence and predictors in a general surgical population.

We have studied before operation 156 patients aged more than 40 yr presenting for elective vascular or non-vascular surgery, using ambulatory ECG monitoring to detect silent myocardial ischaemia (SMI). The prevalence of SMI was 18.2% in the vascular group (n = 102) and 7.6% in the non-vascular group (n = 54). A history of ischaemic heart disease, or an abnormal ECG suggestive of a previous myocardial infarction, predicted a high risk of SMI (28% compared with 9% in the absence of these variables). However, a significant amount of SMI (36% of the total) occurred in patients without one of the defined risk factors. In addition, 24 of the patients with abdominal aortic disease underwent cardiac gated blood pool (MUGA) scans. Abnormal ventricular wall function was observed in 62.5% of the patients. Twenty-nine percent of the patients studied with MUGA scans had SMI and 21% had ejection fractions less than 40%. A significant association (P less than 0.05) existed between the presence of SMI and a ventricular ejection fraction of less than 40%.

Adult↗
PubMed1991

First pass lung uptake of bupivacaine: effect of acidosis in an intact rabbit lung model.

The first pass uptake, metabolism and recovery of bupivacaine were examined in an intact rabbit lung model using a multiple indicator technique with rapid sequential sampling. The rabbits were allocated to an acidotic group (pH 7.0-7.1) (n = 8) and a control group (n = 10) with normal pH. Bupivacaine recovery rates were not significantly different: median 93.2% (range 48.9-116.5%) and 94.5% (54.9-123.1%) in control and acidotic groups, respectively. Median peak percentage fractional concentrations of bupivacaine were greater in the acidotic group: 6.22% (2.5-7.65%) vs 4.1% (2.5-6.7%) (P less than 0.05). Median maximum instantaneous pulmonary percentage extraction was less in the acidotic animals than in animals with normal pH: 81.2% (47.1-91.9%) vs 91.0% (82.6-94.5%) (P less than 0.01). Median normalized mean percentage transit time was less in the acidotic group (245.3% (163.4-465.3%)) than in the control group (423.9% (313.9-740.4%)) (P less than 0.01). There was no evidence for bupivacaine metabolism by the lung. The results suggest that acidosis reduced bupivacaine lung uptake and increased its rate of passage through the lung, but did not influence overall drug recovery rates. This has clinical implications for bupivacaine related cardiac and cerebral toxicity.

Acidosis↗
PubMed1991

Non-invasive measurement of cardiac output by thoracic electrical bioimpedance: a study of reproducibility and comparison with thermodilution.

The performance and reproducibility of the BoMED NCCOM3 thoracic electrical bioimpedance cardiograph (TEB) has been evaluated in volunteers and patients. In resting supine volunteers, we determined the coefficient of variability over short time periods (30 min) and over several days, and examined the effects of differences in electrode type and electrode placement. The mean (range) intra-subject coefficients of variation (CV) for thoracic fluid index (TFI) and stroke volume (SV) were 1.0% (0.4-1.8%) and 4.7% (2.1-8.5%), respectively over a 30-min period. The corresponding CV were 5.6% (2.3-10.9%) and 10.9% (6.1-14.8%) for measurements made at rest on four separate occasions. Use of different electrode types (RedDot and Medicotest) resulted in differences in TFI (P less than 0.01), but not in mean values for SV or cardiac output (Q); their use in individual subjects revealed differences of up to 20% in SV and Q. Alterations in electrode placement by 5 cm in the horizontal and diagonal planes produced no significant changes in TFI, SV or Q; changes in the longitudinal plane produced a graded change. Increases of 5 cm and 10 cm in thoracic length produced mean increases in TFI of 9.8% and 39.8%, respectively, and mean decreases in Q of 8.4% and 16.7% and SV of 7.5% and 15.8%. TEB measurements of Q and SV were compared with thermodilution (TD) in 16 intensive care patients. Mean (SEM) Q by TEB was 5.63 (1.10) litre min-1 compared with TD 4.38 (0.72) litre min-1 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites.

The disposition of buprenorphine has been studied in two patient groups to assess the influence of impaired renal function on the metabolism of buprenorphine and two of its metabolites, buprenorphine-3-glucuronide (B3G) and norbuprenorphine (NorB). A single i.v. dose of 0.3 mg was given to 15 patients (nine with dialysis-dependent renal failure) undergoing lower abdominal or peripheral body surface surgery. Blood was sampled up to 24 h. Concentrations of buprenorphine, B3G and NorB were assayed by a differential radioimmunoassay technique. There were no differences in buprenorphine kinetics between anaesthetized healthy patients and those with renal impairment: mean elimination half-lives 398 and 239 min; clearance 651 and 988 ml min-1; apparent volume of distribution at steady state 313 and 201 litre, respectively. Both metabolites were undetectable following the single i.v. dose. In a second group of 20 patients (eight with renal impairment), buprenorphine was administered by continuous infusion for provision of analgesia and control of ventilation in the ITU (median infusion rate 161 micrograms h-1 (range 36-230 micrograms h-1) for a median duration of 30 h (2-565 h). Buprenorphine clearance in patients with normal and impaired renal function was similar (934 and 1102 ml min-1, respectively), as were dose-corrected plasma concentrations of buprenorphine. In patients with renal failure, plasma concentrations of NorB were increased by a median of four times, and B3G concentrations by a median of 15 times.

Adolescent↗
PubMed1990

Rapid restoration of normoglycaemia using intravenous insulin boluses.

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.

Adult↗
PubMed1989

Studies on morphine disposition: plasma concentrations of morphine and its metabolites in anesthetized middle-aged and elderly surgical patients.

The effects of aging on the disposition of morphine and its metabolites have been investigated in 10 middle-aged patients (36 to 55 years of age) undergoing lower abdominal or body surface surgery, and compared with 10 elderly patients (65 to 83 years of age) undergoing similar surgery. All patients received 10 mg morphine sulphate pentahydrate IV over 30 seconds as part of a balanced anesthetic technique. Peripheral venous blood samples were collected to 180 min, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were assayed by differential radioimmunoassay. There were no differences between the two groups for morphine elimination half-life (middle-aged patients, 129 min; elderly patients, 162 min), mean residence time (154 and 207 min), and apparent volume of distribution at steady state (116 and 107 l). However, clearance was significantly greater in the younger patients (853 vs. 559 ml/min; p less than 0.02). The area under the curve (AUC0-180) for M3G and M6G were similar in the two patient groups, as were the peak metabolite concentrations and times to peak concentrations. M6G has been shown in both animals and humans to exert analgesic properties. Despite the reduced clearance of the parent drug, there was an unaltered AUC for M6G, presumed due to the greater decrease in glomerular filtration rate seen during anesthesia in the elderly patient. This phenomenon may result in enhanced analgesic efficacy from a given dose of morphine in the elderly patient.

Adult↗
PubMed1989

Studies on morphine disposition: influence of general anaesthesia on plasma concentrations of morphine and its metabolites.

The kinetics of morphine were studied during balanced anaesthesia in 10 patients undergoing lower abdominal or body surface surgery, and compared with those obtained in nine awake patients receiving morphine i.v. for the relief of chronic non-cancer pain. All patients received morphine sulfphate pentahydrate 10 mg i.v. over 30 s. Venous blood samples were collected for up to 180 min, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) assayed by a differential radioimmunoassay technique. There were no differences between groups with respect to the elimination half-life (awake group: 207 min; anaesthetized group: 153 min), volume of distribution at steady state (awake: 147 litre; anaesthetized: 128 litre), or clearance (awake: 587 ml min-1; anaesthetized: 766 ml min-1). Peak concentrations of M3G were similar in the two groups, but the peak concentration of M6G was greater in the anaesthetized patients. The AUC for M3G and M6G (0-180 min) also were greater in the anaesthetized patients, presumably as a result of decreases in renal blood flow and glomerular filtration rate during halothane anaesthesia.

Adult↗
PubMed1989

Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites.

The influence of renal failure on the disposition of morphine and its metabolites was studied in nine patients with end-stage renal failure undergoing transplantation, and compared with five healthy anaesthetized patients. All patients received morphine sulphate pentahydrate 10 mg i.v. over 30 s, as part of a balanced anaesthetic technique. Venous blood samples were collected for up to 24 h, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) assayed by a differential radioimmunoassay method. There were no differences between the two groups for morphine elimination half-life (renal failure: 290 min; anaesthetized controls: 286 min), or clearance (renal failure: 533 ml min-1; controls 741 ml min-1). However, the volume of distribution at steady state was greater in the control group (241 litre v. 141 litre; P = 0.002). The peak concentrations of M3G and M6G were greater in the renal transplant patients (P = 0.001 and P = 0.01, respectively), as were the AUC (0-24 h) (P = 0.002 and P = 0.002). M6G has been shown to possess analgesic properties in both man and experimental animals, and therefore the increased AUC for M6G may contribute to the prolonged effect seen with morphine when given to patients with impaired renal function.

Adult↗
PubMed1989

Sufentanil disposition in patients undergoing renal transplantation: influence of choice of kinetic model.

We studied the disposition of sufentanil in 10 patients undergoing renal transplantation, and compared the data with those from eight healthy anaesthetized patients undergoing lower abdominal surgery. Patients received sufentanil 2.5 micrograms kg-1 as part of a balanced anaesthetic technique. Central venous blood samples were collected at intervals up to 600 min, and plasma sufentanil concentrations assayed by radioimmunoassay. Pharmacokinetic parameters were calculated from drug concentration-time profiles by extended least squares non-linear regression analysis (ELSFIT) and by a model independent (MI) approach using AUC and its first moment, AUMC. There were no differences (based on MI results) between the two groups for elimination half-life (T1/2 beta) (renal failure: 188 min; anaesthetized controls: 195 min), clearance (CI) (1030 and 1093 ml min-1) and apparent volume of distribution at steady state (Vss) (223.0 and 215.3 litre). Sufentanil binding to plasma proteins was 91.4% in the renal patients and 92.2% in the healthy group (ns). Comparison of kinetic methods showed significant correlation of the individual estimates for T1/2 beta, CI and Vss (P less than 0.01). The mean absolute differences between methods were: T1/2 beta 2.7 min (95% limits: -26.2 to 31.5), CI 36.5 ml min-1 (-5.5 to 78.4), Vss -18.4 litre (-47.7 to 10.9). When the mean estimate for the two methods [ELSFIT + MI)/2) was compared with the difference, there was no correlation for the estimates of CI and Vss+. MI tended to overestimate clearance and underestimate volume of distribution. There was a significant relationship between estimates for elimination half-life, with a slope greater than zero.

Abdomen↗
PubMed1989

Disposition of alfentanil in patients receiving a renal transplant.

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 micrograms 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.

Adult↗