Biomedical subjects
Publications and source records attributed to J L Plummer.
The reductive metabolism of halothane was studied in 34 adult patients undergoing routine surgery. Reductive biotransformation of halothane was more extensive in females than males and was also enhanced in two patients treated preoperatively with phenytoin, an enzyme-inducing drug. Tobacco, ethanol and the patient's age, body weight and previous exposure to halothane did not influence reductive metabolism of halothane.
The influence of a high-fat meal on blood morphine concentrations after the administration of a morphine solution (50 mg dose) was studied in 12 patients with chronic pain. The oral morphine dose was administered in a total volume of 200 ml to patients either immediately after food intake or while in the fasting state. There was a 34% increase in the area under the curve (AUC) when morphine was administered immediately after food when compared with the fasting state (p less than 0.02). However, there was no significant difference between the maximum blood morphine concentration (Cmax) or the time to maximum concentration (tmax) between the two treatment regimens. The shape of the blood morphine concentration-time curve was consistently altered in the fed patients compared with patients who were in the fasting state, inasmuch as the blood morphine concentrations were maintained at a higher level from 240 to 600 minutes after the dose when the morphine was administered with food (p less than 0.02). It is suggested that morphine concentrations are maintained at higher levels, possibly resulting in more prolonged pain relief, when morphine is administered with food compared with the same dose administered to patients who are in the fasting state.
The efficacy of a range of demand doses of morphine for patient-controlled analgesia was studied. Patients who self-administered the smallest dose (0.5 mg) were frequently unable to achieve good pain control; patients who received the largest dose (2 mg) had a high incidence of ventilatory depression. A dose of 1 mg was the best increment under the conditions of this study but the relationship between increment and lockout interval requires consideration.
The effectiveness of morphine after surgery by patient-controlled analgesia alone or with a concurrent infusion was studied. The infusion did not reduce the dose of self-administered analgesic and patients treated in this way received twice as much drug as those who used patient-controlled analgesia alone. Pain control was similar in both groups. The practice of patient-controlled analgesia plus infusion requires critical review.
Helothane hepatitis is a rare but sometimes fatal complication of halothane anaesthesia. Examination of case reports has pointed to a number of risk factors. Studies in animals and humans in the laboratory have provided evidence of a complex multifactorial basis for halothane hepatotoxicity, with the following factors playing a part: genetic predisposition; metabolism of halothane; repeated halothane anaesthetics; female sex; age of patient; intrahepatic hypoxia; and enzyme induction. Immunologic changes can be detected in a high percentage of cases of halothane hepatitis; however, studies establishing a cause-effect relationship are not available to determine if these changes cause, or result from, hepatic damage.
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Rats were exposed to halothane vapour, 50 p.p.m., or air for a period of four weeks. Within each exposure group, some animals drank plain water, some received water plus phenobarbitone, while some received water plus isoniazid. Halothane exposure resulted in increased serum bromide concentrations and liver injury evidenced by increased serum alanine aminotransferase activity, focal hepatocellular necrosis and fatty change. Administration of isoniazid reduced halothane metabolism by 33% as assessed by serum bromide concentrations, and completely blocked the injurious effects of halothane on the liver, suggesting that halothane metabolism plays a role in halothane hepatotoxicity under these conditions. Administration of phenobarbitone partially prevented the increase in serum alanine aminotransferase activity and hepatocellular necrosis due to halothane. In contrast to isoniazid, phenobarbitone led to a slight increase in halothane metabolism. However, phenobarbitone also caused an increase in liver size, such that the amount of halothane metabolised per gram of liver was reduced by phenobarbitone treatment. These results suggest that metabolism of halothane is an important factor in liver injury due to prolonged, subanaesthetic halothane exposure.
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The inter- and intrasubject variability in blood concentration-analgesic response relationship for fentanyl were investigated using the technique of patient-controlled analgesia (PCA) in 30 consenting patients scheduled for surgical procedures involving an abdominal incision (15 upper and 15 lower abdominal incisions). All patients had a thiopental, nitrous oxide/oxygen, pancuronium anesthetic with 200 microgram fentanyl intraoperatively. Postoperative pain relief was provided with fentanyl from a Janssen On-Demand Analgesic Computer (ODAC) set to provide a basal infusion rate of 20 microgram/hr, a bolus "demand" dose of 20 microgram, and a lockout period of 5 minutes. Frequent blood samples were collected immediately before patients demanded doses, and these were taken as an estimate of the minimum effective concentration (MEC). A mean of 22 samples (range 12 to 45) were collected per patient over a mean study duration of 50 hours (range 24 to 72). The patients required larger hourly fentanyl doses in the first 6-hour period (83.9 +/- 30.1 microgram/hr) than in any other 6-hour period (mean values varied from 37.3 to 63 microgram/hr). The mean (+/- SD) hourly fentanyl dose rate and total cumulative dose were 55.8 +/- 22 microgram/hr (range 28.8 to 136 microgram/hr) and 2739 +/- 1191 microgram (range 900 to 6260 microgram), respectively. The mean (+/- SD) MEC was 0.63 +/- 0.25 ng/ml (five-fold range from 0.23 to 1.18) and the mean intrapatient coefficient of variation in MEC was 30.2% (range 16 to 46%). The MEC values remained relatively constant in all patients over the 48-hour study period.(ABSTRACT TRUNCATED AT 250 WORDS)
The hepatic effects of repeated anesthesia of phenobarbital-induced Fischer 344 rats with 1% halothane/14% oxygen were investigated, after anesthetics were administered at either 1-day or 5-day intervals. Urinary excretion of fluoride, a product of reductive halothane metabolism, was increased in the 24-h period following anesthesia, but was the same after the first, second, and third anesthetics. Rats killed 24 h after a single anesthetic all had centrilobular hepatocellular necrosis. All animals killed 24 h after the second or third anesthetic also had centrilobular necrosis, but, in most animals, this was no more extensive than that following a single anesthetic, regardless of whether the interval between anesthetics was one or five days.
Metabolism of halothane was studied in nine children receiving daily halothane anaesthetics (from 10 up to a maximum of 31) over periods of two to seven weeks. Serum bromide concentrations never exceeded 3.5 mmol/l, a concentration below the toxic threshold. Repeated halothane anaesthetics at short intervals did not induce the reductive metabolism of halothane as assessed by 2-chloro-1,1,1-trifluoroethane (CTF) in the expired breath. One patient developed viral hepatitis A during the course of anaesthetic administration; this patient was the only one whose serum bromide concentrations fell substantially and whose exhaled CTF concentration increased as more anaesthetics were administered.
A survey was conducted to investigate the attitudes of anaesthetists and nurses to anaesthetic pollution. In order that the results could be viewed in context, attitudes to other possible occupational hazards, including radiation exposure and work-related stress, were also investigated. Four hundred (66%) completed questionnaires were returned. All the anaesthetists (n = 81) thought that their work involved some exposure to anaesthetic gases or vapours; however, 21 (7%) of the 319 nurses believed they were not exposed although they spent some time in operating theatres or recovery rooms. Fourteen per cent of anaesthetists and 24% of nurses were 'quite concerned' or 'very concerned' about possible effects of anaesthetic pollution on their health. Levels of concern were similar for radiation exposure; however, both occupational groups expressed higher levels of concern about work-related stress. Seventeen (21%) anaesthetists and 46 (14%) nurses reported having suffered adverse health effects which they thought were due to anaesthetic pollution. The most frequent complaints were headache and fatigue.
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To test the hypothesis that acidosis can increase the toxicity of bupivacaine more than that of lidocaine by increasing the distribution into the brain, myocardium, or both, studies were performed to measure the in vivo tissue:blood partition coefficients during continuous steady state intravenous infusions of these agents in anesthetized sheep during normal acid-base status and during combined respiratory-metabolic acidosis. Acidosis decreased the partition coefficient of both agents into the myocardium and that of bupivacaine into the brain but did not systematically change that of either agent into skeletal muscle or fat. Total body and hepatic drug clearances were not affected systematically, but plasma binding of both agents was decreased. Thus predictions based on the pH partition hypothesis about the effects of acidosis on myocardial:blood partition coefficients being a basis for explaining the relative toxicity of these agents were not supported.
Cardiovascular effects, indocyanine green clearance and the reductive metabolism of halothane were compared in 10 patients having peripheral surgery who received either general anaesthesia or general anaesthesia plus extradural blockade. Bupivacaine or saline was given extradurally 1 h before anaesthesia with nitrous oxide:oxygen (70:30) and halothane (end-tidal concentration 0.35%). Indocyanine green clearance was measured before (stage I) and after (stage II) bupivacaine or saline, during anaesthesia before surgery (stage III), and during surgery (stage IV). Reductive metabolism of halothane was assessed by measurement of exhaled 2-chloro-1,1,1-trifluoroethane. In the general anaesthesia plus extradural blockade group, arterial pressure was decreased to 58% (SD = 6) of stage I values over stages II-IV, whereas no changes were observed in the general anaesthesia group. There was no significant difference in indocyanine green clearance or the reductive metabolism of halothane, despite the occurrence of significant decreases in arterial pressure.
Male Fischer 344 rats were exposed to halothane, enflurane or isoflurane vapour 20 p.p.m., or air, for up to 30 weeks. None of the anaesthetic agents led to hepatocellular necrosis. Exposure to halothane resulted in slight increases in serum alanine aminotransferase activity, an increase in the size of the liver, an increase in hepatic microsomal cytochrome P-450 content and a minimal amount of fatty change in the liver. None of these effects were observed during exposure to enflurane or isoflurane. Urinary fluoride excretion was increased during exposure to either enflurane or isoflurane. Using this increase as an index of anaesthetic biotransformation, we found that the extent of biotransformation of isoflurane was only slightly lower than that of enflurane.
Three volatile anaesthetic agent monitors (Datex Normac Anesthetic Agent Monitor, Engstrom Emma Multigas Monitor and Penlon Halothane Meter) were evaluated for the effects of nitrous oxide or water vapour, and for their linearity, stability, and rate of response to a change in concentration of various anaesthetic agents under simulated working conditions. None was affected by nitrous oxide, and only the Engstrom Emma was affected by water vapour. Linearity was satisfactory for all three devices but stability, with respect to zero and gain drift, was satisfactory only for the Datex Normac and Penlon Meter. Rates of response for 10% to 90% of source signal ranged from 0.8 seconds for the Datex Normac to about three seconds for the Penlon Meter.