Biomedical subjects
W B Runciman
Publications and source records attributed to W B Runciman.
Uptake and output of various forms of choline by organs of the conscious chronically catheterized sheep.
The net uptake and output of plasma unesterified choline, glycerophosphocholine, phosphocholine and lipid choline by organs of the conscious chronically catheterized sheep were measured. There was significant production of plasma unesterified choline by the upper- and lower-body regions and the alimentary tract and uptake by the liver, lungs and kidneys. The upper- and lower-body regions drained by the venae cavae provided the bulk (about 82%) of the total body venous return of plasma unesterified choline. Production of plasma unesterified choline by the alimentary tract was approximately balanced by the plasma unesterified choline taken up by the liver, and was almost equal to the amount of choline secreted in the bile. There was a considerable amount of glycerophosphocholine in the liver and there was production of plasma glycerophosphocholine by the liver and uptake by the lungs and kidneys. Glycerophosphocholine was higher in the plasma of sheep than in that of rats. Plasma phosphocholine was produced by the alimentary tract and kidneys. There was production of plasma lipid choline by the upper- and lower-body regions drained by the venae cavae. The results suggest that the sheep synthesizes substantial amounts of choline in ectrahepatic tissues and has the capacity for extensive retention and recycling of bile choline. These observations, coupled with a slow turnover of the endogenous choline body pool, explain the low requirement of sheep for dietary choline in contrast with non-ruminant species.
A sheep preparation for studying interactions between blood flow and drug disposition. II: Experimental applications.
A sheep preparation has been developed which allows systematic direct studies into the sites and rates of distribution, formation and elimination of both endogenous and exogenous substances and their metabolites. Examples of some experimental applications are presented which provide information not usually available using traditional methods. Substantial metabolism at sites not usually regarded as important (e.g. limbs, lungs) was shown both for exogenous substances (procainamide and chlormethiazole) and for an endogenous substance (choline). Studies on drug clearance by kidney (cefoxitin), liver (chlormethiazole, pethidine and the optical isomers of mepivacaine) and lung (chlormethiazole) demonstrate that simple first-order elimination should not routinely be assumed to occur, as multiple sites and pathways may be involved, and kinetics may be non-linear as a result of characteristics of both organ flow and organ function. It was also shown that large changes (up to three-fold) in arterial blood drug concentrations may occur because of exogenous (anaesthesia) and endogenous (gastric recycling) perturbations, and that simple compartmental kinetics should not be assumed for either the whole body or individual organs. This preparation may be used in conjunction with traditional pharmacokinetic methods to resolve complex problems relating to interactions between drugs and the body, to establish a data base for physiological models of drug disposition, and to gain practical insights for drug treatment in patients.
A sheep preparation for studying interactions between blood flow and drug disposition. III: Effects of general and spinal anaesthesia on regional blood flow and oxygen tensions.
In awake unrestrained sheep the infusions i.v. of five drugs (cefoxitin, pethidine, chlormethiazole, tocainide and lignocaine) with potentially flow-limited clearance were shown to have no significant haemodynamic effects of their own, nor to have any effects on arterial or venous oxygen tensions. Under general anaesthesia (1.5% end-tidal halothane), haemodynamic changes similar to those previously documented in man occurred. Cardiac output and hepatic blood flow were decreased to 70%, and renal blood flow to 50% of control values; heart rate was unchanged and mean arterial pressure decreased by an average of 10%. Hepatic and renal vein oxygen tensions were decreased significantly. Under spinal anaesthesia, apart from a 10% decrease in hepatic blood flow, there were no significant changes in any haemodynamic variables or in the arterial or in any of the venous oxygen tensions. The i.v. infusion of adequate volumes of saline at the time of blockade probably contributed to the maintenance of these indices at their baseline values.
A sheep preparation for studying interactions between blood flow and drug disposition. I: Physiological profile.
A sheep preparation has been developed which allows repeated measurements of regional blood flow, oxygen consumption and drug disposition in awake, unrestrained animals. This allows systematic studies of both acute changes, such as haemodynamic disturbances, and of chronic changes, such as enzyme induction, to be carried out. Good agreement was shown between the values for cardiac output and regional blood flow obtained by the Fick and indicator dilution methods, and those obtained by others using microspheres. Significant day-to-day fluctuations in haemodynamic indices were shown to occur; assumptions that hepatic or renal blood flows are constant fractions of cardiac output, or that renal or hepatic flow indicator extraction ratios remain unchanged from day-to-day, will lead to significant errors. Thus, control measurements for each experiment are necessary. It is proposed that physiological models for studying drug disposition based on data from awake, unrestrained animals may provide insight into some mechanisms of changes in drug disposition that cannot be obtained using the traditional compartmental method.
Pathophysiology of haemorrhagic shock.
The immediate effect of sudden blood loss is the activation of a variety of homeostatic responses. These include increased sympathetic activity and increased release or production of renin, angiotensin, anti-diuretic hormone, aldosterone, adrenocorticotrophic hormone, beta-endorphins, glucocorticoids, glucagon, erythropoeitin, 2-3 diphosphoglycerate, prostaglandins and complement. This may be followed by the release of many substances, some initially appropriate locally, and some the products of damaged cells, which may go on to cause both local and systemic damage. These include lysosomal enzymes, kinins, histamines, serotonin, lactic acid, free oxygen radicals, neutrophil proteases, fibrinogen degradation products, endotoxins, myocardial depressant polypeptides, and passive transferable lethal factor. The early and late effects on the cardiovascular and respiratory systems, and on the blood, brain, kidneys, gut, liver, pancreas, and on overall metabolism and cellular function, are considered in turn. Although an enormous research effort has increased our understanding of the pathophysiology of haemorrhagic shock, no special measures have yet been shown to influence morbidity or mortality in man. Management still hinges on the early recognition and treatment of bleeding, on general supportive measures, and on safeguarding each link in the oxygen delivery chain.
Acute epiglottitis in adults.
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Malignant hyperthermia. Recognition, prevention and management.
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An evaluation of body temperature measurement.
The accuracy of routine body temperature measurements, the suitability of various sites for such measurements, and the performance and practicality of various temperature measuring devices were studied. Oral and axillary temperature measurements made by the nursing staff were within 1 degree C of a reference value (within 0.5 degree C in 67%). Both sites were suitable for routine ward temperature measurement. Mercury-in-glass thermometers are recommended for routine ward use. Electronic and disposable chemical thermometers cost more but the latter are suitable in uncooperative patients and children. Forehead skin temperature measurements using liquid crystal plastic discs were unreliable. Pulmonary artery and rectal temperature measurements were satisfactory in operating theatre and intensive care unit; however, electronic thermometers should be subjected to routine checks. The bladder temperature measuring device proved unsuitable for clinical use. When oesophagus, nasopharynx and tympanum sites are used careful placement is necessary to minimise trauma and obtain reliable measurements.
Effective use of blood in elective surgical procedures. 2. The role of preoperative autologous blood transfusion.
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Versatile portable respirator.
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Direct measurement of chlormethiazole extraction by liver, lung and kidney in man.
1 Chlormethiazole was used as a basal sedative for patients undergoing angiographic procedures. 2 Blood samples were drawn opportunistically to examine chlormethiazole extraction across liver, lungs and kidney. 3 Extraction across liver was typically 70-80% and apparently unrelated to input concentrations. Evidence for extraction across lung and kidney was inconclusive but these could each be approximately 20%. 4 Pharmacokinetics of chlormethiazole derived from compartment models were in accord with previous reports and were characterised by a high total body clearance (1-1.5 l/min). 5 Postural changes associated with the radiological procedures caused fluctuating blood concentrations which appear as noise in curve fitting procedures. 6 Pharmacokinetic properties derived from compartment theory cannot cope with these perturbations because of the restriction imposed by time averaging (i.e. mean clearances, half-lives and volumes are produced). Systematic studies of pharmacokinetic properties of perfusion-limited drugs such as chlormethiazole must be developed in such a way as to allow for independent variation of flow and extraction.
Intravenous chlormethiazole- haemolysis with concentrated solutions.
Since the current clinical concentration of chlormethiazole solutions (0.8%) may require the infusion of large volumes of fluid, it was decided to examine the effects on haemolysis of infusing higher concentrations of chlormethiazole into a central vein. Approximately one gram of chlormethiazole was infused into the inferior vena cavae of six anaesthetised greyhounds over each half hour using, successively, 0.8%, 1.2%, 2%, 5%, 10%, and 20% solutions of chlormethiazole. Free plasma haemoglobin levels were measured at five minute intervals, and blood chlormethiazole levels at 15 minute intervals. A rapidly progressive haemolysis occurred when the 5 or 10% solutions were infused. In a further four greyhounds, one gram of chlormethiazole was infused over each half hour using a 0.8% solution, whilst progressively hyperosmolar dextrose solutions were infused at the same rates in succeeding half hours as the concentrated chlormethiazole solutions had been infused in the first six dogs. No haemolysis occurred in these control animals. Chlormethiazole blood levels were similar in each group. Loss of chlormethiazole into the infusion tubing was examined and found to be 20% for the 0.8% solution, and 10% for the 1.2% solution, but was insignificant with the other subsequently infused concentrations of chlormethiazole. It is concluded that rapid progressive haemolysis occurs in association with the infusion of chlormethiazole solutions when concentrations of greater than 5 or 10% are infused into the inferior vena cavae of anaesthetised greyhounds.
Thermodilution cardiac output--a systematic error.
The purpose of this study was to examine the mechanism and magnitude of a systematic error in thermodilution cardiac output measurement. One hundred and seventy-one thermodilution cardiac output measurements in dogs using a Swan-Ganz catheter were compared with simultaneously made dye dilution measurements under different conditions over a wide range of cardiac outputs. A systematic error with the thermodilution technique was confirmed and was almost identical to that observed in the literature. It is proposed that its mechanism is loss of thermal indicator between the injectate orifice and detection. Application of a further correction factor for thermal indicator loss is suggested.
An evaluation of thermodilution cardiac output measurement using the Swan-Ganz catheter.
Errors in thermodilution cardiac output measurement were quantitated to determine the order of accuracy of routine measurements performed by unskilled personnel. In vitro and in vivo studies were undertaken to examine factors affecting the volume and temperature of the injectate, catheter thermistor and computer performance, effect of respiration, use of cold (0-4 degrees C) versus ambient temperature (20-25 degrees C) injectate, and the interpretation of measurements. Ambient temperature injectate incurred unacceptably large errors; cold injectate (injections were timed with respiration) produced variations in performance by equipment and personnel which accounted for only 2% of the variation between successive measurements. Real changes in cardiac output and inherent variability of the downslope of the thermal curve, necessitating an empirically based calculation, account for up to 10% variation between successive measurements. When cold injectate was used, and the average of three corrected measurements taken, thermodilution cardiac output measurements were within 10% of a simultaneous dye dilution measurement.
An evaluation of blood pressure measurement.
The accuracy of routine measurements by nursing staff of systemic arterial, central venous, pulmonary artery and pulmonary capillary wedge pressures was determined. There was a significant difference between direct mean arterial blood pressure measurements and routine indirect measurements by the nursing staff in the pressure range of 50--100 mmHg, whereas there was no significant difference between direct and indirect measurements when indirect measurements were made by specially trained hypertension clinic personnel. However, there was a good correlation between direct and indirect measurements in each instance, indicating that changes in blood pressure could be adequately followed by both groups. Systems commonly used to measure blood pressure directly were tested. Limits in frequency response preclude the routine direct measurement of systolic or diastolic blood pressures. If direct systolic and diastolic pressure measurements are required, it is necessary to check the performance of the amplifier and recording system, attach the transducer to the patient, and determine and adjust, if necessary, the natural frequency and damping coefficient of each system before each measurement. However, it is suggested that a knowledge of systolic and diastolic pressure measurements seldom improves patient management, and if mean pressures are accepted, reliable routine measurements may be obtained by the nursing staff. The digital display of the systems tested may be accepted for mean arterial pressure, but for accurate mean central venous and pulmonary capillary wedge pressure measurements, it is necessary to interpret the trace on a chart recorder; pulmonary artery pressure can often only be estimated.
Deaths in intensive care: analysis and prediction.
Analysis of the data relating to the most critically ill (grade IV) patients admitted to the intensive care unit at Flinders Medical Centre in 1977 and 1978 has been carried out. The mortality rate in this group was 37% in 1977, and 32% in 1978. No absolute predictors of outcome were found, indicating the need for early aggressive investigation and management of critically ill patients. The disease state, and the presence of coma or renal failure, were useful guides to prognosis. Cardiovascular system failure was the cause of death in 51% of patients, and central nervous system failure the cause of death in 28% of patients. Comparison with other published results was difficult because of the lack of standard methods of data reporting. Maintenance of life support was ceased in 28 patients, 15 of whom did not have brain death. Criteria for making such a decision are proposed.
Sympathomimetic amines.
The autonomic nervous system may play an important role in tissue autoregulation as the neurohumoral transmission process has been shown to constitute the final common pathway by which the effects of many physiological and pharmacological substances are mediated. The effects of the administration of a sympathomimetic amine cannot be accurately predicted in a subject. Choice of which sympathomimetic amine to use should be determined on the basis of data obtained in relevant clinical circumstances, but the dose should always be titrated against the effect in each individual. It is interesting that adrenaline, "the original autonomic drug" with its "venerable history", is still a first line drug in many of the situations for which it was being prescribed in 1907. It is the drug of first choice in anaphylactic reactions and for severe allergic bronchospasm, and is widely used as a vasoconstrictor in surgery and with local anaesthetic agents. Adrenaline in "physiological" doses is a satisfactory and cheap alternative to other available drugs for use in septic shock and in emergence from cardiopulmonary bypass.