Browsing by Author "Hickman, Rosemary"

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    The effect of alcohol intoxication on haemodynamic physiology of acute cardiac tamponade
    (1997) Hewitt, Peter MacDonald; Hickman, Rosemary; Knottenbelt, William John
    It is generally accepted that alcohol impairs haemodynamic physiology in normal subjects. Alcohol is also thought to have a detrimental effect in shock states. However, most research has concentrated on haemorrhagic shock, whereas in cardiac tamponade, the pathophysiology of shock is very different. Although some studies have mentioned alcohol as a negative factor in patients with cardiac tamponade, none have adequately assessed its effect. In a clinical study of 50 patients who presented to Groote Schuur Hospital Trauma Unit with acute cardiac tamponade due to penetrating chest injury, those who were intoxicated fared the same as their sober counterparts. Although more patients in the intoxicated group were "moribund" or "in extremis" on admission, this did not lead to a higher overall mortality. Haemodynamic parameters and results of special investigations in the two groups were also similar. These findings suggested that intoxicated patients with cardiogenic shock, specifically acute cardiac tamponade, behaved differently from intoxicated patients with haemorrhagic shock. However, the multitude of variables and the stress involved in treating patients with life-threatening acute conditions, makes studies such as this difficult. Because of these limitations, an animal model of acute cardiac tamponade was developed, so that actions of alcohol on haemodynamic physiology could be studied in a controlled environment. Fourteen young pigs were randomly assigned to receive either 30% alcohol or tap-water via a gastrostomy. The former resulted in blood alcohol levels which were compatible with moderate to severe intoxication. Cardiac tamponade was then induced by instilling warmed plasmalyte-8 into the pericardia! sac using a pressure-cycled system. Despite the fact that animals in the tamponade/alcohol group were more hypotensive, and reflex increase in heart rate was inhibited, cardiac output was similar in the two groups. The actions of alcohol in isolation were also studied in eight sham-operated pigs. The only noticeable effect in this instance were higher pulmonary artery wedge pressures in the sham/non-alcohol group. In other words, cardiac performance in both the tamponade/alcohol and sham/alcohol groups was at least equal to, or even better than that in animals that did not receive alcohol. It would seem therefore, that alcohol does not have a negative effect on haemodynamic physiology of acute cardiac tamponade. Theoretically, alcohol may "protect" patients with acute cardiac tamponade by decreasing peripheral vascular resistance and "afterload". It is also possible that inhibitory actions on the respiratory centre may prevent hyperpnoea or tachypnoea, and thereby diminish competitive filling of the right and left ventricles. However, further studies of cardiac function in intoxicated subjects with tamponade using more sophisticated techniques are necessary, before mechanisms will become apparent. In practice, an aggressive approach should be adopted towards moribund patients with penetrating chest injuries; if they have acute cardiac tamponade and are intoxicated, their prognosis is not necessarily dismal. This is of particular relevance in Cape Town, where both alcohol abuse and assault are endemic. As for a therapeutic effect of alcohol, these studies do not support its use for pharmacological manipulation of cardiac tamponade.
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    Lignocaine extraction ratio and clearance as an indicator of hypoxic hepatic injury : a study using the in situ and the isolated perfused pig liver
    (1992) Mets, Berend; Folb, Peter I; Hickman, Rosemary
    The metabolism of lignocaine to monoethylglycinexylidide has been found useful as an indicator of hepatic function in association with liver transplantation. It has been postulated that this might be due to the common effect of hypoxic damage on liver function and lignocaine metabolism. The aim of this work was to establish whether hepatic lignocaine elimination was impaired by hypoxia and whether lignocaine extraction ratio and clearance could be used as an indicator of hepatic function. This was studied using the isolated pig liver perfused via the hepatic artery and portal vein. To establish whether the pig liver could be used as a possible human model for this investigation and whether lignocaine had any detrimental effects on liver function and blood flow in vivo, hepatic lignocaine elimination and the effects of lignocaine administration on hepatic function and blood flow were studied in the anaesthetized pig, surgically prepared to allow sampling across the liver and direct hepatic blood flow measurement. Hepatic lignocaine elimination was then studied in the isolated perfused liver to determine whether this was similar to that found in vivo. The definitive studies required preliminary investigations not available from the literature to determine the feasibility of comparing in vivo and ex vivo hepatic function using the same liver. In addition, by studying the decay of lignocaine after bolus dose administration the necessary pharmacokinetic parameters to achieve similar constant hepatic affluent lignocaine concentrations in vivo and in the isolated preparation could be determined. The preliminary investigations showed that a sequential experiment using the same liver to compare in vivo and ex vivo function was inappropriate as the energy state of isolated perfused livers previously studied in vivo was significantly different from that in livers perfused immediately. The decay of lignocaine after a bolus dose in vivo and ex vivo could be described by a two-compartment open model and in both preparations the derived pharmacokinetic parameters from this analysis were used to achieve similar constant hepatic affluent concentrations over the study period used to determine hepatic lignocaine elimination. Lignocaine extraction ratio by the in situ pig liver was similar to that reported in man and together with hepatic clearance and intrinsic clearance was similar to that determined in the isolated state when different livers were used for this comparison. There was no detrimental effect of lignocaine administration on hepatic function and blood flow In vivo. Lignocaine extraction ratio and clearance and monoethylglycinexylidide formation were significantly impaired in livers subjected to hypoxia. Lignocaine elimination correlated strongly with hepatic cellular ATP, energy charge and ATP/ ADP ratio as well as with hepatic potassium release but less strongly with aspartate aminotransferase release when this relationship was tested using the combined data from hypoxic and normoxic livers ex vivo. These correlations were positive for hepatic adenine nucleotide status and negative for hepatic potassium and aspartate aminotransferase release. Neither hepatic alanine aminotransferase release nor lactate utilization were significantly affected by hypoxia. Lignocaine extraction ratio, hepatic oxygen consumption, ATP content, bile flow and potassium release were shown to be equivalent, more highly sensitive, and earlier indicators of hypoxic hepatic injury than hepatic aspartate aminotransferase release in the isolated perfused pig liver.
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    Physical and chemical changes in porcine gastric mucus in the normal and ulcerated status
    (1984) Mall, Anwarul Haq; Hickman, Rosemary
    It has been reported that there is a 100% incidence of ulceration of the squamous pars oesophagea of the pig's stomach following bile duct ligation. The reproducibility of this model has made possible its use in the investigation of the biochemical aspects of mucus secretion in both the normal state and at various states of ulceration. The main findings are summarised below: Mucus scrapings of the cardiac gland region of the pig stomach had a higher water and total protein content in the pre-ulcerated, ulcerated and post-ulcerated states. Gel chromatography on Sepharose CL-4B indicated larger amounts of degraded mucins relative to native mucins in the samples obtained from pre-ulcerated, ulcerated and post-ulcerated stomachs, as compared with the normal and control samples. The amounts of purified mucins obtained after isopycnic centrifugation in CsCl and gel chromatography on Sepharose CL-2B decreased from the normals and controls to the bile duct-ligated pigs. An analysis on SDS-PAGE revealed a considerable degree of proteolytic degradation of the pig gastric mucins in the bile duct-ligated pigs as compared with the normal and control animals. Staining reagents specific for both the protein and the carbohydrate components of the mucus glycoprotein were employed in gel electrophoresis, which also revealed the presence of contaminating protein, viz. haemoglobin, pepsin, albumin and smaller glycoproteins, to a greater extent in the ulcerated than in the normal and control states. Since pig gastric mucins contain 75% of carbohydrate, the determination of the proportions of monosaccharide constituents was essential. This was performed by GLC analysis of the alditol acetate derivatives of the sugars, which were characterised by mass spectrometry as well as by their retention times, relative to standards, on both packed and capillary columns. The most striking changes indicated by the GLC analyses were a decrease in the fucose content of the mucins from the normal to the ulcerated states and an increase in the proportion of N-acetylglucosamine in mucins from sham-operated animals. The control (sham-operated) pig behaved very similarly to the normal pig for up to 24 hours after the surgical procedure. At 48 hours, however, slight changes resembling those following bile duct ligation occurred. This could be due to the trauma of the sham-operation, which involved the surgical insertion of a cannula in the body region of the pig's stomach. It is possible that, under such stress biosynthesis of the mucins may be affected.
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    Pig liver perfusion : a role in hepatic assist?
    (1972) Hickman, Rosemary
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    A study of the effects of sucralfate in the bile duct litigated pig peptic ulcer model with particular reference to the effects on the physico-chemical properties of gastric mucus and including comparisons with famotidine and misoprostol
    (1992) Stapleton, Graham Neil; Hickman, Rosemary
    Sucralfate is a drug that effectively heals duodenal, gastric and oesophageal ulcers. It is not absorbed systemically and it has been shown to act locally by coating the ulcer base. However when it was also shown to prevent stress ulcers and ethanolinduced gastric mucosa! lesions, it seemed likely that it acted in some way to improve the effectiveness of the gastric mucosa! barrier. Some investigators suggested that it did so by stimulating local prostaglandin release. The Slomiany group, on the basis of in vitro work on the effects of Sucralfate on pig gastric mucus, claimed that Sucralfate acted by altering the physico-chemical properties of mucus to increase the viscosity and retard the back diffusion of H+ ions. The work described in this dissertation set out to verify, in vivo, these claimed effects on mucus, using an experimental porcine model of peptic ulceration, the bile duct ligated pig. In addition, the effects of Sucralfate were compared with those of Famotidine and Misoprostol, and changes in mucous prostaglandins, gastric juice pepsin and gastric flora were sought. By way of introduction, the known and postulated actions of Sucralfate, current understanding of gastric mucus physiology and pathogenesis of peptic ulceration, have been reviewed, as have experimental animal models of peptic ulceration, in order to justify using the bile duct ligated pig model.