Oxygen kinetics and energy expenditure in fulminant hepatic failure and during liver transplantation

This thesis examines aspects of oxygen transport and uptake in patients with acute and chronic liver disease with specific reference to the management of fulminant hepatic failure (FHF) and the intraoperative management of patients undergoing liver transplantation.A prospective randomised controlled study was carried out in patients with FHF evaluating the effect of the drug N- acetylcysteine on DO2, VO2, and tissue oxygen extraction. A previous study showed that this drug increased all of these oxygen kinetic variables, which was considered of therapeutic benefit. The present study showed that this earlier finding was an artifact related to the method of calculating oxygen consumption (the Fick method). This method produced unreliable results in patients with FHF because it was inaccurate, non -reproducible, the the relation between DO2 and VO2 was subject to mathematical couplig error. No clinically significant improvements in any oxygen kinetic variables were observed after N- acetylcysteine administration, even when followed for a prolonged period. Variable effects on cardiovascular parameters were found, but overall no differences from the control group were demonstrated. No relationship was found between plasma Nacetylcysteine concentrations and clinical response.A prospective study examining energy expenditure and the acute phase response was carried out in patients with FHF. Energy expenditure was increased by approximately 20 -25% in FHF in comparison with spontaneously breathing healthy volunteers and physically anhepatic patients with chronic liver disease studied during liver transplantation. Plasma TNFa, IL -6, and C- reactive protein were measured. These were significantly elevated in comparison with healthy controls in keeping with a significant acute phase response. The study indicated hypermetabolism during severe FHF despite the loss of functioning liver cell mass and the effects of sedation, analgesia, and mechanical ventilation. This was most likely attributable to a systemic inflammatory response.In patients undergoing liver transplantation indirect calorimetry was used to examine changes in metabolic rate and pulmonary physiology following graft reperfusion. Significant changes in metabolic rate, oxygen transport, and acid -base balance were demonstrated the factors which influence these changes were discussed. The use of the piggyback surgical technique was associated with greater metabolic stability than the use of venovenous bypass.A prospective observational study compared the two methods for managing the anhepatic phase of liver transplantation, namely venovenous bypass or the piggyback surgical technique. This study demonstrated higher cardiac output, VO2, and blood temperature during the anhepatic phase with the piggyback surgical technique. This suggested better preservation of tissue oxygenation with this approach, which may translate into improved postoperative function.Two techniques of graft reperfusion, namely via the portal vein or the hepatic artery, were compared in another prospective observational study. This study indicated that the increase in VO2 after reperfusion occurred more slowly when the hepatic artery was used, but was accompanied by a slower release of acid load into the circulation and less requirement for vasopressor support. Reperfusion via the hepatic artery may therefore be preferable in the patient at risk of haemodynamic or cerebral decompensation following reperfusion, although further studies are required to ensure graft outcome is equivalent with both techniques

Acute lung injury in paediatric intensive care: course and outcome

Introduction: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) carry a high morbidity and mortality (10-90%). ALI is characterised by non-cardiogenic pulmonary oedema and refractory hypoxaemia of multifactorial aetiology [1]. There is limited data about outcome particularly in children. Methods This retrospective cohort study of 85 randomly selected patients with respiratory failure recruited from a prospectively collected database represents 7.1% of 1187 admissions. They include those treated with High Frequency Oscillation Ventilation (HFOV). The patients were admitted between 1 November 1998 and 31 October 2000. Results: Of the 85, 49 developed acute lung injury and 47 had ARDS. There were 26 males and 23 females with a median age and weight of 7.7 months (range 1 day-12.8 years) and 8 kg (range 0.8-40 kg). There were 7 deaths giving a crude mortality of 14.3%, all of which fulfilled the Consensus I [1] criteria for ARDS. Pulmonary occlusion pressures were not routinely measured. The A-a gradient and PaO2/FiO2 ratio (median + [95% CI]) were 37.46 [31.82-43.1] kPa and 19.12 [15.26-22.98] kPa respectively. The non-survivors had a significantly lower PaO2/FiO2 ratio (13 [6.07-19.93] kPa) compared to survivors (23.85 [19.57-28.13] kPa) (P = 0.03) and had a higher A-a gradient (51.05 [35.68-66.42] kPa) compared to survivors (36.07 [30.2-41.94]) kPa though not significant (P = 0.06). Twenty-nine patients (59.2%) were oscillated (Sensormedics 3100A) including all 7 non-survivors. There was no difference in ventilation requirements for CMV prior to oscillation. Seventeen of the 49 (34.7%) were treated with Nitric Oxide including 5 out of 7 non-survivors (71.4%). The median (95% CI) number of failed organs was 3 (1.96-4.04) for non-survivors compared to 1 (0.62-1.62) for survivors (P = 0.03). There were 27 patients with isolated respiratory failure all of whom survived. Six (85.7%) of the non-survivors also required cardiovascular support.Conclusion: A crude mortality of 14.3% compares favourably to published data. The A-a gradient and PaO2/FiO2 ratio may be of help in morbidity scoring in paediatric ARDS. Use of Nitric Oxide and HFOV is associated with increased mortality, which probably relates to the severity of disease. Multiple organ failure particularly respiratory and cardiac disease is associated with increased mortality. ARDS with isolated respiratory failure carries a good prognosis in children

Hepatic First-Pass Clearance of Oral Galactose and its Potential Use in the Assessment of Portasystemic Shunting in Portal Hypertension

Portasystemic shunting is an important consequence of all diseases that lead to portal hypertension. The clinical-pathological problems associated with portasystemic shunting, such as hepatic encephalopathy and oesophageal varices, remain a potent cause of much morbidity and mortality. The aetiology of hepatic encephalopathy remains poorly understood, but it is thought that the more subtle sequallae of portasystemic shunting, such as hormonal (Fischer et al, 1974), and nutritional (Phear et al, 1955; Fischer and Baldessarini, 1971) changes contribute in varying degrees to the onset and progression of the condition. Quantitation of the magnitude of portasystemic shunting is thus potentially most useful in the study of hepatic encephalopathy. Up to now it has not been practical to measure on a routine basis the fraction of portal blood that bypasses functioning hepatocytes to reach the systemic circulation. The available methods are either highly invasive (Okuda et al, 1977), time consuming (McLean et al, 1979), or suffer from known measurement inaccuracies (Porchet and Bircher, 1982; Cavanna et al, 1987), and their applications have been limited to a few studies. The purpose of this thesis is to describe and assess a novel, non-invasive procedure that approaches quantitative assessement of portasystemic shunting. The principle of the method consists of a comparison of the systemic availability of an oral and intravenous dose of galactose. The ability of galactose to quantitate the magnitude of portasystemic shunting associated with portal hypertension has been examined in patients with documented oesophageal varices and in a rat model of prehepatic portal hypertension using partial portal vein ligation. The rat model had been established and characterised previously in the University Department of Surgery, Glasgow Royal Infirmary (Geraghty et al, 1989). Data from the studies described in this thesis has shown a marked difference in the systemic availability of galactose between control patients and patients with liver disease and/or portal hypertension. In the former group only 14 percent of the oral dose appeared in the systemic circulation, whereas in portal hypertensive patients an average of 72 percent (range 38% to 108%) was detected systemically. The absence of a gold standard for portasystemic shunting measurements, and ambiguity in the definition of portasystemic shunting itself, preclude direct validation of the measurements in man. However, the key assumptions about galactose elimination kinetics underlying the measurement technique were tested independently and found to be satisfied. The initial application of the technique in the rat model of prehepatic portal hypertension, in which independent measurements of portasystemic shunting could be performed using a radioactive microsphere technique, failed to show a difference in the systemic availability of oral galactose between control and portal hypertensive rats. Further studies showed this was largely due to erratic and incomplete absorption of galactose from the gastrointestinal tract. A more comprehensive investigation was carried out and the kinetics of hepatic galactose elimination in the rat was studied by direct infusion of galactose into the portal vein. From this it was shown that, in contrast to man, hepatic extraction efficiency in this animal model had a high dependence on circulating blood galactose concentrations. This compromised the accuracy of the technique for quantitation of portasystemic shunting in individual animals because of the variability in kinetic parameters. However, there was a highly significant correlation between the systemic availability of intraportally administered galactose in rats and portasystemic shunting as measured with radioactive microspheres. The galactose technique described in this thesis may thus be regarded as a tool to assess the magitude of portasystemic shunting, and may have a role in the study of the associated complications of hypertension and liver disease

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 279)

This bibliography lists 175 reports, articles, and other documents introduced into the NASA scientific and technical information system in December 1985