Biomedical subjects

N R Webster

Publications and source records attributed to N R Webster.

At least 19 recordsLinked to original sources

PubMed1995

Nitric oxide synthase activity is increased in patients with sepsis syndrome.

1. We measured nitric oxide synthase activity in peripheral blood polymorphonuclear leucocytes from 10 patients with sepsis syndrome and 10 healthy subjects. 2. Synthase activity was significantly higher in patients with sepsis than in control subjects (1202 +/- 579 compared with 595 +/- 544 pmol of nitric oxide min-1 mg-1 of cell protein, P < 0.05). 3. Activity was greatest in those patients with the larger number of organ failures, although this failed to reach significance (1489 +/- 560 in patients with three or more organ failures and 843 +/- 404 pmol of nitric oxide min-1 mg-1 of cell protein in those with less than three, P = 0.11). 4. This study provides evidence for the role of overproduction of the vasodilator nitric oxide in sepsis syndrome.

Adult↗

PubMed1995

Total antioxidant capacity and lipid peroxidation during liver transplantation.

1. We assessed plasma total antioxidant capacity using enhanced chemiluminescence and plasma lipid peroxides in eight patients undergoing orthotopic liver transplantation and 26 healthy control subjects. 2. The antioxidant capacity of plasma decreased significantly on reperfusion of the donor liver (P < 0.05) during liver transplantation, although levels were not lower in patients than in control subjects. 3. Pre-reperfusion antioxidant capacity correlated negatively with the concentration of lipid peroxidation products appearing in the plasma by the end of the transplant (P < 0.02), but did not correlate with vitamin A or E concentrations. 4. This study provides evidence of oxidant stress during liver transplantation, as shown by antioxidant utilization associated with increased lipid peroxidation.

Adult↗

PubMed1995

Anaesthetic agents decrease the activity of nitric oxide synthase from human polymorphonuclear leucocytes.

Nitric oxide (NO) inhibitors reduce the threshold for anaesthesia. We have investigated the action of anaesthetic agents on human nitric oxide synthase (NOS) activity. Thiopentone reduced mean NOS activity to 36.6 (SD 8.9) % of control at 100 mumol litre-1 (P < 0.001) and 50.9 (20.3) % at 1 mmol litre-1 (P < 0.05). Ketamine showed similar effects, with activity reduced to 67.0 (17.6) % (P < 0.05) and 57.7 (8.5) % (P < 0.001) at 100 mumol litre-1 and 1 mmol litre-1, respectively. Etomidate 100 mumol litre-1 did not significantly alter activity (88.2 (8.1) %) but 1 mmol litre-1 did (60.6 (10.4) %, P < 0.005). Halothane also caused a significant decrease in NOS activity at all concentrations. This effect was specific as other enzymes were unaffected. We conclude that anaesthetic agents have a profound effect on NOS activity and as inhibition of NO release augments anaesthesia, we suggest that this may play a role in the mechanism of anaesthesia in humans.

Anesthetics↗

PubMed1995

Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction.

OBJECTIVE: To determine antioxidant vitamin concentrations, lipid peroxidation, and an index of nitric oxide production in patients in the intensive care unit (ICU) with septic shock and relate the findings to the presence of secondary organ failure. DESIGN: A prospective, observational study. SETTING: A nine-bed ICU in a University teaching hospital. PATIENTS: Sixteen consecutive patients with septic shock, defined as: a) clinical evidence of acute infection; b) hypo- or hyperthermia (< 35.6 degrees C or > 38.3 degrees C); c) tachypnea (> 20 breaths/min or being mechanically ventilated); d) tachycardia (> 90 beats/min); e) shock (systolic pressure < 90 mm Hg) or receiving inotropes. Fourteen patients also had secondary organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Antioxidant vitamin concentrations were significantly lower in the patients than the reference range obtained from a comparable group of healthy controls. The mean plasma retinol (vitamin A) concentration was 26.5 +/- 19.3 micrograms/dL compared with 73.5 +/- 18.3 micrograms/dL in healthy subjects (p < .01). Additionally, 13 (81%) patients had retinol values below the lower limit of our reference range (< 37.0 micrograms/dL). Tocopherol (vitamin E) plasma concentrations were below the reference range in all patients (< 9.0 mg/L), with a mean value of 3.6 +/- 2.0 mg/L compared with 11.5 +/- 1.3 mg/L in healthy subjects (p < .001). Plasma beta carotene and lycopene concentrations were undetectable (< 15 micrograms/L) in eight (50%) patients, and below our reference range (< 101 micrograms/L and < 154 micrograms/L, respectively) in the remaining patients. In the five patients with three or more dysfunctional secondary organs, plasma thiobarbituric acid-reactive substances were significantly increased (p < .05), suggesting increased lipid peroxidation. Concentrations of thiobarbituric acid-reactive substances correlated negatively with both plasma retinol and plasma tocopherol (r2 = .42, p < .01 and r2 = .48, p < .005, respectively). In the five patients from whom we were able to collect urine, nitrite excretion was increased approximately 400-fold (p < .001). CONCLUSIONS: These data indicate decreased antioxidant status in the face of enhanced free radical activity, and suggest potential therapeutic strategies involving antioxidant repletion.

APACHE↗

PubMed1995

Cardiac function during orthotopic liver transplantation with venovenous bypass.

We have studied the effect of varying the flow of a venovenous bypass system during orthotopic liver transplantation. During these manipulations, central venous (n = 9) or pulmonary artery occlusion (n = 9) pressures were kept constant. There was no change in right ventricular systolic or diastolic function in either group, suggesting that any conformational change of the ventricle during bypass is not of functional significance. The extrapolated volume loading required to compensate for the absence of bypass is of the order of 3000 ml.

Adult↗

PubMed1995

Acute lung injury in fulminant hepatic failure following paracetamol poisoning.

BACKGROUND: There is little information on the incidence of acute lung injury or changes in the pulmonary circulation in acute liver failure. The aim of this study was to record the incidence of acute lung injury in fulminant hepatic failure caused by paracetamol poisoning, to document the associated pulmonary circulatory changes, and to assess the impact of lung injury on patient outcome. METHODS: The degree of lung injury was retrospectively assessed by a standard scoring system (modified from Murray) in all patients with fulminant hepatic failure caused by paracetamol poisoning, admitted to the intensive care unit over a one year period. The severity of liver failure and illness, other organ system failure, and patient outcome were also analysed. RESULTS: Twenty four patients with paracetamol-induced liver failure were admitted and nine developed lung injury of whom eight (33%) had severe injury (Murray score > 2.5). In two patients hypoxaemia contributed to death. Patients with lung injury had higher median encephalopathy grades (4 v 2 in the non-injured group) and APACHE II scores (29 v 16). Circulatory failure, requiring vasoconstrictor support, occurred in all patients with lung injury but in only 40% of those without. Cerebral oedema, as detected by abnormal rises in intracranial pressure, also occurred in all patients with lung injury but in only 27% of the non-injured patients. The incidence of renal failure requiring renal replacement therapy was similar in both groups (67% and 47%). Pulmonary artery occlusion pressures were normal in the lung injury group. Cardiac output was high (median 11.2 1/min), systemic vascular resistance low (median 503 dynes/s/cm-5), and pulmonary vascular resistance low (median 70 dynes/s/cm-5), but not significantly different from the group without lung injury. Mortality was much higher in the lung injury group than in the non-injured group (89% v 13%). CONCLUSIONS: Acute lung injury was common in patients with paracetamol-induced fulminant hepatic failure and was associated with systemic circulatory failure and cerebral oedema. The development of acute lung injury was associated with high mortality.

APACHE↗

PubMed1995

The effect of anticoagulant choice on apparent total antioxidant capacity using three different methods.

We assessed total antioxidant capacity using three different methods, in plasma samples treated with either EDTA or heparin as anticoagulant, from 26 healthy subjects. Total antioxidant capacity was determined using an oxygen electrode (as the total peroxyl radical-trapping antioxidant parameter), by enhanced chemiluminescence, and by measurement of the antioxidant-mediated quenching of the absorbance of a radical cation. The choice of anticoagulant had a profound effect on antioxidant capacity with heparinized plasma giving consistently higher values than plasma anticoagulated with EDTA. Using the oxygen electrode the mean value was 786.5 +/- 171.5 mumol/L (heparin) compared to 681.4 +/- 160.4 mumol/L (EDTA, P < 0.01). The chemiluminescence technique gave a mean antioxidant capacity of 915.6 +/- 214.1 mumol/L in heparin samples and 714.4 +/- 195.4 mumol/L in EDTA samples (P < 0.0001). The absorbance quenching technique gave a mean value of 867.0 +/- 199.2 mumol/L (heparin) and 675.5 +/- 245.4 mumol/L (EDTA, P < 0.001). All methods tested showed comparable results for EDTA plasma, but the chemiluminescence technique gave higher apparent antioxidant capacity than either of the two techniques when heparin plasma was used. We suggest that either heparin is interacting to enhance antioxidant protection perhaps through release of superoxide dismutase, or the chelation of metal ions by EDTA is limiting the activity of antioxidant metalloenzymes. Consistency in the choice of anticoagulant is clearly extremely important.

Adult↗

PubMed1994

Nitric oxide production by human peripheral blood polymorphonuclear leucocytes.

1. We describe a rapid and reliable technique for the assessment of basal nitric oxide release in clinical situations, using peripheral blood polymorphonuclear leucocytes isolated by a single-step density gradient procedure. The assay is based on the quantitative conversion of oxyhaemoglobin to methaemoglobin by nitric oxide. We have further examined the ability of these cells to respond to various stimuli. 2. Basal (unstimulated) nitric oxide release occurred, which was augmented by superoxide dismutase. The mean value for healthy subjects was 283 +/- 96.7 pmol min-1 10(-6) cells. 3. Both phorbol myristate acetate and N-formyl-methionyl-leucylphenylalanine induced further release of nitric oxide, which was increased by preincubation with lipopolysaccharide, interleukin-6 and interferon-gamma. 4. Preincubation of cells with NG-monomethyl-L-arginine or L-canavanine sulphate inhibited nitric oxide production. 5. The procedure provides a valuable tool for monitoring nitric oxide up-regulation in clinical situations.

Humans↗

PubMed1994

Haemodynamics of liver reperfusion: comparison of two anaesthetic techniques.

Reperfusion during liver transplantation is associated with cardiovascular instability. We have compared the effects of two anaesthetic techniques on these changes. Twenty-six consecutive patients undergoing elective orthotopic liver transplantation were anaesthetized using either isoflurane or propofol. Haemodynamic profiles were studied before and at specific times after liver graft reperfusion. Systemic vascular resistance decreased at reperfusion in both groups (P < 0.0001), which was accompanied by increased cardiac output which attenuated changes in mean arterial pressure. In the isoflurane group, cardiac output was maintained primarily by improvement in stroke volume, whereas in the propofol group the increase in stroke volume was less marked and cardiac output was maintained by a greater heart rate. The cardiovascular changes were tolerated less well in those patients receiving propofol.

Adult↗

PubMed1994

Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort study.

OBJECTIVE: To investigate the relationship between the soluble derivatives of endothelial adhesion molecules liberated by activated vascular endothelium and the development of the systemic inflammatory response syndrome and organ dysfunction in septic patients. DESIGN: Prospective cohort study with controls. SETTING: University hospital intensive care unit. PATIENTS: Healthy volunteers (controls, n = 85), patients with the systemic inflammatory response syndrome (n = 21), patients with systemic inflammatory response syndrome and organ dysfunction (n = 14), and miscellaneous, severely ill patients (n = 5). INTERVENTIONS: Plasma samples were collected from consecutive patients who satisfied the criteria for inclusion in the groups listed above. MEASUREMENTS AND MAIN RESULTS: The plasma was assayed by enzyme-linked immunosorbent assay (ELISA) for each of the three soluble adhesion molecules: sE-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. There were low basal amounts of these adhesion molecules in the healthy volunteers, while plasma concentrations of all three adhesion molecules were increased in the sepsis groups. The median soluble E-selectin concentration was higher in those patients with organ dysfunction compared with the concentrations in patients with uncomplicated sepsis (p < .01 at first and p < .001 when comparing peak values attained). No patient survived when the amount of soluble E-selectin was > 30 units/mL. CONCLUSIONS: Concentrations of circulating vascular endothelial adhesion molecules, especially soluble E-selectin, are increased in patients with systemic inflammatory response syndrome and these concentrations are more increased in patients with organ dysfunction. High plasma concentrations of soluble E-selectin were closely associated with multiple-organ dysfunction and death. Measurement of adhesion molecules, especially soluble E-selectin, might be used to advantage in the management of patients with sepsis.

Adult↗

PubMed1993

Free radicals and antioxidants in sepsis.

OBJECTIVES: The clinical condition of sepsis is caused by the release of numerous mediators from many cells. The purpose of this review is to describe the results of studies in which the role of free radicals and/or the potential therapeutic value of antioxidants are assessed. DATA SOURCES: The studies described in this review come from a variety of sources, including Med-Line CD-ROM computerized database, Index Medicus, and references identified from the bibliographies of pertinent articles and books. Reports were confined to English language articles from 1966 to 1992. STUDY SELECTION: All retrieved references in which free-radical activity was assessed or antioxidants were measured or administered in sepsis or endotoxemia were included. This selection process encompassed clinical, animal and in vitro cell culture work. DATA EXTRACTION: Cited literature was found in reputable peer-reviewed clinical or basic science journals. DATA SYNTHESIS: Any contradictions in the results of studies are discussed. CONCLUSIONS: There is evidence that free radicals play an important role in the pathogenesis of sepsis. Antioxidant therapy has the potential to protect against such injury. It is suggested that combination therapy, which augments the endogenous antioxidant defenses, is likely to be the best approach.

Animals↗

PubMed1993

Alterations in plasma magnesium concentrations during liver transplantation.

Plasma magnesium concentrations were monitored during orthotopic liver transplantation. Magnesium supplementation was not given, although intraoperative calcium, potassium, and sodium bicarbonate were given as required. We found that there were significant falls in magnesium concentration to below our laboratory lower limit of normal, occurring chiefly during the anhepatic phase of surgery. Two patients with hypomagnesemia but normal potassium and calcium ion concentrations developed ventricular extrasystoles. Magnesium is a smooth muscle relaxant, dilating coronary arteries and peripheral vessels. It also exerts an antiarrhythmic effect and may have a permissive effect on the actions of catecholamines. Magnesium supplementation may be indicated during orthotopic liver transplantation because of the potentially beneficial effects and to avoid possible deleterious effects of hypomagnesemia. However, magnesium levels need to be monitored to avoid the unwanted side effects of hypermagnesemia.

Adenosine↗

PubMed1992

The antioxidant potential of propofol (2,6-diisopropylphenol).

We have examined in vitro the antioxidant properties of 2,6-diisopropylphenol. In studies using electron spin resonance spectroscopy we have demonstrated that 2,6-diisopropylphenol acts as an antioxidant by reacting with free radicals to form a phenoxyl radical--a property common to all phenol-based free radical scavengers. In additional experiments, the antioxidant properties of the clinical formulation of 2,6-diisopropylphenol (propofol) have been measured using an assay of antioxidant potential. In these experiments, propofol, but not Intralipid, was found to exhibit significant antioxidant activity, such that in the range of propofol concentrations examined (10(-6)-10(-5) mol litre-1), each molecule of 2,6-diisopropylphenol was able to scavenge two radical species. We conclude that the free radical scavenging properties of 2,6-diisopropylphenol resemble those of the endogenous antioxidant alpha-tocopherol (vitamin E).

Antioxidants↗

PubMed1992

Auditory evoked response and awareness: a study in volunteers at sub-MAC concentrations of isoflurane.

We have investigated the relationship between the auditory evoked response (AER) and simple tests of conscious awareness at four end-expiratory concentrations (0.0, 0.1, 0.2 and 0.4 MAC) of isoflurane in oxygen in each of eight anaesthetist volunteers, in random order, at least 1 week apart. The early cortical AER was recorded from electrodes at the vertex and inion. Amplitudes of the waves Pa, Nb and Pc and latencies of the waves Na, Pa, Nb, Pb and Nc were measured. All the AER variables were highly significantly related to end-expiratory anaesthetic concentration. Amplitudes decreased and latencies increased progressively with increasing anaesthetic concentration. The AER variables were also highly significantly related to the level of response. Amplitudes were greatest and the latencies shortest when there was full response to command. (Nb latency increased from 47.5 to 54.5 ms between partial and no response.) The close correlation between the effects of concentration and level of response, and between concentration and the AER implied that it was difficult to demonstrate those changes in the AER which specifically relate to changes in response. At 0.2 MAC, however, which was the concentration at which all subjects showed some deficit, the response to a shock word was distinguished clearly by Nb latency. In eight of 24 possible comparisons (eight AER variables and three types of psychological test) the AER fitted the response more closely than concentration.

Awareness↗

PubMed1991

Direct detection of free radical generation in an in vivo model of acute lung injury.

Electron spin resonance (ESR) spectroscopy has been used to provide direct evidence that free radical production occurs in an in vivo model of acute lung injury. Two experimental groups of rabbits were given the spin trap alpha-phenyl N-tert.-butyl nitrone (PBN), together with endotoxin in the test group, and saline in the control group. Both groups were subsequently briefly ventilated with air containing cigarette smoke. Plasma samples from the endotoxin pretreated group showed a sudden burst of radical formation, detected as PBN spin adduct, which peaked in the first ten minutes after smoke exposure. No signals were detected in the control group. Permeability of the alveolar capillary barrier of the lung, measured by the clearance of 99mTc-DTPA, demonstrated significantly greater damage following smoke in the endotoxin primed animals than in the controls. Temporal studies suggest that this increase in permeability occurred after a burst of radical production. These studies provide supportive evidence for the hypothesis that endotoxin promotes the accumulation of a population of primed white cells within the lung, which when triggered by cigarette smoke, are able to generate a burst of free radicals which produce tissue damage and acute lung injury.

Animals↗

PubMed1990

Levels of consciousness in volunteers breathing sub-MAC concentrations of isoflurane.

Eight volunteers inhaled isoflurane in concentrations of 0.1, 0.2 and 0.4 MAC, and 100% oxygen as control in separate sessions more than 1 week apart. When the end-expiratory isoflurane concentration was stable, response to verbal commands was tested, and the subjects were read 30 words in two lists. Response to the commands was impaired at 0.1 MAC in three subjects and lost at 0.2 MAC in two subjects. No subject responded at 0.4 MAC. When the subjects were questioned 1 h after exposure, memory of response to commands was lost also at these concentrations. Frequently, those who responded to the command "open your eyes" failed to remember having done so; non-responders remembered nothing. At the time of that test, at 0.4 MAC, five of eight subjects had no eyelash reflex. Both recall and recognition of neutral words was lost at 0.2 MAC and greater, but the effect of attention was demonstrated by the memory of a "shock" word by four of eight subjects at 0.2 MAC.

Adult↗

PubMed1990

Hyperoxia and salicylate metabolism in rats.

Following the administration of aspirin to rats by gavage, both 2,3- and 2,5-dihydroxybenzoate appeared in the plasma. The concentration of the 2,3-dihydroxybenzoate was significantly higher in animals exposed to 100% O2 for 60 h than in air breathing controls. These data are evidence that increased salicylate hydroxylation is associated with oxidative stress.

Animals↗

PubMed1990

Time course of changes in lung permeability and edema in the rat exposed to 100% oxygen.

Rats were exposed to 100% oxygen for up to 60 h to determine early changes in lung permeability leading to the development of pulmonary edema. The time course of development of increased solute flux was assessed by the clearance of 99mTc-labeled diethylenetriamine pentaacetate (99mTc-DTPA) from the lung and the accumulation of 125I-labeled albumin (125I-albumin) in the lung. These end points were related to the development of pulmonary edema by the measurement of the wet-to-dry weight ratio of the lung and the weight of fluid in the pleural cavity. No significant changes occurred until 48 h of hyperoxia, when sharp increases in both indexes of lung permeability and wet-to-dry weight ratio occurred. By 60 h of exposure, pleural effusions had developed. The volume of this effusion was significantly correlated to both 99mTc-DTPA clearance and 125I-albumin flux.

Albumins↗