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Biomedical subjects

N R Webster

Publications and source records attributed to N R Webster.

At least 73 records · Page 4Linked to original sources
PubMed1997

Changes in inflammatory mediators during orthotopic liver transplantation.

Transplantation is associated with an inflammatory rejection response. Graft reperfusion causes typical haemodynamic and biochemical responses. In this study we have investigated the relationship between these haemodynamic responses and changes in circulating inflammatory mediators after graft reperfusion in 10 consecutive patients undergoing orthotopic liver transplantation. After reperfusion, systemic vascular resistance index decreased (P = 0.011) and cardiac index increased (P = 0.038). These characteristic haemodynamic changes of the reperfusion syndrome were accompanied by global increases in cytokine concentrations. Plasma concentrations of leukotrienes decreased, while thromboxane B2 and platelet activating factor remained increased throughout. Reperfusion-mediated changes in inflammatory mediators may account for the haemodynamic disturbance.

Adult↗
PubMed1997

Effect of ciprofloxacin on the accumulation of interleukin-6, interleukin-8, and nitrite from a human endothelial cell model of sepsis.

OBJECTIVE: To determine the effect of the quinolone antibiotic ciprofloxacin, on interleukin-6, interleukin-8, and nitrite production by human endothelial cells. DESIGN: Controlled cell culture experiments examining the immunomodulatory effects of an antibiotic. SETTING: University research laboratory attached to a large teaching hospital. SUBJECTS: A human endothelial cell line. MEASUREMENTS AND MAIN RESULTS: Cells were incubated with tumor necrosis factor-alpha and interleukin-1beta in the presence of a range of ciprofloxacin concentrations. Interleukin-6, interleukin-8, and nitrite concentrations were measured in culture supernatants after 24 hrs using enzyme immunoassay. Ciprofloxacin decreased interleukin-6 accumulation (p = .001). Interleukin-8 was decreased at lower ciprofloxacin concentrations (p = .017) but was increased at 100 microg/mL (p = .0039). Ciprofloxacin had no effect on nitrite accumulation (p = .38). CONCLUSIONS: Ciprofloxacin differentially modulates interleukin-6 and interleukin-8 expression. The response to infection is coordinated by a cascade of cytokines and other mediators. The widespread use of ciprofloxacin in patients with severe infections is likely to result in alterations in local concentrations of cytokines. Selective control of cytokine concentrations by antibacterial agents will clearly have important therapeutic implications and may be a future research consideration in antibiotic drug design.

Anti-Infective Agents↗
PubMed1996

Inhaled nitric oxide.

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Administration, Inhalation↗
PubMed1996

Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome.

OBJECTIVE: To determine serum bleomycin-detectable ¿free' iron in patients with septic shock and to relate these findings to both outcome and a marker of free radical damage. DESIGN: A prospective observational study. SETTING: A nine-bed intensive care unit in a university teaching hospital. PATIENTS: Sixteen consecutive patients with septic shock, defined as: (1) Clinical evidence of acute infection; (2) hypo- or hyperthermia ( < 35.6 degrees or > 38.3 degrees C); (3) tachypnoea ( > 20 breaths/min or ventilated); (4) tachycardia ( > 90 beats min); (5) shock (systolic pressure < 90mmHg) or on inotropes. Fourteen patients also had secondary organ dysfunction. MEASUREMENTS AND RESULTS: Bleomycin-detectable iron concentrations were elevated in all patients (37.2 +/- 11.0 mumols/l vs 5.1 +/- 3.3 mumols/l in healthy subjects, P < 0.0001), but there was no difference between patients who died and those who survived (39.2 +/- 9.3 and 36.2 +/- 12.3 mumols/l, respectively). Thiobarbituric acid reactive substances (an index of lipid peroxidation) were higher in those who died (3.33 +/- 2.29 mumols/l) than in the surviving patients (0.99 +/- 0.14 mumols/l, P < 0.01) or healthy subjects (0.92 +/- 0.39 mumols/l, P < 0.01). Free iron did not correlate with thiobarbituric acid-reactive substances. However, a significant correlation was found between lipid peroxidation and clinical severity (APACHE II) score (r = 0.54, P < 0.05). CONCLUSIONS: The present study provides evidence of lipid peroxidation in patients who die with septic shock. The data suggest that iron-catalysed hydroxyl radical generation does not form an important contribution to this lipid peroxidation in patients with sepsis.

APACHE↗
PubMed1996

Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading.

Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage. Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions. We measured baseline total vitamin C and bleomycin-detectable "free" iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects. Vitamin C concentrations were decreased in patients compared to healthy subjects (p < 0.0001), and "free" iron was increased (p < 0.002). Preinfusion ascorbyl radical concentrations were not different in patients and controls. Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls. In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging. This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised "free" iron levels.

Anti-Bacterial Agents↗
PubMed1996

Regulation of nitric oxide synthase activity in cultured human endothelial cells: effect of antioxidants.

Nitric oxide release is induced in many cells, including vascular endothelium, as part of the host response to inflammation. Nitric oxide synthase activity is increased in patients with sepsis, associated with increased oxidant demands and decreased antioxidant protection. We used a human vascular endothelial cell line to investigate the influence of antioxidants on nitric oxide synthase activity. Cells were cultured to confluence and incubated with interferon gamma, tumor necrosis factor, and lipopolysaccharide in the combined presence of the antioxidants ascorbic acid, Trolox, catalase, or superoxide dismutase, singly and in combination, for 48 h. Additionally, some cells were incubated with hypoxanthine-xanthine oxidase or a nitric oxide donor. Nitric oxide synthase activity was upregulated by cytokine exposure (p < .0005). Ascorbic acid and superoxide dismutase/ catalase resulted in decreased enzyme activity (p < .05). Superoxide anion release from xanthine oxidase caused increased activity (p < .05) and exogenous nitric oxide tended to suppress synthase activity. We suggest that antioxidants scavenge superoxide anion, enabling feedback inhibition of nitric oxide synthase activity by nitric oxide, and thus reducing enzyme activity. Exogenous nitric oxide also has a similar effect. Superoxide generation suppresses this feedback inhibition. This study has important implications in patients with sepsis in whom nitric oxide synthase inhibitor therapy is currently under investigation.

Animals↗
PubMed1996

Soluble E-cadherin concentrations in patients with systemic inflammatory response syndrome and multiorgan dysfunction syndrome.

We have assessed the role of the cell-cell adhesion molecule, E-cadherin, in the pathogenesis of multiorgan failure in 24 intensive care patients with sepsis and varying degrees of organ dysfunction, compared with 21 healthy subjects. Plasma soluble E-cadherin (sE-cadherin) was measured by enzyme immunoassay. The median concentration of sE-cadherin in normal subjects was 3.21 micrograms ml-1 compared with 6.00 micrograms ml-1 in patients with sepsis and organ dysfunction (P = 0.0019). There was no statistically significant difference in concentrations of sE-cadherin in survivors compared with non-survivors. Concentrations of sE-cadherin tended to increase with the severity of organ failure. We conclude that sE-cadherin is increased in inflammation and injury, and may be related to the degree of multiorgan failure after sepsis.

APACHE↗
PubMed1996

Brain nitric oxide synthase activity is decreased by intravenous anesthetics.

Nitric oxide is produced from L-arginine in a variety of cells, and in neuronal tissue, by the action of nitric oxide synthase. Inhibitors to nitric oxide synthase reduce the threshold for anesthesia and anesthetics reduce nitric oxide synthase activity in neutrophils. We investigated the effect of four intravenous anesthetics and an anticonvulsant on rat brain nitric oxide synthase activity using the stoichiometric conversion of oxyhemoglobin to methemoglobin by nitric oxide. Enzyme activity was assayed in the presence of 0, 0.01, 0.1, and 1.00 microM thiopental, ketamine, etomidate, midazolam, and phenytoin. Thiopental (P = 0.001), ketamine (P = 0.0002), midazolam (P = 0.0024), and etomidate (P = 0.0006) caused a decrease in nitric oxide synthase activity. Phenytoin had no effect on enzyme activity. We conclude that the intravenous anesthetics, but not the nonsedative anticonvulsant tested, have a significant effect on neuronal nitric oxide synthase activity.

Anesthetics, Intravenous↗
PubMed1996

Plasma antioxidant potential in severe sepsis: a comparison of survivors and nonsurvivors.

OBJECTIVE: To determine the plasma antioxidant potential of patients in the intensive care unit (ICU) with severe sepsis and secondary organ dysfunction and relate these findings to outcome. DESIGN: A prospective, cohort study. SETTING: A nine-bed ICU in a university teaching hospital. PATIENTS: Fifteen consecutive patients, who were within 16 hrs of development of severe sepsis and secondary organ dysfunction. INTERVENTIONS: Plasma samples were obtained within 16 hrs of the onset of secondary organ dysfunction and subsequently on days 2, 3, 4, 6, 8, 10, and 15 until patients either left the ICU or died. Plasma antioxidant potential was determined by an ultraviolet spectrophotometric technique. MEASUREMENTS AND MAIN RESULTS: The mean initial plasma antioxidant potential was lower than our range for healthy volunteers (p < .05). Survivors had an initial plasma antioxidant potential that was greater than nonsurvivors (p < .01), and serial subset analysis demonstrated that survivors, despite having a low initial plasma antioxidant potential rapidly attained normal or supranormal values. While plasma antioxidant potential also increased in nonsurvivors over time, values in this subset never reached the normal range and remained below values in survivors at all time points studied (p < .05). CONCLUSIONS: Plasma antioxidant potential is initially decreased in patients with sepsis who develop organ dysfunction, and it increases over time. While we have no clear evidence to prove that this reduction has a causal relationship, failure to achieve a normal plasma antioxidant potential is strongly associated with an unfavorable outcome.

APACHE↗
PubMed1996

Xanthine oxidase activity and free radical generation in patients with sepsis syndrome.

OBJECTIVE: To determine xanthine oxidase activity, free radical concentrations, and lipid peroxidation in patients with sepsis syndrome compared with noninfected critically ill patients. DESIGN: A prospective observational study. SETTING: A nine-bed intensive care unit in a university teaching hospital trust. PATIENTS: Fourteen consecutive patients who met the established criteria for sepsis syndrome with multiple organ dysfunction syndrome, and ten noninfected critically ill patients were studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Xanthine oxidase activity was increased in septic patients compared with both healthy volunteers (p < .01) and noninfected patients (p < .05), and was highest in the six patients who survived (p < .05). Lipid peroxides were increased in both septic patients (p < .001) and nonseptic controls (p < .001). Xanthine oxidase activity did not relate to the Acute Physiology and Chronic Health Evaluation (APACHE) II score or to the presence of organ dysfunction. The mean ascorbyl radical concentration (arbitrary units) determined by electron paramagnetic resonance following spin trapping was increased in patients compared with healthy subjects (p < .05). CONCLUSIONS: Patients with sepsis have xanthine oxidase activation, high free-radical concentrations, and evidence of free radical damage. The finding that xanthine oxidase activity was lower in those patients who died, coupled with increased lactate concentrations implies more severe ischemia with incomplete reperfusion resulting in less xanthine oxidase "wash out" into the circulation. Increased ascorbyl radical concentrations may be due to an increased radical generation and oxidant scavenging, but appears to be unrelated to xanthine oxidase activity within the circulation.

APACHE↗
PubMed1996

Central venous line sepsis in the intensive care unit. A study comparing antibiotic coated catheters with plain catheters.

A randomized controlled clinical trial was undertaken to evaluate the efficacy of antibiotic bonded lines in the reduction of central venous catheter infection. One hundred and seventy-six plain and bonded catheters were inserted into one hundred and ten patients in an intensive care unit, many of whom were admitted with evidence of sepsis. The catheters used in the study group, which had been pre-treated by the manufacturers with the cationic surfactant tridodecylmethylammonium chloride, were bonded with vancomycin 1 g made up in 10 ml of water immediately prior to insertion. The catheters used in the control group were neither pre-treated nor bonded with vancomycin. Eighty percent of control group catheters were infected compared with 62% of study catheters (p = 0.01). The most common organism isolated was coagulase negative staphylococcus. We conclude that antibiotic bonding can reduce central venous catheter infection even in a patient population with a high incidence of sepsis.

Anti-Bacterial Agents↗
PubMed1996

Mediators of fibrinolysis in orthotopic liver transplantation.

Activation of fibrinolysis remains a clinical problem in orthotopic liver transplantation. We have measured tissue plasminogen activator (t-PA), plasmin and alpha-2-anti-plasmin (alpha 2AP) activities in plasma from 10 patients undergoing elective transplantation. t-PA activity increased during the anhepatic phase and immediately after graft reperfusion (p > 0.001). This increase could not be attributed to t-PA released by the donor liver. Overall transfusion requirements did not relate with either t-PA or alpha 2AP activities individually, but were strongly correlated with the ratio t-PA/ alpha 2AP (p > 0.02). These results suggest that routine prophylactic use of antifibrinolytic agents may be beneficial.

Adult↗
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↗