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Biomedical subjects

N R Webster

Publications and source records attributed to N R Webster.

At least 37 records · Page 2Linked to original sources
PubMed2000

Phase II multicenter clinical study of the platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis.

OBJECTIVE: To evaluate the safety and efficacy of the platelet-activating factor receptor antagonist BB-882 in the treatment of patients with sepsis. DESIGN: Double-blind, placebo-controlled, randomized, multi-centered study. SETTING: Thirty-four European intensive care units. PATIENTS: One hundred fifty-two patients with clinical suspicion of infection and a mean APACHE II score between 15 and 35 in the 24 hrs before entry into the trial. INTERVENTIONS: Patients received either a loading dose of 4 mg of BB-882 on the first day, followed by an intravenous infusion of 96 mg/24 hrs for up to 120 hrs, or placebo. MEASUREMENTS: Hemodynamic, respiratory and oxygen transport variables, blood lactate concentrations, interleukin-6, interleukin-8, tumor necrosis factor (TNF)-alpha, soluble TNF receptor concentrations, organ failure score, 28-day mortality rate, Acute Physiology And Chronic Health Evaluation (APACHE) II score within 24 hrs of entry. RESULTS: Sixty-nine patients (42 male, 27 female) received placebo and 83 (59 male, 24 female) received BB-882. Patients ranged in age from 16 to 89 yrs (mean, 60 yrs). No important differences existed between the two groups in terms of gender distribution, age, or initial APACHE II score. Sepsis was identified as Gram-positive in 49 patients, Gram-negative in 40, mixed in 37, and unknown in 26. No important differences were shown in hemodynamic, respiratory, or oxygen transport variables between groups during the study. Organ failure scores were similar in the two groups throughout the study. Cytokine concentrations were not significantly different in the two groups. Within 28 days of entering the study, 75 patients died, including 31 (45%) in the placebo group and 44 (53%) in the treatment group, p = .32. The median time to death in the placebo group was 6.0 days, and in the treatment group, it was 4.5 days (p = .30). CONCLUSION: Treatment of sepsis with the platelet-activating factor antagonist BB-882 offers no advantage over placebo on survival, hemodynamic status, respiratory function, or organ failure scores.

APACHE↗
PubMed2000

Increased nuclear factor kappa B activation in critically ill patients who die.

OBJECTIVES: To determine nuclear factor kappa B (NF-kappa B) activation in mononuclear and neutrophils from critically ill patients and to compare NF-kappa B activation with circulating concentrations of interleukin (IL)-6, IL-8, and soluble intercellular adhesion molecule (sICAM)-1. DESIGN: Observational study. SETTING: University Teaching Hospital, eight-bed intensive care unit in northeast Scotland. PATIENTS: Ten patients admitted to the intensive care unit who fulfilled the criteria for systemic inflammatory response syndrome were studied at 0, 24, 48, and 72 hrs. Six healthy volunteers were also studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: NF-kappa B activation was significantly higher in patients compared to healthy volunteers in both neutrophils (p = .001) and mononuclear leukocytes (p = .013). In the six patients who survived to 96 hrs, the level of NF-kappa B activation in mononuclear cells remained constant (p = .9). However, in the four patients who died before 96 hrs, mononuclear cell NF-kappa B activation increased markedly and was significantly higher before death than in those who survived to 96 hrs (p = .0105). NF-kappa B activation in neutrophils similarly remained constant in patients who survived to 96 hrs (p = .4) but did not show the same increase before death. Circulating concentrations of IL-6, IL-8, and sICAM-1 were elevated but were unrelated to leukocyte NF-kappa B activation. CONCLUSIONS: We found NF-kappa B activation in mononuclear and neutrophils in patients with systemic inflammatory response syndrome, which increased markedly before death in mononuclear leukocytes and was not related to plasma IL-6, IL-8, and sICAM-1 concentrations. These data support the need for further study of the role of NF-kappa B activation in mortality from systemic inflammatory response syndrome and sepsis.

APACHE↗
PubMed2000

Effect of inhaled nitric oxide on key mediators of the inflammatory response in patients with acute lung injury.

OBJECTIVE: Inhaled nitric oxide is used to treat hypoxia associated with acute lung injury. Endogenous nitric oxide regulates inflammatory responses, but the effect of inhaled nitric oxide therapy is unknown. We hypothesized that inhaled nitric oxide may alter inflammatory responses and endogenous nitric oxide synthase activity. DESIGN: A randomized, prospective interventional study. SETTING: A university hospital's general intensive care unit. PATIENTS: Thirty-two patients with acute lung injury. INTERVENTIONS: Patients who responded to test doses of nitric oxide were randomized to ventilator therapy with and without inhaled nitric oxide. The inhaled concentration of nitric oxide was determined by dose titration at 0, 2, 10, and 40 ppm and the minimum concentration used, which resulted in an increase in the PaO2/FIO2 ratio of at least 25%. MEASUREMENTS AND MAIN RESULTS: Patients were followed up for 30 days or until death, and bronchoalveolar lavage (BAL) was performed at 0, 24, and 72 hrs. Nitric oxide synthase activity was measured spectrophotometrically, and myeloperoxidase, elastase, interleukin-8, and leukotrienes were measured in BAL fluid by enzyme immunoassay. Total nitrite and lipid peroxides in serum were measured colorimetrically. Nitric oxide synthase activity decreased (p = .01) and total nitrite increased (p = .02) in patients receiving inhaled nitric oxide. Other markers of inflammation in BAL fluid did not change. Lipid peroxide concentrations also did not alter. CONCLUSIONS: The decrease in activity of nitric oxide synthase in patients receiving nitric oxide is likely to be the result of feedback inhibition of the enzyme. This study shows that inhaled nitric oxide has no effect on several markers of the inflammatory response system and does not lead to increased oxidant stress.

Acute Disease↗
PubMed2000

Sepsis and the systemic inflammatory response syndrome.

Sepsis and the systemic inflammatory response syndrome are common and represent a major factor in morbidity and mortality in intensive care units and the critically ill. The pathogenesis of these syndromes is becoming increasingly understood and it is hoped that this will result in improved outcome. However, novel treatments have so far failed to live up to the expectations following extensive and promising in vitro and in vivo animal studies. The aim of this review is to detail the currently used definitions of systemic inflammatory response syndrome, sepsis and septic shock and to present an overview of our current understanding of the pathophysiology which underline these conditions.

Biomarkers↗
PubMed2000

Effect of ciprofloxacin on the activation of the transcription factors nuclear factor kappaB, activator protein-1 and nuclear factor-interleukin-6, and interleukin-6 and interleukin-8 mRNA expression in a human endothelial cell line.

Quinolone antibiotics such as ciprofloxacin modify immune and inflammatory responses in some cells. We have shown previously that ciprofloxacin decreases the accumulation of interleukin (IL)-6 protein from a human endothelial cell line, whilst IL-8 protein production was increased. It is not known whether this occurs through effects on transcription and mRNA expression. We therefore investigated the effect of ciprofloxacin on mRNA for IL-6 and IL-8, and on three transcription factors known to be involved in the regulation of these cytokines. We investigated the effect of ciprofloxacin on tumour necrosis factor alpha- and IL-1beta-mediated activation of the transcription factors nuclear factor kappaB (NFkappaB), activator protein-1 (AP-1) and nuclear factor IL-6 (NF-IL-6) using an electrophoretic mobility shift assay, and the effect on expression of mRNA for IL-6 and IL-8 by reverse transcriptase-PCR in the EAhy926 endothelial cell line. Ciprofloxacin decreased IL-6 mRNA (P<0.05) and increased IL-8 mRNA (P<0.05) expression. Ciprofloxacin did not modulate activation of NFkappaB or AP-1. However, NF-IL-6 binding was decreased in the presence of 100 microg/ml ciprofloxacin (P<0.05). The study shows that ciprofloxacin-mediated decreased IL-6 release by a human endothelial cell line is reflected by decreased mRNA expression and decreased NF-IL-6 but not NFkappaB or AP-1 activation. Increased IL-8 mRNA in response to ciprofloxacin was not reflected by altered transcription factor activation and may represent increased mRNA stability.

Anti-Infective Agents↗
PubMed2000

Why is the patient still hypoxic despite being ventilated?

The passage of oxygen from the atmosphere to the mitochondria is a complex process. Pathological conditions may affect this transfer at any step. The patient on the intensive care unit is particularly likely to be affected by disease or iatrogenic intervention. Hypoxia may be caused by an abnormal supply of oxygen, abnormalities of gas exchange, deficient transport in the blood or alterations in localized tissue utilization. An understanding of the principles involved will enable effective interpretation and subsequent management of the hypoxic patient.

Critical Care↗
PubMed2000

Nutrition in the critically ill patient.

Critically ill patients are hypermetabolic and have increased nutrient requirements. Although it is assumed that nutritional support is beneficial in this group of patients there are no well designed clinical trials to test this hypothesis. The rationale for nutritional support, therefore, is based upon clinical judgement. Although it is not known how long a critically ill patient can tolerate what is effectively starvation, the loss of lean tissue which occurs in catabolic patients (20-40 g nitrogen/day) suggests that depletion to a critical level may occur after 14 days. Total parenteral nutrition given to malnourished patients with gastrointestinal cancer for 7 to 10 days before surgery has been shown to decrease complications by about 10%. Wound healing and normal immune responses are dependent upon adequate nutrient intake, and it seems reasonable, therefore, to commence feeding as soon as possible. Earlier feeding may decrease length of stay and complication rates in both critically ill patients and following surgery. It has been shown in randomised controlled trials of both enteral and parenteral feeding in the critically ill, that current regimens are sub-optimal. Calorie intake was shown to be often considerably in excess of metabolic requirements alone, and variable study design has made comparisons impossible. Despite the lack of knowledge regarding even the most simple of nutritional requirements in these patients, the administration of specific micronutrients and specialised supplements has attracted attention. Again, many of these more recent studies are limited because of poor study design.

Arginine↗
PubMed1999

Increased mortality associated with growth hormone treatment in critically ill adults.

BACKGROUND: The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. METHODS: We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [+/-SD] daily dose, 0.10 +/- 0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. RESULTS: The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group. CONCLUSIONS: In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality.

Adolescent↗
PubMed1999

T helper cell subset ratios in patients with severe sepsis.

BACKGROUND: T helper 1 (Thl) lymphocytes produce interferon gamma (IFNgamma), favouring cell mediated immunity; Th2 cells secrete interleukin-4 (IL-4), favouring humoral immunity. Cytokines produced in sepsis may effect Th subset predominance and subsequent immune responses. METHODS: We measured Th subsets in ten patients with severe sepsis, seven APACHE II score-matched non-septic critically ill control patients, and ten healthy subjects. Mononuclear leukocytes were isolated and Th subsets identified by flow cytometry. RESULTS: The median (range) Th1/Th2 ratio was 0.46 (0.2-2.5) in patients with sepsis, which was significantly lower than both non-septic controls (median 2.5 (0.2-5.9), p = 0.050) and healthy subjects (median 3.9 (1.2-10.8), p = 0.01). CONCLUSIONS: In patients with sepsis, Th2 antibody mediated (humoral) immune responses predominate. This type of response may lead to fibroblast activation and ultimately immunosuppression. Modulation of Th cell subset predominance may present a novel therapeutic option in the treatment of severe sepsis.

APACHE↗
PubMed1999

Acidosis and tissue hypoxia in the critically ill: how to measure it and what does it mean.

We routinely monitor blood gases to determine the adequacy of ventilation and the presence of acid-base abnormalities. Changes in the blood are easily assessed, but of more importance is the abnormality at tissue level. Defects in acid-base homoeostasis have major effects on protein function, thus affecting tissue and organ performance. We concentrate on the changes seen in critically ill patients with acidosis because they form a large portion of the workload of the average intensive care unit. In addition, such patients have significant morbidity and mortality. The development of acidemia in the critically ill is often attributed to reductions in oxygen utilization, which in the past has generally been regarded as dysregulation of tissue blood supply. Resulting tissue hypoperfusion leads to anaerobic metabolism and lactic acidosis. Carbon dioxide production increases as anaerobically produced hydrogen ions are buffered by extracellular bicarbonate. The effectiveness of tissue perfusion is the target of much research, and in this review we outline factors that affect tissue acid-base status, techniques to measure tissue acid-base status, and explore the relationship between tissue acidosis and hypoxia in the critically ill. However, things are not always as simple as they may first appear.

Acid-Base Equilibrium↗
PubMed1999

Metabolic alkalosis in the critically ill.

Metabolic alkalosis is the commonest form of acid-base disorder seen in critically ill patients. Although the effects of acidosis have long been known, those of severe metabolic alkalosis are only slowly being recognized. Metabolic alkalosis is itself associated with an increased mortality and a knowledge of the causative factors and treatment options is important. In one study, around 50% of general surgical patients developed postoperative metabolic alkalosis, whereas other acid-base disturbances were uncommon. Metabolic alkalosis results from an accumulation of alkali or a loss of acid. Clinical signs are nonspecific but dehydration may be prominent because of a contraction of the extracellular fluid volume due to loss of chloride. Metabolic alkalosis leads to hypoventilation in patients both with and without lung disease, although in the latter, the effect is relatively transient. In patients with chronic obstructive lung disease, however, the development of metabolic alkalosis leads to prolonged hypoventilation and the establishment of a mixed acid-base disorder that may cause difficulty in weaning in the ventilated patient. This is an often forgotten cause of prolonged stay in the intensive care unit with consequent cost and morbidity implications.

Acetazolamide↗
PubMed1999

Mitochondrial redox state in the critically ill.

Abnormal oxygen use and organ failure in the critically ill may result from 'poisoning' of mitochondrial function. Measurement of arterial ketone body ratio (AKBR) has been proposed to reflect mitochondrial redox state and may provide a useful marker to monitor mitochondrial function in the critically ill. We measured AKBR (acetoacetate to beta-hydroxybutyrate) and plasma lactate concentrations in 20 critically ill patients, on 3 consecutive days after admission to the intensive care unit. Nine (45%) patients died (five with sepsis) within the 30-day follow-up period. AKBR increased significantly over the 3 days of the study in patients who died (P = 0.034) and decreased in those who survived (P < 0.0001). In addition, there was a significant difference between survivors and non-survivors (P = 0.015). We conclude that serial AKBR measurement may be useful in the management of septic patients.

3-Hydroxybutyric Acid↗