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Xavier Wittebole

Publications and source records attributed to Xavier Wittebole.

15 recordsLinked to original sources
PubMed2006

Use of an integrated clinical trial database to evaluate the effect of timing of drotrecogin alfa (activated) treatment in severe sepsis.

INTRODUCTION: Several studies have indicated that early identification and treatment of patients with severe sepsis using standard supportive care improves outcomes. Earlier treatment with drotrecogin alfa (activated) (DrotAA) may also improve outcomes in severe sepsis. Using a recently constructed integrated severe sepsis database, our objectives in this study were to describe the influence of baseline clinical characteristics on timing of DrotAA treatment in patients with severe sepsis, to evaluate the efficacy of DrotAA with respect to timing of administration, and to examine the association between early intervention with DrotAA and patient outcomes, using adjustments for imbalances. METHODS: The database comprises data from 4,459 patients with severe sepsis (DrotAA, n = 3,228; placebo, n = 1,231) included in five clinical trials conducted in tertiary care institutions in 28 countries. Placebo data came only from randomized trials, whereas data for the DrotAA group came from randomized (PROWESS) and open-label/observational (ENHANCE) trials. RESULTS: Increased time-to-treatment with DrotAA was significantly associated with more organ dysfunction, greater need of mechanical ventilation, vasopressor use, or recent surgery. Earlier treatment was associated with higher baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. Adjusted and unadjusted survival analyses suggested that compared with placebo, DrotAA treatment provided a potential survival benefit, regardless of time to treatment. Survival curves of DrotAA patients treated early compared with those treated late began to separate at 14 days. By 28 days, patients treated earlier had higher survival than those treated later (76.4% versus 73.5%, p = 0.03). Sepsis-induced multiorgan dysfunction was the most common cause of death followed by refractory shock and respiratory failure. Modeling of the treatment effect, as a function of time to treatment, suggested increased benefit with earlier treatment. CONCLUSION: Using an integrated database of five severe sepsis trials and appropriate statistical adjustments to reduce sources of potential bias, earlier treatment with DrotAA seemed to be associated with a lower risk-adjusted mortality than later treatment. These data suggest that earlier treatment with DrotAA may provide most benefit for appropriate patients.

Adult↗
PubMed2006

Pharmacological inhibition of tissue factor.

Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies.

Animals↗
PubMed2005

Electrocardiographic changes after head trauma.

We report the case of a patient who developed, a few days after a closed head injury, marked electrocardiographic changes mimicking an acute coronary event, in the absence of actual cardiac damage. The electrocardiographic changes were fully reversible, paralleling the neurologic status. Neuroimaging examinations excluded subarachnoid hemorrhage or space-occupying hematoma, but demonstrated diffuse axonal injury using susceptibility-weighted magnetic resonance techniques. This kind of traumatic brain injury thus may be responsible for a pseudo-acute myocardial ischemic syndrome.

Adult↗
PubMed2005

A pilot-controlled study of a polymyxin B-immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-abdominal infection.

Endotoxin is an important pathogenic trigger for sepsis. The polymyxin B-immobilized endotoxin removal hemoperfusion cartridge, Toraymyxin (hereafter PMX), has been shown to remove endotoxin in preclinical and open-label clinical studies. In a multicenter, open-label, pilot, randomized, controlled study conducted in the intensive care unit in six academic medical centers in Europe, 36 postsurgical patients with severe sepsis or septic shock secondary to intra-abdominal infection were randomized to PMX treatment of 2 h (n = 17) or standard therapy (n = 19). PMX was well tolerated and showed no significant side effects. There were no statistically significant differences in the change in endotoxin levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups. There was also no significant difference in the change in interleukin (IL)-6 levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups. Patients treated with PMX demonstrated significant increases in cardiac index (CI; P = 0.012 and 0.032 at days 1 and 2, respectively), left ventricular stroke work index (LVSWI, P = 0.015 at day 2), and oxygen delivery index (DO2I, P = 0.007 at day 2) compared with the controls. The need for continuous renal replacement therapy (CRRT) after study entry was reduced in the PMX group (P = 0.043). There was no significant difference between the groups in organ dysfunction as assessed by the Sequential Organ Failure Assessment (SOFA) scores from day 0 (baseline) to day 6. Treatment using the PMX cartridge is safe and may improve cardiac and renal dysfunction due to sepsis or septic shock. Further studies are needed to prove this effectiveness.

Adult↗
PubMed2004

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

Compartmentalization of the inflammatory response during acute pancreatitis: correlation with local and systemic complications.

Local and systemic inflammation has been implicated in the pathogenesis of acute pancreatitis and secondary multisystem organ failure. To assess the pro- and antiinflammatory response, the site of mediator production, and their route of diffusion, we sampled simultaneously ascites, thoracic lymph, and blood at the onset of end-organ dysfunction and for the following 6 days in 60 patients with acute pancreatitis. We used immunoassays to measure pro- and antiinflammatory cytokines and cell-based bioassays to assess the net pro- and antiinflammatory activity elicited by the biological fluids. Tumor necrosis factor-alpha and interleukin-1beta were detected in less than 15% of blood and lymph samples. Secondary pro- and antiinflammatory cytokines were found to be elevated early and throughout the sampling period in all compartments. Cytokine levels decreased from ascites to lymph to blood, suggesting a splanchnic origin. Prolonged diversion of ascites and lymph did not alter cytokine gradients, suggesting mediator transfer via the splanchnic blood circulation. Although a net proinflammatory activity ascribed to interleukin-1beta was detected in ascites, a net antiinflammatory activity was measured in virtually all lymph and blood samples, suggesting that the pancreas and the splanchnic area are sites of a proinflammatory response and that an early, dominant, and sustained antiinflammatory activity takes place in circulating compartments.

Ascitic Fluid↗
PubMed2003

Clinical review: Drotrecogin alfa (activated) as adjunctive therapy for severe sepsis--practical aspects at the bedside and patient identification.

Administration of drotrecogin alfa (activated) has been demonstrated to reduce mortality in patients with severe sepsis who are at high risk for death or who have multiple organ dysfunction. This benefit was associated with an increased incidence of bleeding events, but the latter were mainly procedure related. Drug infusion interruptions should be instituted, in accordance with recent recommendations. Monitoring coagulation parameters may help in identifying patients at higher risk for bleeding but it is not indicated to adjust drug dosage. Acute renal failure and hemodialysis are not contraindications to this therapy, and no drug dosage adjustment is indicated. Finally, the type and source of infection, and its anticipated natural history, may determine whether drotrecogin alfa (activated) is indicated as well as the timing of its administration.

Anti-Infective Agents↗
PubMed2003

Defibrination and systemic bleeding caused by an imported African snakebite.

A 55-year-old man was referred from Burkina Fasso for coagulation disorders with severe spontaneous systemic bleeding. He had been bitten six days before by a snake that could not be definitely identified. No specific treatment had been started in Africa. The patient was admitted with severe anaemia, incoagulable blood with undetectable fibrinogen. Multiple haematomas in the chest and abdomen were found at computed tomography. Blood transfusions and the administration of fresh frozen plasma and fibrinogen did not result in any clinical or biological improvement. The clinical course was dramatically reversed after the infusion of two vials of Pasteur polyspecific antivenom (Echis-Bitis-Naja). According to the geographical distribution of this snake species, it seems very likely that the snakebite was caused by Echis ocellatus. Even given with delay, the antivenom was effective and well tolerated.

Antivenins↗
PubMed2003

Anticoagulant therapy in acute lung injury.

OBJECTIVE: To review the rationale for evaluating anticoagulant therapies in acute lung injury (ALI) and to review selected data regarding the effectiveness of anticoagulants in animals and human patients with ALI and acute respiratory distress syndrome. DATA SOURCES: Published literature on coagulation alterations and anticoagulant strategies in ALI during the past 25 yrs. DATA EXTRACTION AND SYNTHESIS: In the lung, alveolar and interstitial fibrin deposition are the hallmarks of early phase ALI. Local procoagulant activity and reduced fibrinolysis constitute the rationale for anticoagulant use in the treatment of ALI. An activated complex of tissue factor and factor VIIa triggers procoagulant activity in the lung, with subsequent thrombin formation and fibrin deposition. Increased pulmonary vascular permeability and leukocyte accumulation have been successfully prevented in animals treated with tissue factor/activated factor VII pathway inhibitor. In humans, a phase II study evaluating tissue factor pathway inhibitor in the treatment of severe sepsis suggested that lung function in acute respiratory distress syndrome patients was improved. However, the phase III trial failed to demonstrate a survival benefit; data regarding respiratory dysfunction have not yet been published. Heparin, despite effectively inhibiting thrombin formation, has not shown consistent benefits in reducing lung injury, and its efficacy has not yet been evaluated in a controlled study. Antithrombin administration in animals has shown consistent benefits with ALI, but clinical studies have failed to demonstrate reductions in mortality and lung injury. Activated protein C administration has been shown to improve survival and lung function in both animal and clinical studies. Soluble thrombomodulin has been shown to improve ALI in animals, and it is currently being evaluated in humans with sepsis. Finally, plasminogen activators may improve gas exchange in ALI, but studies in humans are limited.

Animals↗
PubMed2003

Surgical clipping may lead to better results than coil embolization: results from a series of 101 consecutive unruptured intracranial aneurysms.

OBJECTIVE: Recent reports in the literature have described a significant discrepancy in adverse outcomes between coil embolization (CE; 10%) and surgical clipping (SC; 25%) for the management of unruptured intracranial aneurysms (UIA). This discrepancy led us to analyze our experience. METHODS: In 1996, we designed a prospective study of patients with UIA in which CE was considered the treatment of choice and was performed if the interventional neuroradiologists deemed the aneurysm's fundus-to-neck ratio accessible for CE. SC was performed only if complete CE was unlikely to be achieved or in patients in whom CE already had failed. RESULTS: CE was performed in 38 patients with at least one UIA (41 UIAs, 83% in the anterior circulation). SC was performed in 39 patients with at least one UIA unsuitable for CE (59 UIAs, including 6 after failed CE, 96.5% in the anterior circulation). For CE, the total obliteration rate was 56.1%, the subtotal was 14.6%, and CE failed in 29.3%. There were transient complications in 10% of the cases and permanent complications in 7.5%. Of the 12 failed CE procedures, 7 (58%) were performed for middle cerebral artery aneurysms. For SC, the total obliteration rate was 93.2%, the subtotal was 1.7%, and SC failed (wrapping) in 5.1%. There were transient complications in 16.3% of the patients and permanent complications in 1.7%. The success rate for CE was similar to that for SC only when CE was used for aneurysms with a fundus-to-neck ratio of at least 2.5. CONCLUSION: SC can produce better results than CE in patients with UIA of the anterior circulation. CE as a first-line treatment should be reserved for patients with UIAs with a fundus-to-neck ratio of 2.5 or greater.

Adult↗
PubMed2002

Lipopolysaccharide-binding protein serum levels in patients with severe sepsis due to gram-positive and fungal infections.

Lipopolysaccharide-binding protein (LBP) is increased in patients with severe gram-negative infections, but LBP serum levels have not been reported for in patients with gram-positive and fungal infections. LBP serum levels were determined in patients with severe sepsis secondary to gram-positive or fungal infections and were compared with LBP serum levels obtained from patients with gram-negative mixed infections and from healthy volunteers. Thirty-seven episodes of severe sepsis were analyzed among 24 patients. LBP serum levels were significantly increased in patients with severe sepsis (46.4+/-28.3 microg/mL), compared with that of healthy volunteers (5.7+/-1.9 microg/mL; P<.0001). On the other hand, LBP serum levels obtained from patients with gram-negative infections (40.80+/-34.79 microg/mL) did not differ from those obtained from patients with gram-positive (35.55+/-23.95 microg/mL) or fungal (39.90+/-22.19 microg/mL) infections. These data suggest that LBP is an aspecific marker of sepsis, and the response was not clearly correlated with severity. Furthermore, in patients with multiple episodes of sepsis, LBP response seems to be of lesser magnitude after each subsequent episode of severe sepsis.

Acute-Phase Proteins↗
PubMed2002

Effervescent paracetamol poisoning: a case report.

Severe poisoning with effervescent paracetamol tablets has never been described in the literature. Indeed, the effervescent formulation contains high amounts of sodium and bicarbonate, both responsible for important emetic properties in the case of massive ingestion. Moreover, dissolving more than 6-8 tablets in the same glass appears to be difficult. We report a well-documented case of a patient with potentially hepatotoxic serum levels after the ingestion of 16 g effervescent paracetamol, apparently without vomiting. We show that the difficulties of a massive oral intake may be overcome by a slow intake. Nevertheless, this case report does not modify the important assertion that effervescent paracetamol use could limit the risk of life-threatening intoxication by a single massive acute overdose.

Acetaminophen↗
PubMedDate not supplied

Acute renal injury following methanol poisoning: analysis of a case series.

The objective of this paper is to document the prevalence of indicators of acute renal injury in a series of methanol-poisoned patients treated in an intensive care unit and to discuss the possible mechanisms. This is a retrospective analysis of the medical records of 25 consecutive patients admitted to the intensive care unit after severe intentional methanol poisoning. Acute renal impairment was defined as a serum creatinine concentration higher than 177 micro mol/L and/or a urinary output on admission and for the first 24 h below 0.5 ml/kg/h. Clinical pathological signs of acute renal injury were found in 15 patients. In comparison with the 10 other patients taken as control group, the patients who developed renal injury had a lower blood pH value on admission, a higher serum osmolality, and a higher peak formate concentration. Two factors contributing to renal injury could be identified: hemolysis and myoglobinuria. The role of osmotic changes (osmotic nephrosis) or of a direct cytotoxic effect of formic acid remains speculative. Analysis of proteinuria suggests that proximal tubular cells may be preferentially affected. Results of histopathological evaluation of the kidney on a limited sample size (n = 5) were inconclusive but suggestive of possible hydropic changes in the proximal tubule secondary to methanol toxicity. Acute renal injury may be associated with other signs of severity in methanol poisoning, but it is almost always reversible in survivors. Indicators of acute renal injury were identified. The pathophysiology of this acute renal injury is multifactorial and far more complex than shock-related tubular necrosis.

Acute Kidney Injury↗
PubMedDate not supplied

Long-term medical complications and quality of life in adult recipients surviving 10 years or more after liver transplantation.

BACKGROUND AND STUDY AIMS: Little information is available about long-term results after adult liver transplantation. This study analyses long-term medical complications, changes of immunosuppression, recurrence of primary disease and quality of life 10 years after liver transplantation. MATERIAL AND METHODS: During the period February 1984-April 1994, 324 LT were performed in 282 adults (>15 years). One hundred forty-seven (52%) patients survived more than 10 years. Data regarding health status of 103 patients exclusively followed-up in our institution were analyzed. RESULTS: Actual 1, 5, 10 years survival rates of the 282 recipients were 76.6%, 64.9% and 52% respectively. Forty eight (46.6%) of the 103 studied patients had normal liver tests in their tenth year of the follow-up. Seventy-one (69%) patients were on a CyA, TAC or MMF monotherapy; 31 (30%) patients had CyA levels of less than 100ng/ml. Forty five patients had recurrent allograft disease. Twenty-four (40.6%) of 59 liver biopsy available at 10th year were normal. Thirty five (34%) patients developed chronic renal failure; nine (8.7%) of them had end-stage renal disease. New onset hypertension (>140/100 mmHg) developed in 49 (47.6%) patients; fourteen (13.6%) developed diabetes (glucose blood level > 140 mg/dl) and twenty five (24.2%) patients had serious cardiovascular events. Thirteen (12.6%) patients had a BMI>28 and thirty six (35%) patients had elevated serum cholesterol (>220 mg/dl). Cataract was present in 8 (7.7%) patients. De novo malignancy developed in 23 (22.3%) patients. One patient each developed nasopharyngeal lymphoproliferative disease and myeloma. Quality of life of this patient cohort was excellent as shown by a Karnofsky score of more than 80% in 96.6% of patients. CONCLUSION: The high rate of medical complications and especially of malignant tumours in this long-term follow-up study indicate that further optimization and especially minimization of immunosuppressive therapy as well as development of newer therapies in order to prevent recurrent allograft diseases are the priority for the future development of transplant medicine.

Adult↗