Confirmatory platelet-activating factor receptor antagonist trial in patients with severe Gram-negative bacterial sepsis

Dhainaut, Jean François; Tenaillon, Alain; Hemmer, Michèle; Damas, Pierre; Tulzo, Yves Le; Radermacher, Peter; Schaller, Marie-Denise; Sollet, J.-P.; Wolff, Michel; Holzapfel, L.; Zéni, Fabrice; Vedrinne, J. M.; Vathaire, Florent de; Gourlay, Margaret L.; Guinot, Philippe; Mira, Jean‐Paul

doi:10.1097/00003246-199812000-00021

Cited by 142 publications

(18 citation statements)

References 36 publications

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“…Several clinical trials of anti-inflammatory mediators used liberal inclusion windows [22-24] notwithstanding the fact that the extent of inflammation in critically ill patients depends on the time elapsed since the initial injury [25]. The typical time course starts with an early phase of hyperinflammation, where anti-inflammatory mediators may theoretically be promising [26], and a prolonged period of immunosuppression, where anti-inflammatory treatment may supposedly be detrimental.…”

Section: Timing Of the Study Interventionmentioning

confidence: 99%

Translational research in sepsis - an ultimate challenge?

Kampmeier

Ertmer

Rehberg

2011

Exp & Trans Stroke Med

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In the era of evidence-based medicine, large, randomized, controlled, multicenter studies represent the "summit of evidence". In contrast to specialties like cardiology, the majority of randomized, controlled trials in critical care medicine, however, have failed to demonstrate a survival benefit; notably, despite encouraging results from experimental and phase-II clinical studies. The difficulty in translating our theoretical knowledge into successful multicenter randomized, controlled trials and subsequent treatment recommendations may represent one reason, why the mortality of septic shock still averages between 40-60%, although our knowledge about the underlying pathophysiology has considerably increased and international guidelines have widely been implemented. The present article elucidates some of the difficulties in translating research from bench to bedside.

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Section: Timing Of the Study Interventionmentioning

confidence: 99%

Translational research in sepsis - an ultimate challenge?

Kampmeier

Ertmer

Rehberg

2011

Exp & Trans Stroke Med

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“…(56–59) In general, subgroup analyses not defined by design a priori should be avoided, because any post-randomization differences (e.g. bias) will undermine the original randomization assignment.…”

Section: Internal and External Validitymentioning

confidence: 99%

Critical care trial design and interpretation: A primer

Sevransky

Martin

2010

Critical Care Medicine

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Objective Better understanding of the pathophysiology of critical illness has led to an increase in clinical trials designed to improve the clinical care and outcomes of patients with life threatening illness. Knowledge of basic principles of clinical trial design and interpretation will assist the clinician in better applying the results of these studies into clinical practice. Data Sources We review selected clinical trials to highlight important design features that will improve understanding of the results of critical care clinical trials. Main Results Trial design features such as patient selection, sample size calculation, and primary outcome measure may influence the results of a critical care clinical study. In conjunction with trial design knowledge, understanding the size of the anticipated treatment effect, the importance of any clinical endpoint achieved, and whether patients in the trial are representative of typical patients with the illness will assist the reader in determining whether the results should be applied to usual clinical practice. Conclusions Better understanding of important aspects of trial design and interpretation, such as whether patients enrolled in both intervention arms were comparable and whether the primary outcome of the trial is clinically important, will assist the reader in determining whether to apply the findings from the clinical study into clinical practice.

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“…A randomized, double-blind and controlled multicenter study of 600 patients with severe sepsis which tested PAF receptor antagonist for four days, did not demonstrate any reduction in mortality rate. 36 It is now known that nitric oxide production, (NO endogenous vasodilator), is responsible for some of the harmful effects of the inflammatory response on target organs (vasodilation and hypotension; myocardial depression in septic shock). It is produced from L-arginine with the aid of NO synthase (NOs) and its inhibition or blockage is a therapeutic strategy to minimize these effects.…”

Section: Treatment Aimed At Improving Innate Immunitymentioning

confidence: 99%

Avanços no diagnóstico e tratamento da sepse

Carvalho¹,

Trotta²

2003

J. Pediatr. (Rio J.)

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Objective: To present a critical and updated review about sepsis, focusing especially on diagnosis and treatment. Sources of data:Literature review of Medline, including review articles, clinical trials and original research. Summary of the findings:The International Sepsis Definitions Conference amplified the list of possible clinical and laboratory signs of sepsis, which may allow for more efficacious suspicion and management. In terms of laboratory evaluation, in addition to the research for infectious agents, many inflammatory response markers, such as inflammatory cytokines and procalcitonin, have been identified. However, they lack sensitivity and specificity for safe diagnosis. In terms of treatment, early intervention to prevent hemodynamic disturbances is still essential for a positive outcome, together with the appropriate use of antimicrobials. The value of treatments to remove toxins and to increase the innate immune response has not yet been established. The use of isolated inflammatory response blockers, at any stage of sepsis, does not decrease mortality. The use of corticosteroid makes a comeback with encouraging results, even in patients without sepsis-related adrenal insufficiency. A large study on activated protein C (drotrecogin-α) reports a 6% decrease in mortality in a selected sample, suggesting the possibility of a better prognosis for sepsis patients. Conclusions:In comparison to the advances of the past few years, little has been achieved in terms of decreasing sepsis-related mortality due to the complexity of the pathogen-host relationships. The individual regulation of host reactions did not have the expected effects. The benefits of some known strategies were confirmed. Other types of treatment, such as corticosteroids and activated protein C therapies, are emerging as promising alternatives. Research indicates that the combination of immune modulator therapies is probably the best choice to improve outcomes in sepsis.J Pediatr (Rio J) 2003;79(Suppl 2):S195-S204: Sepsis, systemic inflammatory response syndrome, critical care. Advances in sepsis diagnosis and treatment

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Confirmatory platelet-activating factor receptor antagonist trial in patients with severe Gram-negative bacterial sepsis

Cited by 142 publications

References 36 publications

Translational research in sepsis - an ultimate challenge?

Translational research in sepsis - an ultimate challenge?

Critical care trial design and interpretation: A primer

Avanços no diagnóstico e tratamento da sepse

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