Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.

Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.

Fluid therapy in septic shock.

PURPOSE OF REVIEW: To examine the role of fluid therapy in the pathogenesis of severe sepsis and septic shock. The type, composition, titration, management strategies and complications of fluid administration will be examined in respect to outcomes. RECENT FINDINGS: Fluids have a critical role in the pathogenesis and treatment of early resuscitation of severe sepsis and septic shock. SUMMARY: Although this pathogenesis is evolving, early titrated fluid administration modulates inflammation, improves microvascular perfusion, impacts organ function and outcome. Fluid administration has limited impact on tissue perfusion during the later stages of sepsis and excess fluid is deleterious to outcome. The type of fluid solution does not seem to influence these observations.

The incidence and significance of bacteremia in out of hospital cardiac arrest.

BACKGROUND: The most common etiology of cardiac arrest is presumed of myocardial origin. Recent retrospective studies indicate that preexisting pneumonia, a form of sepsis, is frequent in patients who decompensate with abrupt cardiac arrest without preceding signs of septic shock, respiratory failure or severe metabolic disorders shortly after hospitalization. The contribution of pre-existing infection on pre and post cardiac arrest events remains unknown and has not been studied in a prospective fashion. We sought to examine the incidence of pre-existing infection in out-of hospital cardiac arrest (OHCA) and assess characteristics associated with bacteremia, the goal standard for presence of infection. METHODS AND RESULTS: We prospectively observed 250 OHCA adult patients who presented to the Emergency Department (ED) between 2007 and 2009 to an urban academic teaching institution. Bacteremia was defined as one positive blood culture with non-skin flora bacteria or two positive blood cultures with skin flora bacteria. 77 met pre-defined exclusion criteria. Of the 173 OHCA adults, 65 (38%) were found to be bacteremic with asystole and PEA as the most common presenting rhythms. Mortality in the ED was significantly higher in bacteremic OHCA (75.4%) compared to non-bacteremic OHCA (60.2%, p<0.05). After adjustment for potential confounders, predictive factors associated with bacteremic OHCA were lower initial arterial pH, higher lactate, WBC, BUN and creatinine. CONCLUSIONS: Over one-third of OHCA adults were bacteremic upon presentation. These patients have greater hemodynamic instability and significantly increased short-term mortality. Further studies are warranted to address the epidemiology of infection as possible cause of cardiac arrest.

Early biomarker activity in severe sepsis and septic shock and a contemporary review of immunotherapy trials: not a time to give up, but to give it earlier.

Improving time to diagnosis and intervention has positively impacted outcomes in acute myocardial infarction, stroke, and trauma through elucidating the early pathogenesis of those diseases. This insight may partly explain the futility of time-insensitive immunotherapy trials for severe sepsis and septic shock. The aim of this study was to examine the early natural history of circulatory biomarker activity in sepsis, relative to previous animal and human outcome trials. We conducted a literature search using PubMed, MEDLINE, and Google Scholar to identify outcome trials targeting biomarkers with emphasis on the timing of therapy. These findings were compared with the biomarker activity observed over the first 72 h of hospital presentation in a cohort of severe sepsis and septic shock patients. Biomarker levels in animal and human research models are elevated within 30 min after exposure to an inflammatory septic stimulus. Consistent with these findings, the biomarker cascade is activated at the most proximal point of hospital presentation in our patient cohort. These circulatory biomarkers overlap; some have bimodal patterns and generally peak between 3 and 36 h while diminishing over the subsequent 72 h of observation. When this is taken into account, prior outcome immunotherapy trials have generally enrolled patients after peak circulatory biomarker concentrations. In previous immunotherapy sepsis trials, intervention was delayed after the optimal window of peak biomarker activity. As a result, future studies need to recalibrate the timing of enrollment and administration of immunotherapy agents that still may hold great promise for this deadly disease.