Aseem Kumar

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Objective:To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. Design:A retrospective cohort study performed between July 1989 and June 2004. Setting:Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. Patients:Medical records of 2,731 adult patients with septic shock. Interventions:None. Measurements and Main Results:The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103–1.136, p < .0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12–2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25–75th percentile, 2.0–15.0 hrs). Conclusions:Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.

Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase.

Double‐stranded RNA‐dependent protein kinase (PKR) has been implicated in interferon (IFN) induction, antiviral response and tumor suppression. We have generated mice devoid of functional PKR (Pkr%). Although the mice are physically normal and the induction of type I IFN genes by poly(I).poly(C) (pIC) and virus is unimpaired, the antiviral response induced by IFN‐gamma and pIC was diminished. However, in embryo fibroblasts from Pkr knockout mice, the induction of type I IFN as well as the activation of NF‐kappa B by pIC, were strongly impaired but restored by priming with IFN. Thus, PKR is not directly essential for responses to pIC, and a pIC‐responsive system independent of PKR is induced by IFN. No evidence of the tumor suppressor activity of PKR was demonstrated.

Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.

OBJECTIVE Our goal was to determine the impact of the initiation of inappropriate antimicrobial therapy on survival to hospital discharge of patients with septic shock. METHODS The appropriateness of initial antimicrobial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries. RESULTS Therapy with appropriate antimicrobial agents was initiated in 80.1% of cases. Overall, the survival rate was 43.7%. There were marked differences in the distribution of comorbidities, clinical infections, and pathogens in patients who received appropriate and inappropriate initial antimicrobial therapy (p < 0.0001 for each). The survival rates after appropriate and inappropriate initial therapy were 52.0% and 10.3%, respectively (odds ratio [OR], 9.45; 95% CI, 7.74 to 11.54; p < 0.0001). Similar differences in survival were seen in all major epidemiologic, clinical, and organism subgroups. The decrease in survival with inappropriate initial therapy ranged from 2.3-fold for pneumococcal infection to 17.6-fold with primary bacteremia. After adjustment for acute physiology and chronic health evaluation II score, comorbidities, hospital site, and other potential risk factors, the inappropriateness of initial antimicrobial therapy remained most highly associated with risk of death (OR, 8.99; 95% CI, 6.60 to 12.23). CONCLUSIONS Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of patients and is associated with a fivefold reduction in survival. Efforts to increase the frequency of the appropriateness of initial antimicrobial therapy must be central to efforts to reduce the mortality of patients with septic shock.

Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF‐1 and NF‐κB

The interferon (IFN)‐induced double‐stranded RNA (dsRNA)‐activated Ser/Thr protein kinase (PKR) plays a role in the antiviral and antiproliferative effects of IFN. PKR phosphorylates initiation factor eIF2α, thereby inhibiting protein synthesis, and also activates the transcription factor, nuclear factor‐κB (NF‐κB), by phosphorylating the inhibitor of NF‐κB, IκB. Mice devoid of functional PKR (Pkr°/°) derived by targeted gene disruption exhibit a diminished response to IFN‐γ and poly(rI:rC) (pIC). In embryo fibroblasts derived from Pkr°/° mice, interferon regulatory factor 1 (IRF‐1) or guanylate binding protein (Gbp) promoter–reporter constructs were unresponsive to IFN‐γ or pIC but response could be restored by co‐transfection with PKR. The lack of responsiveness could be attributed to a diminished activation of IRF‐1 and/or NF‐κB in response to IFN‐γ or pIC. Thus, PKR acts as a signal transducer for IFN‐stimulated genes dependent on the transcription factors IRF‐1 and NF‐κB.

Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis.

Background:Septic shock represents the major cause of infection-associated mortality in the intensive care unit. The possibility that combination antibiotic therapy of bacterial septic shock improves outcome is controversial. Current guidelines do not recommend combination therapy except for the express purpose of broadening coverage when resistant pathogens are a concern. Objective:To evaluate the therapeutic benefit of early combination therapy comprising at least two antibiotics of different mechanisms with in vitro activity for the isolated pathogen in patients with bacterial septic shock. Design:Retrospective, propensity matched, multicenter, cohort study. Setting:Intensive care units of 28 academic and community hospitals in three countries between 1996 and 2007. Subjects:A total of 4662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated. Measurements and Main Results:The primary outcome of study was 28-day mortality. Using a Cox proportional hazards model, combination therapy was associated with decreased 28-day mortality (444 of 1223 [36.3%] vs. 355 of 1223 [29.0%]; hazard ratio, 0.77; 95% confidence interval, 0.67-0.88; p = .0002). The beneficial impact of combination therapy applied to both Gram-positive and Gram-negative infections but was restricted to patients treated with &bgr;-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Combination therapy was also associated with significant reductions in intensive care unit (437 of 1223 [35.7%] vs. 352 of 1223 [28.8%]; odds ratio, 0.75; 95% confidence interval, 0.63-0.92; p = .0006) and hospital mortality (584 of 1223 [47.8%] vs. 457 of 1223 [37.4%]; odds ratio, 0.69; 95% confidence interval, 0.59-0.81; p < .0001). The use of combination therapy was associated with increased ventilator (median and [interquartile range], 10 [0-25] vs. 17 [0-26]; p = .008) and pressor/inotrope-free days (median and [interquartile range], 23 [0-28] vs. 25 [0-28]; p = .007) up to 30 days. Conclusion:Early combination antibiotic therapy is associated with decreased mortality in septic shock. Prospective randomized trials are needed.

The Duration of Hypotension before the Initiation of Antibiotic Treatment Is a Critical Determinant of Survival in a Murine Model of Escherichia coli Septic Shock: Association with Serum Lactate and Inflammatory Cytokine Levels

BACKGROUND This study was designed to examine the relationship between the timing of antibiotic treatment and both survival rates and hemodynamic/inflammatory correlates of survival in a murine model of Escherichia coli septic shock. METHODS Surgical implantation of an E. coli (O18:K1:H7)-laced, gelatin capsule-encased fibrinogen clot was used to generate a bacteremic model of murine septic shock. Survival duration, hemodynamic responses, and circulating serum tumor necrosis factor (TNF)-alpha , interleukin (IL)-6, and lactate levels were assessed in relation to increasing delays in or absence of antibiotic treatment. RESULTS A critical inflection point with respect to survival occurred between 12 and 15 h after implantation. When initiated at or before 12 h, antibiotic treatment resulted in < or = 20% mortality, but, when initiated at or after 15 h, it resulted in >85% mortality. Physiologically relevant hypotension developed in untreated septic mice by 12 h after implantation. Values for heart rate differed between untreated septic mice and sham-infected control mice by 6 h after implantation, whereas values for cardiac output and stroke volume did not differ until at least 18-24 h after implantation. Antibiotic treatment initiated > or = 12 h after implantation was associated with persistence of increased circulating serum lactate, TNF- alpha , and IL-6 levels. CONCLUSIONS The timing of antibiotic treatment relative to hypotension is closely associated with survival in this murine model of septic shock. Delay in antibiotic treatment results in the persistence of inflammatory/stress markers even after antibiotic treatment is initiated.

Cytokine modulation in sepsis and septic shock

Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit. Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30 – 50% range. Sepsis constitutes the systemic response to infection. This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines. Among the most important pro-inflammatory cytokines are TNF-α and IL-1β. The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-β. Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies. This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-α and IL-1β activity. This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-β, granulocyte colony-stimulating factor and IFN-γ. Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study

See related commentary by Dickerson, http://ccforum.com/content/17/3/154IntroductionData are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients.MethodsWe performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality.ResultsOf the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese).ConclusionsThe obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.

Association between Source of Infection and Hospital Mortality in Patients Who Have Septic Shock

RATIONALE Mortality caused by septic shock may be determined by a systemic inflammatory response, independent of the inciting infection, but it may also be influenced by the anatomic source of infection. OBJECTIVES To determine the association between the anatomic source of infection and hospital mortality in critically ill patients who have septic shock. METHODS This was a retrospective, multicenter cohort study of 7,974 patients who had septic shock in 29 academic and community intensive care units in Canada, the United States, and Saudi Arabia from January 1989 to May 2008. MEASUREMENTS AND MAIN RESULTS Subjects were assigned 1 of 20 anatomic sources of infection based on clinical diagnosis and/or isolation of pathogens. The primary outcome was hospital mortality. Overall crude hospital mortality was 52% (21-85% across sources of infection). Variation in mortality remained after adjusting for year of admission, geographic source of admission, age, sex, comorbidities, community- versus hospital-acquired infection, and organism type. The source of infection with the highest standardized hospital mortality was ischemic bowel (75%); the lowest was obstructive uropathy-associated urinary tract infection (26%). Residual variation in adjusted hospital mortality was not explained by Acute Physiology and Chronic Health Evaluation II score, number of Day 1 organ failures, bacteremia, appropriateness of empiric antimicrobials, or adjunct therapies. In patients who received appropriate antimicrobials after onset of hypotension, source of infection was associated with death after adjustment for both predisposing and downstream factors. CONCLUSIONS Anatomic source of infection should be considered in future trial designs and analyses, and in development of prognostic scoring systems.

Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study.

Objective:Fluids and vasoactive agents are both used to treat septic shock, but little is known about how they interact or the optimal way to administer them. We sought to determine how hospital mortality was influenced by combined use of these two treatments. Design:Retrospective evaluation using multivariable logistic regression to evaluate the association between hospital mortality and categorical variables representing initiation of vasoactive agents and volumes of IV fluids given 0–1, 1–6, and 6–24 hours after onset, including interactions and adjusting for potential confounders. Setting:ICUs of 24 hospitals in 3 countries. Patients:Two thousand eight hundred forty-nine patients who survived more than 24 hours after after onset of septic shock, admitted between 1989 and 2007. Interventions:None. Measurements and Main Results:Fluids and vasoactive agents had strong, interacting associations with mortality (p < 0.0001). Mortality was lowest when vasoactive agents were begun 1–6 hours after onset, with more than 1 L of fluids in the initial hour after shock onset, more than 2.4 L from hours 1–6, and 1.6–3.5 L from 6 to 24 hours. The lowest mortality rates were associated with starting vasoactive agents 1–6 hours after onset. Conclusions:The focus during the first hour of resuscitation for septic shock should be aggressive fluid administration, only thereafter starting vasoactive agents, while continuing aggressive fluid administration. Starting vasoactive agents in the initial hour may be detrimental, and not all of that association is due to less fluids being given with such early initiation of vasoactive agents.