Michael A. Puskarich

Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol.

Objective:We sought to determine the association between time to initial antibiotics and mortality of patients with septic shock treated with an emergency department-based early resuscitation protocol. Design:Preplanned analysis of a multicenter randomized controlled trial of early sepsis resuscitation. Setting:Three urban U.S. emergency departments. Patients:Adult patients with septic shock. Interventions:A quantitative resuscitation protocol in the emergency department targeting three physiological variables: central venous pressure, mean arterial pressure, and either central venous oxygen saturation or lactate clearance. The study protocol was continued until all end points were achieved or a maximum of 6 hrs. Measurements and Main Results:Data on patients who received an initial dose of antibiotics after presentation to the emergency department were categorized based on both time from triage and time from shock recognition to initiation of antibiotics. The primary outcome was inhospital mortality. Of 291 included patients, mortality did not change with hourly delays in antibiotic administration up to 6 hrs after triage: 1 hr (odds ratio [OR], 1.2; 0.6–2.5), 2 hrs (OR, 0.71; 0.4–1.3), 3 hrs (OR, 0.59; 0.3–1.3). Mortality was significantly increased in patients who received initial antibiotics after shock recognition (n = 172 [59%]) compared with before shock recognition (OR, 2.4; 1.1–4.5); however, among patients who received antibiotics after shock recognition, mortality did not change with hourly delays in antibiotic administration. Conclusion:In this large, prospective study of emergency department patients with septic shock, we found no increase in mortality with each hour delay to administration of antibiotics after triage. However, delay in antibiotics until after shock recognition was associated with increased mortality.

The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis

Objectives:We sought to systematically review and meta-analyze the available data on the association between timing of antibiotic administration and mortality in severe sepsis and septic shock. Data Sources:A comprehensive search criteria was performed using a predefined protocol. Study Selection:Inclusion criteria: adult patients with severe sepsis or septic shock, reported time to antibiotic administration in relation to emergency department triage and/or shock recognition, and mortality. Exclusion criteria: immunosuppressed populations, review article, editorial, or nonhuman studies. Data Extraction:Two reviewers screened abstracts with a third reviewer arbitrating. The effect of time to antibiotic administration on mortality was based on current guideline recommendations: 1) administration within 3 hours of emergency department triage and 2) administration within 1 hour of severe sepsis/septic shock recognition. Odds ratios were calculated using a random effect model. The primary outcome was mortality. Data Synthesis:A total of 1,123 publications were identified and 11 were included in the analysis. Among the 11 included studies, 16,178 patients were evaluable for antibiotic administration from emergency department triage. Patients who received antibiotics more than 3 hours after emergency department triage (< 3 hr reference) had a pooled odds ratio for mortality of 1.16 (0.92–1.46; p = 0.21). A total of 11,017 patients were evaluable for antibiotic administration from severe sepsis/septic shock recognition. Patients who received antibiotics more than 1 hour after severe sepsis/shock recognition (< 1 hr reference) had a pooled odds ratio for mortality of 1.46 (0.89–2.40; p = 0.13). There was no increased mortality in the pooled odds ratios for each hourly delay from less than 1 to more than 5 hours in antibiotic administration from severe sepsis/shock recognition. Conclusion:Using the available pooled data, we found no significant mortality benefit of administering antibiotics within 3 hours of emergency department triage or within 1 hour of shock recognition in severe sepsis and septic shock. These results suggest that currently recommended timing metrics as measures of quality of care are not supported by the available evidence.

Outcomes of Patients Undergoing Early Sepsis Resuscitation for Cryptic Shock Compared with Overt Shock

INTRODUCTION We sought to compare the outcomes of patients with cryptic versus overt shock treated with an emergency department (ED) based early sepsis resuscitation protocol. METHODS Pre-planned secondary analysis of a large, multicenter ED-based randomized controlled trial of early sepsis resuscitation. All subjects were treated with a quantitative resuscitation protocol in the ED targeting 3 physiological variables: central venous pressure, mean arterial pressure and either central venous oxygen saturation or lactate clearance. The study protocol was continued until all endpoints were achieved or a maximum of 6h. Outcomes data of patients who were enrolled with a lactate ≥ 4mmol/L and normotension (cryptic shock) were compared to those enrolled with sustained hypotension after fluid challenge (overt shock). The primary outcome was in-hospital mortality. RESULTS A total of 300 subjects were enrolled, 53 in the cryptic shock group and 247 in the overt shock group. The demographics and baseline characteristics were similar between the groups. The primary endpoint of in-hospital mortality was observed in 11/53 (20%, 95% CI 11-34) in the cryptic shock group and 48/247 (19%, 95% CI 15-25) in the overt shock group, difference of 1% (95% CI -10 to 14; log rank test p=0.81). CONCLUSION Severe sepsis with cryptic shock carries a mortality rate not significantly different from that of overt septic shock. These data suggest the need for early aggressive screening for and treatment of patients with an elevated serum lactate in the absence of hypotension.

Whole Blood Lactate Kinetics in Patients Undergoing Quantitative Resuscitation for Severe Sepsis and Septic Shock

BACKGROUND We sought to compare the association of whole-blood lactate kinetics with survival in patients with septic shock undergoing early quantitative resuscitation. METHODS This was a preplanned analysis of a multicenter, ED-based, randomized, controlled trial of early sepsis resuscitation. Inclusion criteria were suspected infection, two or more systemic inflammation criteria, either systolic BP< 90 mm Hg after a fluid bolus or lactate level > 4 mM, two serial lactate measurements, and an initial lactate level > 2.0 mM. We calculated the relative lactate clearance, rate of lactate clearance, and occurrence of early lactate normalization (decline to < 2.0 mM in the first 6 h). Area under the receiver operating characteristic curve (AUC) and multivariate logistic regression were used to determine the lactate kinetic parameters that were the strongest predictors of survival. RESULTS The analysis included 187 patients, of whom 36% (n = 68) normalized their lactate level. Overall survival was 76.5% (143 of 187 patients), and the AUC of initial lactate to predict survival was 0.64. The AUCs for relative lactate clearance and lactate clearance rate were 0.67 and 0.58, respectively. Lactate normalization was the strongest predictor of survival (adjusted OR, 5.2; 95% CI, 1.7-15.8), followed by lactate clearance ≥ 50% (OR, 4.0; 95% CI, 1.6-10.0). Lactate clearance ≥ 10% (OR, 1.6; 95% CI, 0.6-4.4) was not a significant independent predictor in this cohort. CONCLUSIONS In patients in the ED with a sepsis diagnosis, early lactate normalization during the first 6 h of resuscitation was the strongest independent predictor of survival and was superior to other measures of lactate kinetics. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00372502; URL: clinicaltrials.gov.

Biomarkers of endothelial cell activation in early sepsis.

Purpose The objective of this study was to investigate the association of endothelial-related markers with organ dysfunction and in-hospital mortality to validate our earlier findings in a multicenter study. We hypothesize that (i) endothelial biomarkers will be associated with organ dysfunction and mortality in sepsis and that (ii) soluble fms-like tyrosine kinase 1 (sFlt-1) holds promise as a novel prognostic marker in sepsis. Methods This was a prospective, multicenter, observational study of a convenience sample of emergency department (ED) patients with a suspected infection presenting to one of four urban, academic medical center EDs between January 2009 and January 2010. We collected plasma while the patients were in the ED and subsequently assayed endothelial-related biomarkers, namely, sFlt-1, soluble E-selectin, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and plasminogen activator inhibitor 1 (PAI-1). Outcomes were organ dysfunction and in-hospital mortality. Results We enrolled a total of 166 patients: 63 with sepsis (38%), 61 with severe sepsis (37%), and 42 with septic shock (25%). All endothelial biomarkers were significantly associated with sepsis severity, P < 0.002. We found a significant intercorrelation between all biomarkers, strongest between sFlt-1 and PAI-1 (r = 0.61, P < 0.001) and PAI-1 and soluble E-selectin and soluble intercellular adhesion molecule 1 (r = 0.49, P < 0.001). Among the endothelial biomarkers, sFlt-1 had the strongest association with Sequential Organ Failure Assessment score (r = 0.58, P < 0.001). Soluble fms-like tyrosine kinase 1 and PAI-1 had the highest area under the operating receiver characteristic curve for mortality of 0.87. Conclusions This multicenter validation study confirms that markers of endothelial activation are associated with sepsis severity, organ dysfunction, and mortality in sepsis. This supports the hypothesis that the endothelium plays a central role in the pathophysiology of sepsis and may serve as a more accurate prediction tool and a target for therapies aimed at ameliorating endothelial cell dysfunction. In addition, sFLT-1 holds promise as a novel sepsis severity biomarker.

Prognostic Value and Agreement of Achieving Lactate Clearance or Central Venous Oxygen Saturation Goals During Early Sepsis Resuscitation

OBJECTIVES Lactate clearance (LC) and central venous oxygen saturation (ScvO(2)) have been proposed as goals of early sepsis resuscitation. The authors sought to determine the agreement and prognostic value of achieving ScvO(2) or LC goals in septic shock patients undergoing emergency department (ED)-based early resuscitation. METHODS This was a preplanned analysis of a multicenter ED randomized controlled trial of early sepsis resuscitation targeting three variables: central venous pressure, mean arterial pressure, and either ScvO(2) or LC. Inclusion criteria included suspected infection, two or more systemic inflammation criteria, and either systolic blood pressure of <90 mm Hg after intravenous fluid bolus or lactate level of >4 mmol/L. Both ScvO(2) and LC were measured simultaneously. The ScvO(2) goal was defined as ≥70%. Lactate was measured at enrollment and every 2 hours until the goal was reached or up to 6 hours. LC goal was defined as a decrease of ≥10% from initial measurement. The primary outcome was in-hospital mortality. RESULTS A total of 203 subjects were included, with an overall mortality of 19.7%. Achievement of the ScvO(2) goal only was associated with a mortality rate of 41% (9/22), while achievement of the LC goal only was associated with a mortality rate of 8% (2/25; proportion difference = 33%; 95% confidence interval [CI] = 9% to 55%). No agreement was found between goal achievement (κ = -0.02), and exact test for matched pairs demonstrated no significant difference between discordant pairs (p = 0.78). CONCLUSIONS No agreement was found between LC and ScvO(2) goal achievement in early sepsis resuscitation. Achievement of a ScvO(2) ≥ 70% without LC ≥ 10% was more strongly associated with mortality than achievement of LC ≥ 10% with failure to achieve ScvO(2) ≥ 70%.

Sepsis-Induced Tissue Hypoperfusion

Sepsis affects the cardiovascular system through multiple mechanisms, and often these derangements result in tissue hypoperfusion. Tissue hypoperfusion is often present in the setting of overt shock, but it can also be present in patients without obvious shock physiology. If left untreated, tissue hypoperfusion contributes to the development of multiple organ dysfunction and, ultimately, death. Therefore, it is critical for the clinician to understand the pathophysiology, recognition, and treatment of sepsis-induced hypoperfusion.

The Surviving Sepsis Campaign Guidelines 2012: Update for Emergency Physicians

The Surviving Sepsis Campaign recently developed and published an updated version in 2012 of the international guidelines for the assessment and management of severe sepsis and septic shock. These guidelines reflect literature published in the last 5 years, and many of the recommendations have direct implications for emergency physicians. In this review, we present a concise summary of these recommendations, with a particular focus on those that have changed and those that have direct relevance to the clinical practice of emergency medicine.

Prognosis of emergency department patients with suspected infection and intermediate lactate levels: a systematic review.

PURPOSE Previous studies have shown a correlation between blood lactate greater than 4.0 mmol/L and mortality in patients with suspected infection in the emergency department (ED), but data are more limited regarding the prognosis of intermediate blood lactate (2.0-3.9 mmol/L), particularly in the absence of hemodynamic instability. We sought to quantify the prognostic significance of intermediate blood lactate levels in ED patients with suspected infection, emphasizing patients without hypotension. METHODS A systematic review of 4 databases was conducted to identify studies using a comprehensive search strategy. All studies performed on adult ED patients with suspected infection and available data on hemodynamics, intermediate lactate levels, and mortality rates were included. RESULTS We identified 20 potential publications, 8 of which were included. Intermediate lactate elevation was found in 11,062 patients with suspected or confirmed infection, 1672 (15.1%) of whom died. Subgroup analysis of normotensive patients demonstrated a mortality of 1561 (14.9%) of 10,442, with rates from individual studies between 3.2% and 16.4%. CONCLUSION This systematic review found that among ED patients with suspected infection, intermediate lactate elevation is associated with a moderate to high risk of mortality, even among patients without hypotension. Physicians should consider close monitoring and aggressive treatment for such patients.

Plasma Levels of Mitochondrial DNA in Patients Presenting to the Emergency Department with Sepsis

ABSTRACT Elevated levels of plasma mitochondrial DNA (mtDNA) have been reported in trauma patients and may contribute to the systemic immune response. We sought to determine the plasma levels of mtDNA in emergency department (ED) patients with and without sepsis and evaluate their association with severity of illness. This was a prospective observational study of patients presenting to one of three large, urban, tertiary care EDs. Patients were enrolled into one of three cohorts: (i) sepsis defined as suspected infection and two or more systemic inflammatory response criteria without hypotension, (ii) septic shock defined as sepsis plus hypotension despite an adequate fluid challenge, and (iii) control defined as noninfected ED patients without systemic inflammatory response/hypotension. Plasma levels of three mtDNAs were measured using real-time quantitative polymerase chain reaction. Levels of mtDNAs were compared among the three cohorts, and linear regression was used to assess the association between mtDNAs, interleukin 6, interleukin 10, and Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. We enrolled 93 patients: 24 control subjects, 29 patients with sepsis, and 40 patients with septic shock. As expected, comorbidities and SOFA score increased across categories. We found no difference in mtDNA levels between the three groups (P = 0.14–0.30). Among patients with sepsis, we found a small but significant negative association between mtDNA level and SOFA score, most clearly with cytochrome b (P = 0.03). We found no difference in mtDNA levels between control subjects and patients with sepsis. Mitochondrial DNA levels were negatively associated with organ dysfunction, suggesting that plasma mtDNA does not significantly contribute to the pathophysiology of sepsis.