David F. Gaieski

Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department

Objective:To study the association between time to antibiotic administration and survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Design:Single-center cohort study. Setting:The emergency department of an academic tertiary care center from 2005 through 2006. Patients:Two hundred sixty-one patients undergoing early goal-directed therapy. Interventions:None. Measurements and Main Results:Effects of different time cutoffs from triage to antibiotic administration, qualification for early goal-directed therapy to antibiotic administration, triage to appropriate antibiotic administration, and qualification for early goal-directed therapy to appropriate antibiotic administration on in-hospital mortality were examined. The mean age of the 261 patients was 59 ± 16 yrs; 41% were female. In-hospital mortality was 31%. Median time from triage to antibiotics was 119 mins (interquartile range, 76–192 mins) and from qualification to antibiotics was 42 mins (interquartile range, 0–93 mins). There was no significant association between time from triage or time from qualification for early goal-directed therapy to antibiotics and mortality when assessed at different hourly cutoffs. When analyzed for time from triage to appropriate antibiotics, there was a significant association at the <1 hr (mortality 19.5 vs. 33.2%; odds ratio, 0.30 [95% confidence interval, 0.11–0.83]; p = .02) time cutoff; similarly, for time from qualification for early goal-directed therapy to appropriate antibiotics, a significant association was seen at the ≤1 hr (mortality 25.0 vs. 38.5%; odds ratio, 0.50 [95% confidence interval, 0.27–0.92]; p = .03) time cutoff. Conclusions:Elapsed times from triage and qualification for early goal-directed therapy to administration of appropriate antimicrobials are primary determinants of mortality in patients with severe sepsis and septic shock treated with early goal-directed therapy.

Benchmarking the incidence and mortality of severe sepsis in the United States.

Background:In 1992, the first consensus definition of severe sepsis was published. Subsequent epidemiologic estimates were collected using administrative data, but ongoing discrepancies in the definition of severe sepsis produced large differences in estimates. Objectives:We seek to describe the variations in incidence and mortality of severe sepsis in the United States using four methods of database abstraction. We hypothesized that different methodologies of capturing cases of severe sepsis would result in disparate estimates of incidence and mortality. Design, Setting, Participants:Using a nationally representative sample, four previously published methods (Angus et al, Martin et al, Dombrovskiy et al, and Wang et al) were used to gather cases of severe sepsis over a 6-year period (2004–2009). In addition, the use of new International Statistical Classification of Diseases, 9th Edition (ICD-9), sepsis codes was compared with previous methods. Measurements:Annual national incidence and in-hospital mortality of severe sepsis. Results:The average annual incidence varied by as much as 3.5-fold depending on method used and ranged from 894,013 (300/100,000 population) to 3,110,630 (1,031/100,000) using the methods of Dombrovskiy et al and Wang et al, respectively. Average annual increase in the incidence of severe sepsis was similar (13.0% to 13.3%) across all methods. In-hospital mortality ranged from 14.7% to 29.9% using abstraction methods of Wang et al and Dombrovskiy et al. Using all methods, there was a decrease in in-hospital mortality across the 6-year period (35.2% to 25.6% [Dombrovskiy et al] and 17.8% to 12.1% [Wang et al]). Use of ICD-9 sepsis codes more than doubled over the 6-year period (158,722 – 489,632 [995.92 severe sepsis], 131,719 – 303,615 [785.52 septic shock]). Conclusion:There is substantial variability in incidence and mortality of severe sepsis depending on the method of database abstraction used. A uniform, consistent method is needed for use in national registries to facilitate accurate assessment of clinical interventions and outcome comparisons between hospitals and regions.

Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock

Principle:Serum lactate is a potentially useful biomarker to risk-stratify patients with severe sepsis; however, it is plausible that elevated serum lactate is simply a manifestation of clinically apparent organ dysfunction and/or shock (i.e., refractory hypotension). Objective:To test whether the association between initial serum lactate level and mortality in patients presenting to the emergency department (ED) with severe sepsis is independent of organ dysfunction and shock. Design:Single-center cohort study. The primary outcome was 28-day mortality and the risk factor variable was initial venous lactate (mmol/L), categorized as low (<2), intermediate (2–3.9), or high (≥4). Potential covariates included age, sex, race, acute and chronic organ dysfunction, severity of illness, and initiation of early goal-directed therapy. Multivariable logistic regression analyses were stratified on the presence or absence of shock. Setting:The ED of an academic tertiary care center from 2005 to 2007. Patients:Eight hundred thirty adults admitted with severe sepsis in the ED. Interventions:None. Measurements and Main Results:Mortality at 28 days was 22.9% and median serum lactate was 2.9 mmol/L. Intermediate (odds ratio {lsqb;OR{rsqb; = 2.05, p = 0.024) and high serum lactate levels (OR = 4.87, p < 0.001) were associated with mortality in the nonshock subgroup. In the shock subgroup, intermediate (OR = 3.27, p = 0.022) and high serum lactate levels (OR = 4.87, p = 0.001) were also associated with mortality. After adjusting for potential confounders, intermediate and high serum lactate levels remained significantly associated with mortality within shock and nonshock strata. Conclusions:Initial serum lactate was associated with mortality independent of clinically apparent organ dysfunction and shock in patients admitted to the ED with severe sepsis. Both intermediate and high serum lactate levels were independently associated with mortality.

Early Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.

Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest

BACKGROUND Comatose survivors of out-of-hospital cardiac arrest (OHCA) have high in-hospital mortality due to a complex pathophysiology that includes cardiovascular dysfunction, inflammation, coagulopathy, brain injury and persistence of the precipitating pathology. Therapeutic hypothermia (TH) is the only intervention that has been shown to improve outcomes in this patient population. Due to the similarities between the post-cardiac arrest state and severe sepsis, it has been postulated that early goal-directed hemodyamic optimization (EGDHO) combined with TH would improve outcome of comatose cardiac arrest survivors. OBJECTIVE We examined the feasibility of establishing an integrated post-cardiac arrest resuscitation (PCAR) algorithm combining TH and EGDHO within 6h of emergency department (ED) presentation. METHODS In May, 2005 we began prospectively identifying comatose (Glasgow Motor Score<6) survivors of OHCA treated with our PCAR protocol. The PCAR patients were compared to matched historic controls from a cardiac arrest database maintained at our institution. RESULTS Between May, 2005 and January, 2008, 18/20 (90%) eligible patients were enrolled in the PCAR protocol. They were compared to historic controls from 2001 to 2005, during which time 18 patients met inclusion criteria for the PCAR protocol. Mean time from initiation of TH to target temperature (33 degrees C) was 2.8h (range 0.8-23.2; SD=h); 78% (14/18) had interventions based upon EGDHO parameters; 72% (13/18) of patients achieved their EGDHO goals within 6h of return of spontaneous circulation (ROSC). Mortality for historic controls who qualified for the PCAR protocol was 78% (14/18); mortality for those treated with the PCAR protocol was 50% (9/18) (p=0.15). CONCLUSIONS In patients with ROSC after OHCA, EGDHO and TH can be implemented simultaneously.

Postgraduate Education CornerEarly Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.

A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis

Objective:To define a biomarker panel to predict organ dysfunction, shock, and in-hospital mortality in emergency department (ED) patients with suspected sepsis. Design:Prospective observational study. Setting:EDs of ten academic medical centers. Patients:There were 971 patients enrolled. Inclusion criteria: 1) ED patients age > 18; 2) suspected infection or a serum lactate level > 2.5 mmol/L; and 3) two or more systemic inflammatory response syndrome criteria. Exclusion criteria: pregnancy, do-not-resuscitate status, or cardiac arrest. Measurements and Main Results:Nine biomarkers were assayed from blood draws obtained on ED presentation. Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. The derived formula for weighting biomarker values was used to calculate a “sepsis score,” which was the predicted probability of the primary outcome of severe sepsis (sepsis plus organ dysfunction) within 72 hrs. We also assessed the ability of the sepsis score to predict secondary outcome measures of septic shock within 72 hrs and in-hospital mortality. The overall rates of each outcome were severe sepsis, 52%; septic shock, 39%; and in-hospital mortality 7%. Among the nine biomarkers tested, the optimal 3-marker panel was neutrophil gelatinase-associated lipocalin, protein C, and interleukin−1 receptor antagonist. The area under the curve for the accuracy of the sepsis score derived from these three biomarkers was 0.80 for severe sepsis, 0.77 for septic shock, and 0.79 for death. When included in multivariate models with clinical variables, the sepsis score remained highly significant (p < 0.001) for all the three outcomes. Conclusions:A biomarker panel of neutrophil gelatinase-associated lipocalin, interleukin-1ra, and Protein C was predictive of severe sepsis, septic shock, and death in ED patients with suspected sepsis. Further study is warranted to prospectively validate the clinical utility of these biomarkers and the sepsis score in risk-stratifying patients with suspected sepsis.

The Diagnostic Accuracy of Plasma Neutrophil Gelatinase–Associated Lipocalin in the Prediction of Acute Kidney Injury in Emergency Department Patients With Suspected Sepsis

STUDY OBJECTIVE We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. METHODS We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. RESULTS There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). CONCLUSION In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.

Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences.

Objectives:We sought to review findings from recent literature on the postresuscitation care of cardiac arrest patients using therapeutic hypothermia as part of nontrial treatment. Design:Literature review. Setting:Hospital-based environment. Subjects:Patients initially resuscitated from cardiac arrest who underwent hypothermia induction as a treatment regimen or historical control patients who did not receive hypothermia therapy. Measurements:We compiled protocol methodology from the various studies, as well as survival-to-hospital discharge and neurological outcomes. Main Results:Although varied in their protocols and outcome reporting, results from published investigations confirmed the findings from landmark randomized controlled trials, in that the use of therapeutic hypothermia increased survival with an odds ratio of 2.5 (95% confidence interval, 1.8-3.3) and favorable outcome with an odds ratio of 2.5 (95% confidence interval, 1.9-3.4). Conclusions:The survival and neurological outcomes benefit from therapeutic hypothermia are robust when compared over a wide range of studies of actual implementation.

The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia ,

AIM The incidence and timing of electrographic seizures and epileptiform activity in comatose, adult, post-cardiac arrest syndrome (PCAS) patients treated with therapeutic hypothermia (TH) have not been extensively investigated. We hypothesized that onset most frequently occurs within the first 24 h post-arrest and is associated with poor neurologic outcome. METHODS Single-center, retrospective analysis of a cohort of 38 comatose PCAS patients treated with TH and continuous-EEG-monitoring (cEEG), initiated as soon as possible after ICU admission. All raw cEEG waveform records were cleared of annotations and clinical information and classified by two fellowship-trained electroencephalographers. RESULTS Twenty-three percent (9/38) of patients had electrographic seizures (median onset 19 h post-arrest); 5/9 (56%) had seizure-onset prior to rewarming; 7/9 (78%) had status epilepticus. Forty-five percent (17/38) had evidence of epileptiform activity (electrographic seizures or interictal epileptiform discharges), typically occurring during first 24 h post-arrest. Interictal epileptiform activity was highly associated with later detection of electrographic seizures (6/14, 43%, p=0.001). Ninety-four percent (16/17) of patients with epileptiform activity had poor neurologic outcome or death at discharge (Cerebral Performance Category scale 3-5; p=0.002) as did all (9/9) patients with electrographic seizures (p=0.034). CONCLUSIONS Electrographic seizures and epileptiform activity are common cEEG findings in comatose, PCAS patients treated with TH. In this preliminary study, most seizures were status epilepticus, had onset prior to rewarming, evolved from prior interictal epileptiform activity, and were associated with short-term mortality and poor neurologic outcome. Larger, prospective studies are needed to further characterize seizure activity in comatose post-arrest patients.