Mark E. Mikkelsen

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.

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 Identification of Patients at Risk of Acute Lung Injury: Evaluation of Lung Injury Prediction Score in a Multicenter Cohort Study

RATIONALE Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. OBJECTIVES To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). METHODS In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. MEASUREMENTS AND MAIN RESULTS Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). CONCLUSIONS ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: Long-Term Neuropsychological Function in Survivors of Acute Lung Injury

RATIONALE Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. OBJECTIVES To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment. METHODS As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge. MEASUREMENTS AND MAIN RESULTS Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02). CONCLUSIONS Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

Underuse of lung protective ventilation: analysis of potential factors to explain physician behavior.

Objective:To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume. Design:Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002. Setting:Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital. Measurements and Main Results:Measurements included the proportion for whom the ventilation tidal volume (TV) was ≤7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was ≤6.5 and ≤8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV ≤7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006). Conclusions:Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians’ underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

Severe Sepsis Cohorts Derived From Claims-based Strategies Appear to be Biased Toward a More Severely Ill Patient Population*

Objective:The epidemiology of severe sepsis is derived from administrative databases that rely on International Classification of Diseases, 9th Revision, Clinical Modification (ICD–9-CM) codes to select cases. We compared the sensitivity of two code abstraction methods in identifying severe sepsis cases using a severe sepsis registry. Design:Single-center retrospective cohort study. Setting:Tertiary care, Academic, University Hospital. Patients:One thousand seven hundred thirty-five patients with severe sepsis or septic shock. Interventions:None. Measurements:Proportion identified as severe sepsis using two code abstraction methods: 1) the new specific ICD-9 codes for severe sepsis and septic shock, and 2) a validated method requiring two ICD-9 codes for infection and end-organ dysfunction. Multivariable logistic regression was performed to determine sociodemographics and clinical characteristics associated with documentation and coding accuracy. Main Results:The strategy combining a code for infection and end-organ dysfunction was more sensitive in identifying cases than the method requiring specific ICD-9 codes for severe sepsis or septic shock (47% vs. 21%). Elevated serum lactate level (p < 0.001), ICU admission (p < 0.001), presence of shock (p < 0.001), bacteremia as the source of sepsis (p = 0.02), and increased Acute Physiology and Chronic Health Evaluation II score (p < 0.001) were independently associated with being appropriately documented and coded. The 28-day mortality was significantly higher in those who were accurately documented/coded (41%, compared with 14% in those who were not, p < 0.001), reflective of a more severe presentation on admission. Conclusions:Patients admitted with severe sepsis and septic shock were incompletely documented and under-coded, using either ICD-9 code abstracting method. Documentation of subsequent coding of severe sepsis was more common in more severely ill patients. These findings are important when evaluating current national estimates and when interpreting epidemiologic studies of severe sepsis as cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population.

Factors Associated With Nonadherence to Early Goal-Directed Therapy in the ED

BACKGROUND Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the ED. EGDT appears to be underused, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED. METHODS This was a cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005 to 2007. EGDT eligibility was defined as a serum lactate >or= 4 mmol/L or systolic BP< 90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was used to adjust for potential confounding. RESULTS EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0% to 100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female sex of the patient (P = .001), female sex of the clinician (P = .041), serum lactate (rather than hemodynamic) criterion for EGDT (P = .018), and nonconsultation to the Severe Sepsis Service (P < .001). CONCLUSIONS Despite a formalized protocol, we found that EGDT was underused. We identified potential barriers to the effective implementation of EGDT at the patient, clinician, and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence.

The Epidemiology of Acute Respiratory Distress Syndrome in Patients Presenting to the Emergency Department With Severe Sepsis.

ABSTRACT Background: Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED). Methods: This was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development. Results: The incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care: 0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2–3.9 mmol/L) (P = 0.04) and high (≥4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01). Conclusions: In patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis.

Emergency department lactate is associated with mortality in older adults admitted with and without infections.

OBJECTIVES Serum lactate values in the emergency department (ED) have been associated with mortality in diverse populations of critically ill patients. This study investigates whether serum lactate values measured in the ED are associated with mortality in older patients admitted to the hospital, both with and without infections. METHODS This is a retrospective cohort study performed at two urban teaching hospitals. The study population includes 1,655 older ED patients (age>or=65 years) over a 3-year period (2004-2006) who had serum lactate measured prior to admission. The presence or absence of infection was determined by review of International Classification of Diseases Ninth Revision (ICD-9) admission diagnosis codes. Mortality during hospitalization was determined by review of inpatient records. Mortality at 30 and at 60 days was determined using a state death registry. RESULTS In patients with infections, increasing serum lactate values of >or=2.0 mmol/L were linearly associated with relative risk (RR) of mortality during hospitalization (RR=1.9 to 3.6 with increasing lactate), at 30 days (RR=1.7 to 2.6), and at 60 days (RR=1.4 to 2.3) when compared to patients with serum lactate levels of <2.0 mmol/L. In patients without infections, a similar association was observed (RR=1.1 to 3.9 during hospitalization, RR=1.2 to 2.6 at 30 days, RR=1.1 to 2.4 at 60 days). In both groups of patients, serum lactate had a greater magnitude of association with mortality than either of two other commonly ordered laboratory tests, leukocyte count and serum creatinine. CONCLUSIONS Higher ED lactate values are associated with greater mortality in a broad cohort of admitted patients over age 65 years, regardless of the presence or absence of infection.

Out-of-hospital characteristics and care of patients with severe sepsis: A cohort study

PURPOSE Early recognition and treatment in severe sepsis improve outcomes. However, out-of-hospital patient characteristics and emergency medical services (EMS) care in severe sepsis is understudied. Our goals were to describe out-of-hospital characteristics and EMS care in patients with severe sepsis and to evaluate associations between out-of-hospital characteristics and severity of organ dysfunction in the emergency department (ED). MATERIALS AND METHODS We performed a secondary data analysis of existing data from patients with severe sepsis transported by EMS to an academic medical center. We constructed multivariable linear regression models to determine if out-of-hospital factors are associated with serum lactate and sequential organ failure assessment (SOFA) in the ED. RESULTS Two hundred sixteen patients with severe sepsis arrived by EMS. Median serum lactate in the ED was 3.0 mmol/L (interquartile range, 2.0-5.0) and median SOFA score was 4 (interquartile range, 2-6). Sixty-three percent (135) of patients were transported by advanced life support providers and 30% (62) received intravenous fluid. Lower out-of-hospital Glasgow Coma Scale score was independently associated with elevated serum lactate (P < .01). Out-of-hospital hypotension, greater respiratory rate, and lower Glasgow Coma Scale score were associated with greater SOFA (P < .01). CONCLUSIONS Out-of-hospital fluid resuscitation occurred in less than one third of patients with severe sepsis, and routinely measured out-of-hospital variables were associated with greater serum lactate and SOFA in the ED.