Nathan I. Shapiro

A Randomized Trial of Protocol-Based Care for Early Septic Shock

BACKGROUND In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. METHODS In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy A Randomized Clinical Trial

CONTEXT Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department. OBJECTIVE To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation. DESIGN, SETTING, AND PATIENTS Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals. INTERVENTIONS We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. MAIN OUTCOME MEASURE The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%. RESULTS Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups. CONCLUSION Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00372502.

Association Between Arterial Hyperoxia Following Resuscitation From Cardiac Arrest and In-Hospital Mortality

CONTEXT Laboratory investigations suggest that exposure to hyperoxia after resuscitation from cardiac arrest may worsen anoxic brain injury; however, clinical data are lacking. OBJECTIVE To test the hypothesis that postresuscitation hyperoxia is associated with increased mortality. DESIGN, SETTING, AND PATIENTS Multicenter cohort study using the Project IMPACT critical care database of intensive care units (ICUs) at 120 US hospitals between 2001 and 2005. Patient inclusion criteria were age older than 17 years, nontraumatic cardiac arrest, cardiopulmonary resuscitation within 24 hours prior to ICU arrival, and arterial blood gas analysis performed within 24 hours following ICU arrival. Patients were divided into 3 groups defined a priori based on PaO(2) on the first arterial blood gas values obtained in the ICU. Hyperoxia was defined as PaO(2) of 300 mm Hg or greater; hypoxia, PaO(2) of less than 60 mm Hg (or ratio of PaO(2) to fraction of inspired oxygen <300); and normoxia, not classified as hyperoxia or hypoxia. MAIN OUTCOME MEASURE In-hospital mortality. RESULTS Of 6326 patients, 1156 had hyperoxia (18%), 3999 had hypoxia (63%), and 1171 had normoxia (19%). The hyperoxia group had significantly higher in-hospital mortality (732/1156 [63%; 95% confidence interval {CI}, 60%-66%]) compared with the normoxia group (532/1171 [45%; 95% CI, 43%-48%]; proportion difference, 18% [95% CI, 14%-22%]) and the hypoxia group (2297/3999 [57%; 95% CI, 56%-59%]; proportion difference, 6% [95% CI, 3%-9%]). In a model controlling for potential confounders (eg, age, preadmission functional status, comorbid conditions, vital signs, and other physiological indices), hyperoxia exposure had an odds ratio for death of 1.8 (95% CI, 1.5-2.2). CONCLUSION Among patients admitted to the ICU following resuscitation from cardiac arrest, arterial hyperoxia was independently associated with increased in-hospital mortality compared with either hypoxia or normoxia.

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol.

Objectives:To describe the effectiveness of a comprehensive, interdisciplinary sepsis treatment protocol with regard to both implementation and outcomes and to compare the mortality rates and therapies of patients with septic shock with similar historical controls. Design:Prospective, interventional cohort study with a historical control comparison group. Setting:Urban, tertiary care, university hospital with 46,000 emergency department visits and 4,100 intensive care unit admissions annually. Patients:Inclusion criteria were a) emergency department patients aged ≥18 yrs, b) suspected infection, and c) lactate of >4 mmol/L or septic shock. Exclusion criteria were a) emergent operation, b) prehospital cardiac arrest, and c) comfort measures only. Time period: protocol, November 10, 2003, through November 9, 2004; historical controls, February 1, 2000, through January 31, 2001. Intervention:A sepsis treatment pathway incorporating empirical antibiotics, early goal-directed therapy, drotrecogin alfa, steroids, intensive insulin therapy, and lung-protective ventilation. Measurements and Main Results:There were 116 protocol patients, with a mortality rate of 18% (11–25%), of which 79 patients had septic shock. Comparing these patients with 51 historical controls, protocol patients received more fluid (4.0 vs. 2.5 L crystalloid, p < .001), earlier antibiotics (90 vs. 120 mins, p < .013), more appropriate empirical coverage (97% vs. 88%, p < .05), more vasopressors in the first 6 hrs (80% vs. 45%, p < .001), tighter glucose control (mean morning glucose, 123 vs. 140, p < .001), and more frequent assessment of adrenal function (82% vs. 10%, p < .001), with a nonstatistically significant increase in dobutamine use (14% vs. 4%, p = .06) and red blood cell transfusions (30% vs. 18%, p = .07) in the first 24 hrs. For protocol patients with septic shock, 28-day in-hospital mortality was 20.3% compared with 29.4% for historical controls (p = .3). Conclusions:Clinical implementation of a comprehensive sepsis treatment protocol is feasible and is associated with changes in therapies such as time to antibiotics, intravenous fluid delivery, and vasopressor use in the first 6 hrs. No statistically significant decrease in mortality was demonstrated, as this trial was not sufficiently powered to assess mortality benefits.

Mortality in Emergency Department Sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule.

ObjectivesOur objectives were a) to identify univariate correlates of death in emergency department patients at risk for infection; b) to perform multivariate analyses and identify independent predictors of death; and c) to develop and internally validate a prediction rule that may be used in the emergency department to risk stratify patients into different risk groups to predict their mortality rate. DesignProspective cohort study. SettingEmergency department of an urban university referral center. PatientsConsecutive emergency department patients, aged 18 or older, who were at risk for infection, as indicated by the emergency department physician ordering a blood culture between February 1, 2000, and February 1, 2001. Of 3,301 eligible patient visits, 3,179 (96%) were enrolled. InterventionsNone. Measurements and Main ResultsThe primary outcome was 28-day in-hospital mortality rate. There were 2,070 visits in the derivation set, with 110 deaths (5.3%), and 1,109 visits in the validation set, with 63 deaths (5.7%). Independent multivariate predictors of death were terminal illness (odds ratio, 6.1; 95% confidence interval, 3.6–10.2), tachypnea or hypoxia (2.7, 1.6–4.3), septic shock (2.7, 1.2–5.7), platelet count <150,000 (2.5, 1.5–4.3), band proportion >5% (2.3, 1.5–3.5), age >65 (2.2, 1.3–3.6), lower respiratory infection (1.9, 1.2–3.0), nursing home residence (1.9, 1.2–3.0), and altered mental status (1.6, 1.0–2.6). The clinical prediction rule stratified patients into mortality risk groups of very low, 0.9% (95% confidence interval, 0.2–1.5%); low, 2.0% (0.8–3.2%); moderate, 7.8% (5.6–10%); high, 20% (13–27%); and very high, 50% (36.1–64%) in the derivation set. Mortality rates for the corresponding risk groups in the validation set were 1.1%, 4.4%, 9.3%, 16%, and 39%, respectively. The receiver operating characteristic area for the rule was 0.82 in the derivation set and 0.78 in the validation set. ConclusionsIn patients with suspected infection, this model identifies significant correlates of death and allows stratification of patients according to mortality risk. As new therapies become available for patients with sepsis syndromes, the ability to predict mortality risk may be helpful in triage and treatment decisions.

National estimates of severe sepsis in United States emergency departments.

Objective:The emergency department (ED) often serves as the first site for the recognition and treatment of patients with suspected severe sepsis. However, few evaluations of the national epidemiology and distribution of severe sepsis in the ED exist. We sought to determine national estimates of the number, timing, ED length of stay, and case distribution of patients presenting to the ED with suspected severe sepsis. Design:Analysis of 2001–2004 ED data from the National Hospital Ambulatory Medical Care Survey. Setting:National multistage probability sample of United States ED data. Patients:Adult (age, ≥18 yrs) patients with suspected severe sepsis, defined as the concurrent presence of an infec-tion (ED International Classification of Diseases, 9th Revision; ICD-9) diagnosis of infection, or a triage temperature <96.8°F or ≥100.4°F) and organ dysfunction (ED ICD-9) diagnosis of organ dysfunction, intubation, or a triage systolic blood pressure ≤90 mm Hg). Interventions:None. Measurements:Estimated number of ED patients presenting with suspected severe sepsis, and their times of arrival, ED lengths of stay, and clinical characteristics. Main Results:Of 331.5 million adult ED visits, approximately 2.3 million (571,000 annually, 0.69%; 95% confidence interval [CI], 0.61–0.77%) were for suspected severe sepsis. Mean ED length of stay for suspected severe sepsis was 4.7 hrs (95% CI, 4.3–5.1 hrs), with 20.4% spending >6 hrs in the ED. Of suspected severe sepsis patients, 20.6% presented to a low-volume ED (≤20,000 annual visits), 15.6% presented to ED in non–Metropolitan Statistical Areas, and 53.5% presented to EDs without medical school affiliations. More than half arrived by ambulance. Conclusions:Suspected severe sepsis patients account for more than 500,000 ED visits annually, with individual patients spending an average of almost 5 hrs in the ED. These national data offer key systemwide information for designing and implementing strategies for severe sepsis treatment.

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.

Relationship Between Supranormal Oxygen Tension and Outcome After Resuscitation From Cardiac Arrest

Background— Laboratory and recent clinical data suggest that hyperoxemia after resuscitation from cardiac arrest is harmful; however, it remains unclear if the risk of adverse outcome is a threshold effect at a specific supranormal oxygen tension, or is a dose-dependent association. We aimed to define the relationship between supranormal oxygen tension and outcome in postresuscitation patients. Methods and Results— This was a multicenter cohort study using the Project IMPACT database (intensive care units at 120 US hospitals). Inclusion criteria were age >17 years, nontrauma, cardiopulmonary resuscitation preceding intensive care unit arrival, and postresuscitation arterial blood gas obtained. We excluded patients with hypoxia or severe oxygenation impairment. We defined the exposure by the highest partial pressure of arterial oxygen (PaO2) over the first 24 hours in the ICU. The primary outcome measure was in-hospital mortality. We tested the association between PaO2 (continuous variable) and mortality using multivariable logistic regression adjusted for patient-oriented covariates and potential hospital effects. Of 4459 patients, 54% died. The median postresuscitation PaO2 was 231 (interquartile range 149 to 349) mm Hg. Over ascending ranges of oxygen tension, we found significant linear trends of increasing in-hospital mortality and decreasing survival as functionally independent. On multivariable analysis, a 100 mm Hg increase in PaO2 was associated with a 24% increase in mortality risk (odds ratio 1.24 [95% confidence interval 1.18 to 1.31]. We observed no evidence supporting a single threshold for harm from supranormal oxygen tension. Conclusion— In this large sample of postresuscitation patients, we found a dose-dependent association between supranormal oxygen tension and risk of in-hospital death.

Multicenter Study of Central Venous Oxygen Saturation (ScvO2) as a Predictor of Mortality in Patients With Sepsis

STUDY OBJECTIVE Abnormal (both low and high) central venous saturation (ScvO(2)) is associated with increased mortality in emergency department (ED) patients with suspected sepsis. METHODS This was a secondary analysis of 4 prospectively collected registries of ED patients treated with early goal-directed therapy-based sepsis resuscitation protocols from 4 urban tertiary care hospitals. Inclusion criteria were sepsis, hypoperfusion defined by systolic blood pressure less than 90 mm Hg or lactate level greater than or equal to 4 mmol/L, and early goal-directed therapy treatment. ScvO(2) levels were stratified into 3 groups: hypoxia (ScvO(2) <70%); normoxia (ScvO(2) 71% to 89%); and hyperoxia (ScvO(2) 90% to 100%). The primary exposures were initial ScvO(2) and maximum ScvO(2) achieved, with the primary outcome as inhospital mortality. Multivariate analysis was performed. RESULTS There were 619 patients who met criteria and were included. For the maximum ScvO(2), compared with the mortality rate in the normoxia group of 96 of 465 (21%; 95% confidence interval [CI] 17% to 25%), both the hypoxia mortality rate, 25 of 62 (40%; 95% CI 29% to 53%) and hyperoxia mortality rate, 31 of 92 (34%; 95% CI 25% to 44%) were significantly higher, which remained significant in a multivariate modeling. When the initial ScvO(2) measurement was analyzed in a multivariate model, only hyperoxia was significantly higher. CONCLUSION The maximum ScvO(2) value achieved in the ED (both abnormally low and high) was associated with increased mortality. In multivariate analysis for initial ScvO(2), the hyperoxia group was associated with increased mortality, but not the hypoxia group. This study suggests that future research aimed at targeting methods to normalize high ScvO(2) values by therapies that improve microcirculatory flow or mitochondrial dysfunction may be warranted.