Christopher W. Seymour

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

IMPORTANCEnDefinitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.nnnOBJECTIVEnTo evaluate and, as needed, update definitions for sepsis and septic shock.nnnPROCESSnA task force (nu2009=u200919) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).nnnKEY FINDINGS FROM EVIDENCE SYNTHESISnLimitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.nnnRECOMMENDATIONSnSepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.nnnCONCLUSIONS AND RELEVANCEnThese updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

IMPORTANCEnThe Third International Consensus Definitions Task Force defined sepsis as life-threatening organ dysfunction due to a dysregulated host response to infection. The performance of clinical criteria for this sepsis definition is unknown.nnnOBJECTIVEnTo evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis.nnnDESIGN, SETTINGS, AND POPULATIONnAmong 1.3 million electronic health record encounters from January 1, 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania, we identified those with suspected infection in whom to compare criteria. Confirmatory analyses were performed in 4 data sets of 706,399 out-of-hospital and hospital encounters at 165 US and non-US hospitals ranging from January 1, 2008, until December 31, 2013.nnnEXPOSURESnSequential [Sepsis-related] Organ Failure Assessment (SOFA) score, systemic inflammatory response syndrome (SIRS) criteria, Logistic Organ Dysfunction System (LODS) score, and a new model derived using multivariable logistic regression in a split sample, the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score (range, 0-3 points, with 1 point each for systolic hypotension [≤100 mm Hg], tachypnea [≥22/min], or altered mentation).nnnMAIN OUTCOMES AND MEASURESnFor construct validity, pairwise agreement was assessed. For predictive validity, the discrimination for outcomes (primary: in-hospital mortality; secondary: in-hospital mortality or intensive care unit [ICU] length of stay ≥3 days) more common in sepsis than uncomplicated infection was determined. Results were expressed as the fold change in outcome over deciles of baseline risk of death and area under the receiver operating characteristic curve (AUROC).nnnRESULTSnIn the primary cohort, 148,907 encounters had suspected infection (nu2009=u200974,453 derivation; nu2009=u200974,454 validation), of whom 6347 (4%) died. Among ICU encounters in the validation cohort (nu2009=u20097932 with suspected infection, of whom 1289 [16%] died), the predictive validity for in-hospital mortality was lower for SIRS (AUROCu2009=u20090.64; 95% CI, 0.62-0.66) and qSOFA (AUROCu2009=u20090.66; 95% CI, 0.64-0.68) vs SOFA (AUROCu2009=u20090.74; 95% CI, 0.73-0.76; Pu2009<u2009.001 for both) or LODS (AUROCu2009=u20090.75; 95% CI, 0.73-0.76; Pu2009<u2009.001 for both). Among non-ICU encounters in the validation cohort (nu2009=u200966u202f522 with suspected infection, of whom 1886 [3%] died), qSOFA had predictive validity (AUROCu2009=u20090.81; 95% CI, 0.80-0.82) that was greater than SOFA (AUROCu2009=u20090.79; 95% CI, 0.78-0.80; Pu2009<u2009.001) and SIRS (AUROCu2009=u20090.76; 95% CI, 0.75-0.77; Pu2009<u2009.001). Relative to qSOFA scores lower than 2, encounters with qSOFA scores of 2 or higher had a 3- to 14-fold increase in hospital mortality across baseline risk deciles. Findings were similar in external data sets and for the secondary outcome.nnnCONCLUSIONS AND RELEVANCEnAmong ICU encounters with suspected infection, the predictive validity for in-hospital mortality of SOFA was not significantly different than the more complex LODS but was statistically greater than SIRS and qSOFA, supporting its use in clinical criteria for sepsis. Among encounters with suspected infection outside of the ICU, the predictive validity for in-hospital mortality of qSOFA was statistically greater than SOFA and SIRS, supporting its use as a prompt to consider possible sepsis.

Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

IMPORTANCEnSeptic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.nnnOBJECTIVEnTo develop a new definition and clinical criteria for identifying septic shock in adults.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; nu2009=u200928,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; nu2009=u20091,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; nu2009=u20091,847,165) electronic health record (EHR) data sets.nnnMAIN OUTCOMES AND MEASURESnEvidence for and agreement on septic shock definitions and criteria.nnnRESULTSnThe systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2u2009=u200999.5%; τ2u2009=u2009182.5; Pu2009<u2009.001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets.nnnCONCLUSIONS AND RELEVANCEnBased on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

Time to Treatment and Mortality during Mandated Emergency Care for Sepsis

BACKGROUND In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. METHODS We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3‐hour bundle of care for patients with sepsis (i.e., blood cultures, broad‐spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3‐hour bundle and risk‐adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. RESULTS Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3‐hour bundle completed within 3 hours. The median time to completion of the 3‐hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3‐hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk‐adjusted in‐hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). CONCLUSIONS More rapid completion of a 3‐hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk‐adjusted in‐hospital mortality. (Funded by the National Institutes of Health and others.)

Severe Sepsis in Pre-Hospital Emergency Care: Analysis of Incidence, Care, and Outcome

RATIONALEnSevere sepsis is common and highly morbid, yet the epidemiology of severe sepsis at the frontier of the health care system-pre-hospital emergency care-is unknown.nnnOBJECTIVESnWe examined the epidemiology of pre-hospital severe sepsis among emergency medical services (EMS) encounters, relative to acute myocardial infarction and stroke.nnnMETHODSnRetrospective study using a community-based cohort of all nonarrest, nontrauma King County EMS encounters from 2000 to 2009 who were transported to a hospital.nnnMEASUREMENTS AND MAIN RESULTSnOverall incidence rate of hospitalization with severe sepsis among EMS encounters, as well as pre-hospital characteristics, admission diagnosis, and outcomes. Among 407,176 EMS encounters, we identified 13,249 hospitalizations for severe sepsis, of whom 2,596 died in the hospital (19.6%). The crude incidence rate of severe sepsis was 3.3 per 100 EMS encounters, greater than for acute myocardial infarction or stroke (2.3 per 100 and 2.2 per 100 EMS encounters, respectively). More than 40% of all severe sepsis hospitalizations arrived at the emergency department after EMS transport, and 80% of cases were diagnosed on admission. Pre-hospital care intervals, on average, exceeded 45 minutes for those hospitalized with severe sepsis. One-half or fewer of patients with severe sepsis were transported by paramedics (n = 7,114; 54%) or received pre-hospital intravenous access (n = 4,842; 37%).nnnCONCLUSIONSnEMS personnel care for a substantial and increasing number of patients with severe sepsis, and spend considerable time on scene and during transport. Given the emphasis on rapid diagnosis and intervention for sepsis, the pre-hospital interval may represent an important opportunity for recognition and care of sepsis.

Developing a New Definition and Assessing New Clinical Criteria for Septic Shock

IMPORTANCEnSeptic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.nnnOBJECTIVEnTo develop a new definition and clinical criteria for identifying septic shock in adults.nnnDESIGN, SETTING, AND PARTICIPANTSnThe Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; nu2009=u200928,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; nu2009=u20091,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; nu2009=u20091,847,165) electronic health record (EHR) data sets.nnnMAIN OUTCOMES AND MEASURESnEvidence for and agreement on septic shock definitions and criteria.nnnRESULTSnThe systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2u2009=u200999.5%; τ2u2009=u2009182.5; Pu2009<u2009.001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets.nnnCONCLUSIONS AND RELEVANCEnBased on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

Hospital‐Level Variation in the Use of Intensive Care

OBJECTIVEnTo determine the extent to which hospitals vary in the use of intensive care, and the proportion of variation attributable to differences in hospital practice that is independent of known patient and hospital factors.nnnDATA SOURCEnHospital discharge data in the State Inpatient Database for Maryland and Washington States in 2006.nnnSTUDY DESIGNnCross-sectional analysis of 90 short-term, acute care hospitals with critical care capabilities. DATA COLLECTION/METHODS: We quantified the proportion of variation in intensive care use attributable to hospitals using intraclass correlation coefficients derived from mixed-effects logistic regression models after successive adjustment for known patient and hospital factors.nnnPRINCIPAL FINDINGSnThe proportion of hospitalized patients admitted to an intensive care unit (ICU) across hospitals ranged from 3 to 55 percent (median 12 percent; IQR: 9, 17 percent). After adjustment for patient factors, 19.7 percent (95 percent CI: 15.1, 24.4) of total variation in ICU use across hospitals was attributable to hospitals. When observed hospital characteristics were added, the proportion of total variation in intensive care use attributable to unmeasured hospital factors decreased by 26-14.6 percent (95 percent CI: 11, 18.3 percent).nnnCONCLUSIONSnWide variability exists in the use of intensive care across hospitals, not attributable to known patient or hospital factors, and may be a target to improve efficiency and quality of critical care.

Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014

Importance Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity and can be affected by changing diagnosis and coding practices over time. Objective To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. Design, Setting, and Population Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. Exposures Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance. Main Outcomes and Measures Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews. Results A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%] women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y [95% CI, −2.3% to 3.5%], Pu2009=u2009.67) whereas incidence per claims increased (+10.3%/y [95% CI, 7.2% to 13.3%], Pu2009<u2009.001). In-hospital mortality using clinical criteria declined (−3.3%/y [95% CI, −5.6% to −1.0%], Pu2009=u2009.004), but there was no significant change in the combined outcome of death or discharge to hospice (−1.3%/y [95% CI, −3.2% to 0.6%], Pu2009=u2009.19). In contrast, mortality using claims declined significantly (−7.0%/y [95% CI, −8.8% to −5.2%], Pu2009<u2009.001), as did death or discharge to hospice (−4.5%/y [95% CI, −6.1% to −2.8%], Pu2009<u2009.001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], Pu2009<u2009.001), with comparable positive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI, 69.8% to 80.6%], Pu2009=u2009.23). Conclusions and Relevance In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.

Septic Shock: Advances in Diagnosis and Treatment

IMPORTANCEnSeptic shock is a clinical emergency that occurs in more than 230,000 US patients each year. OBSERVATIONS AND ADVANCES: In the setting of suspected or documented infection, septic shock is typically defined in a clinical setting by low systolic (≤90 mm Hg) or mean arterial blood pressure (≤65 mm Hg) accompanied by signs of hypoperfusion (eg, oliguria, hyperlactemia, poor peripheral perfusion, or altered mental status). Focused ultrasonography is recommended for the prompt recognition of complicating physiology (eg, hypovolemia or cardiogenic shock), while invasive hemodynamic monitoring is recommended only for select patients. In septic shock, 3 randomized clinical trials demonstrate that protocolized care offers little advantage compared with management without a protocol. Hydroxyethyl starch is no longer recommended, and debate continues about the role of various crystalloid solutions and albumin.nnnCONCLUSIONS AND RELEVANCEnThe prompt diagnosis of septic shock begins with obtainment of medical history and performance of a physical examination for signs and symptoms of infection and may require focused ultrasonography to recognize more complex physiologic manifestations of shock. Clinicians should understand the importance of prompt administration of intravenous fluids and vasoactive medications aimed at restoring adequate circulation, and the limitations of protocol-based therapy, as guided by recent evidence.

Critical Care Bed Growth in the United States. A Comparison of Regional and National Trends

RATIONALEnAlthough the number of intensive care unit (ICU) beds in the United States is increasing, it is unknown whether this trend is consistent across all regions.nnnOBJECTIVESnWe sought to better characterize regional variation in ICU bed changes over time and identify regional characteristics associated with these changes.nnnMETHODSnWe used data from the Centers for Medicare and Medicaid Services and the U.S. Census to summarize the numbers of hospitals, hospital beds, ICU beds, and ICU occupancy at the level of Dartmouth Atlas hospital referral region from 2000 to 2009. We categorized regions into quartiles of bed change over the study interval and examined the relationship between change categories, regional characteristics, and population characteristics over time.nnnMEASUREMENTS AND MAIN RESULTSnFrom 2000 to 2009 the national number of ICU beds increased 15%, from 67,579 to 77,809, mirroring population. However, there was substantial regional variation in absolute changes (median, +16 ICU beds; interquartile range, -3 to +51) and population-adjusted changes (median, +0.9 ICU beds per 100,000; interquartile range, -3.8 to +5.9), with 25.0% of regions accounting for 74.8% of overall growth. At baseline, regions with increasing numbers of ICU beds had larger populations, lower ICU beds per 100,000 capita, higher average ICU occupancy, and greater market competition as measured by the Herfindahl-Hirschman Index (Pu2009<u20090.001 for all comparisons).nnnCONCLUSIONSnNational trends in ICU bed growth are not uniformly reflected at the regional level, with most growth occurring in a small number of highly populated regions.