Sepsis


Chapter 31
Sepsis


Lucas Oliveira Junqueira e Silva1,2 and Fernanda Bellolio2


1 Department of Emergency Medicine, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil


2 Department of Emergency Medicine, Mayo Clinic, Rochester, MN, USA


Background


Sepsis is a clinical syndrome that was initially seen as a systemic inflammatory response that is a sequela of an acute infection. Further understanding of the pathophysiology of sepsis demonstrated that it is not simply systemic inflammation that leads to pathology but also major modifications in nonimmunologic pathways.1 Given significant changes in the understanding of the disease, the Third Annual Consensus Definitions for Sepsis and Septic Shock (Sepsis‐3) redefined the core concepts in 2016 using a data‐driven approach.2 The systemic inflammatory response syndrome (SIRS) criteria (Table 31.1) from the definition of sepsis were removed and sepsis was defined as a “life‐threatening organ dysfunction caused by a dysregulated host response to infection.” Table 31.2 illustrates the old (based on Sepsis‐1 and Sepsis‐2 consensus)3,4 and new (based on Sepsis‐3 consensus)2,5 definitions of sepsis.


Recent estimates indicate that in the United States (U.S.), up to 850,000 sepsis‐related emergency department (ED) visits occur annually, with an approximately 70% admission rate.6 The burden associated with sepsis includes significant morbidity and mortality across all ages and populations. Although high‐income countries have reported decreasing mortality rates,7 the mortality rates in low‐ and middle‐income countries (LMICs) are still high, ranging from 30% to 70%.8


Table 31.1 Systemic inflammatory response syndrome (SIRS) criteria


Source: Data from [3].













SIRS is defined as the presence of two or more of the following:


  • Heart rate >90 beats/min


  • Respiratory rate >20 breaths/min or oxygen saturation <90% or need for >0.4 FiO2 to maintain saturation


  • Temperature >38 °C or <35.5 °C


  • White blood cell count >15,000 cells/mm3 or bands >10%

Table 31.2 Old and new definitions of sepsis
























Sepsis‐1 and Sepsis‐23,4 Sepsis‐32
Sepsis The presence of two or more SIRS criteria associated with the presence of an infection “Life‐threatening organ dysfunction caused by a dysregulated host response to infection”
Organ dysfunction is identified as an acute change in total SOFA score ε 2 consequent to the infection
Outside the ICU, qSOFA ε 2 should be used as a predictor of in‐hospital mortality and ICU stay
Severe sepsis Sepsis and at least one sign of hypoperfusion or organ dysfunction This term no longer exists
Septic shock Sepsis and at least one sign of hypoperfusion or the requirement for a vasopressor Septic patient with persisting hypotension requiring vasopressors to maintain MAP ε 65 mmHg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation

MAP = mean arterial pressure; qSOFA = quick SOFA; SOFA = sequential (sepsis‐related) organ failure assessment.


In the ED, clinicians are challenged to identify sepsis early in its course and to identify patients at risk of adverse events. Early identification is required to initiate a bundle of interventions associated with improved outcomes such as early antibiotics, source control, hemodynamically‐based fluid resuscitation, and vasopressors.9 The diagnosis of sepsis is often a challenging task for the emergency physician as it is largely a clinical diagnosis and lacks a gold standard diagnostic test.


Clinical question


Can clinical scoring systems identify patients with suspected infection in the ED who are at high risk of clinical deterioration?


The Sepsis‐3 Task Force recommends the use of quick sequential (sepsis‐related) organ failure assessment (qSOFA, Table 31.3) in the ED to identify among patients with suspected infection as those with a higher risk of poor outcomes.2 They suggest the use of this score rather than the old SIRS‐based criteria to further investigate for organ dysfunction and initiate or escalate therapy as appropriate for the clinical syndrome of sepsis. In their proposed algorithm, any patient with suspected infection and qSOFA ε 2 should undergo evaluation for evidence of organ dysfunction and, if they have a sequential (sepsis‐related) organ failure assessment (SOFA) ε 2, they are considered septic2,10 (Tables 31.3 and 31.4).


The qSOFA was derived and internally validated through a large retrospective U.S.‐based cohort study including both encounters in‐ and outside of the intensive care unit (ICU).10 The primary cohort included 148,907 encounters with suspected infection of whom 6347 (4%) died in the hospital. In the population outside of the ICU (i.e., ED and wards), there were 66,617 encounters in the derivation cohort and 66,522 in the validation cohort. Patients with suspected infection were defined as those who had body fluids sampled for culture and received antibiotics. The primary outcome was in‐hospital mortality. In the derivation cohort, the area under the curve (AUC) for in‐hospital mortality of qSOFA was 0.81 (confidence interval [CI] 0.80–0.82). In the validation cohort (n = 66,552 with suspected infection of whom 1886 [3%] died), qSOFA had the same AUC of 0.81 (95% CI 0.80–0.82), which was better than SOFA (AUC 0.79) and SIRS (AUC 0.76). The same authors explored the discrimination of qSOFA to predict in‐hospital mortality in external datasets including four U.S.‐based cohorts and one cohort from Germany. The AUCs of qSOFA ranged from 0.71 (95% CI 0.69–0.73) in a cohort of 6508 patients with community‐acquired infections to 0.78 (95% CI 0.78–0.79) in a cohort of 377,325 patients with all types of suspected infections. Although the authors stated that the failure to meet the two or more qSOFA criteria should not delay the management deemed appropriate by providers, this tool became a screening tool to “rule out” sepsis in many EDs, especially in resource‐limited settings where laboratory testing is often not readily available.11


Table 31.3 Quick SOFA (qSOFA)


Source: Data from [2].











Patients with suspected infection who are likely to have prolonged ICU stay or to die in the hospital can be identified at the beside with the presence of two or more of the following:


  • Respiratory rate ε 22/min


  • Altered mental status


  • Systolic blood pressure δ 100 mmHg

Table 31.4 Sequential (sepsis‐related) organ failure assessment (SOFA)


Source: Data from [2].

















A SOFA score of two or more reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection


  • Respiration: PaO2/FiO2 ε 400 mmHg (0 points), <400 (1 point), <300 (2 points), <200 with respiratory support (3 points), <100 with respiratory support (4 points)


  • Coagulation: platelets ε 150 × 103/μL (0 points), <150 (1 point), <100 (2 points), <50 (3 points), <20 (4 points)


  • Liver: bilirubin <1.2 mg/dL (0 points), 1.2–1.9 (1 point), 2.0–5.9 (2 point), 6.0–11.9 (3 points), >12 (4 points)


  • Cardiovascular: MAP ε 70 mmHg (0 points), MAP <70 (1 point), Dopamine <5 or dobutamine (any dose) (2 points), dopamine 5.1–15 or epinephrine δ 0.1 or norepinephrine δ 0.1 (3 points), dopamine >15 or epinephrine >0.1 or norepinephrine >0.1 (4 points)


  • Central nervous system: GCS 15 (0 points), GCS 13–14 (1 point), GCS 10–12 (2 points), GCS 6–9 (3 points), GCS <6 (4 points)


  • Renal: creatinine <1.2 mg/dL (0 points), 1.2–1.9 (1 point), 2.0–3.4 (2 points), 3.5–4.9 (3 points), >5 (4 points). Urine output <500 mL/day (3 points), <200 (4 points)

After the publication of Sepsis‐3, several external validation studies were carried out and the evidence was comprehensively analyzed by subsequent systematic reviews and meta‐analyses. Fernando et al.12 compared the prognostic accuracy of qSOFA and SIRS for mortality in patients with suspected infection. They included 19 ED‐based cohorts including 61,894 patients and found a pooled sensitivity and specificity for qSOFA ε 2 of 46.7% (95% CI 38.3–55.2%) and 81.3% (95% CI 72.8–87.5%), respectively. Among 9 ED‐based cohorts with 49,640, SIRS ε 2 had a higher sensitivity although lower specificity (sensitivity 83.6% [95% CI 75.9–89.1%], specificity 30.6% [95% CI 17.7–39.5%]). It is important to note that studies have used different definitions for the primary outcome such as in‐hospital mortality, 28‐ or 30‐day mortality. However, the summary estimates did not significantly change in subgroup and sensitivity analyses. Serafim et al.13 compared qSOFA with SIRS for the diagnosis of sepsis. They included 10 studies with a total of 229,480 patients. The sensitivity of SIRS ε 2 for diagnosis of sepsis ranged from 39.5% to 88.3%, while the sensitivity of qSOFA ε 2 ranged from 10.2% to 54.4%. Song et al.14, compared both tools for in‐hospital mortality prediction and acute organ dysfunction. They included 23 studies with a total of 146,551 patients in their quantitative analysis. In the meta‐analysis, qSOFA had AUCs for in‐hospital mortality and acute organ dysfunction of 0.74 (95% CI 0.70–0.78) and 0.86 (95% CI 0.83–0.89), respectively; SIRS had an AUC of 0.71 (CI 0.67–0.75) for predicting in‐hospital mortality and of 0.76 (95% CI 0.73–0.80) for predicting acute organ dysfunction. The sensitivities for both outcomes were significantly higher with SIRS (Table 31.5). Jiang et al.15 included 8 studies with 52,849 patients in their systematic review. The pooled sensitivity for predicting mortality in infected ED patients was higher with SIRS (81% [95% CI 75–86%]) than with qSOFA (42% [95% CI 31–54%]). Tan et al.16 included 35 studies that looked at short‐term mortality outcomes among 269,544 patients presenting outside of the ICU. The pooled sensitivity and specificity of qSOFA were 48% and 86%, respectively. In 2019, Liu et al.17 performed a systematic review and analyzed 17 ED‐based studies with 71,331 patients. For studies that used in‐hospital mortality as the primary outcome (13 studies, 27,978 patients), sensitivity of qSOFA was 61% (95% CI 50–71) and specificity was 70% (95% CI 59–82%). For studies that used 28‐ or 30‐day mortality outcomes (4 studies, 11,954 patients), sensitivity of qSOFA was 32% (95% CI 15–49) and specificity was 92% (95% CI 85–99).


The lower sensitivity of the qSOFA across several external validation studies raises concerns regarding potential delays in sepsis identification and treatment. Prasad et al.18 compared SIRS with qSOFA and SOFA with regards to their time to recognition of sepsis in a large retrospective study including 16,612 patients. SIRS resulted in earlier electronic health record sepsis identification in greater than 50% of patients.


In places where laboratory testing is often not available, providers might be tempted to use qSOFA as a “rule out” screening tool. However, this approach might lead to significant consequences. In a large observational study in Brazil including 4711 patients presenting outside the ICU with sepsis from 54 different hospitals,11 the mortality rate for patients with qSOFA δ 1 was 17.3%. The authors suggested the use of a cutoff of one or more, which increased the sensitivity of qSOFA from 53.9% to 84.9%. Rudd et al.19 also evaluated the qSOFA in LMICs and found an 8% mortality rate among those patients with a qSOFA δ 1.


Table 31.5 Main results of systematic reviews comparing qSOFA and SIRS



























































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May 14, 2023 | Posted by in Uncategorized | Comments Off on Sepsis

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Score AUC (95% CI) Sensitivity (95% CI) Specificity (95% CI)
Fernando et al.12 (19 ED‐based studies for qSOFA and 9 ED‐based studies for SIRS)


  • Outcome of mortality (in‐hospital or 28‐ or 30‐day mortality)
qSOFA NR 46.7% (38.3–55.2%) 81.3% (72.8–87.5%)
SIRS NR 83.6% (75.9–89.1%) 30.6% (17.7–39.5%)
Serafim et al.13 (10 all‐settings studies)


  • Outcome of diagnosis of sepsis
qSOFA NR 10.2–54.4%* 97.3%**
SIRS NR 39.5–88.3%* 84.4%**
Serafim et al.13 (10 all‐settings studies)


  • Outcome of mortality (in‐hospital or 28‐ or 30‐day mortality)
qSOFA NR 22.8–90% 27.4–91.3%
SIRS NR 19.9–97.4% 2.3–90.2%
Song et al.14 (23 studies outside of the ICU)


  • Outcome of in‐hospital mortality
qSOFA 0.74 (0.70–0.78) 51% (39–62%)