Systemic inflammatory response syndrome in Sepsis-3: a retrospective study

This retrospective study was conducted in a general intensive care unit (ICU) and included adult patients with sepsis or septic shock according to the Sepsis-3 definition from 1 January to 31 December 2015, using data from the Sichuan University West China Hospital Critical Care Medicine Sepsis-3 Database. This study was approved by the Ethics Committee of Sichuan University West China Hospital (No. 315, 2016). Due to the retrospective study design involving electronic health records and no additional interventions, written informed consent was not obtained from the patients or their relatives. This study was registered at the Chinese Clinical Trial Register (CCTR number: ChiCTR-ORC-16010138, registered 12 December 2016). URL: http://​www.​chictr.​org.​cn/​showproj.​aspx?​proj=​16715.

In this study, we regarded SIRS-positive sepsis as the primary outcome and followed up all patients before hospital discharge using their medical records. All-cause in-hospital mortality was the secondary outcome.

Indicators were generated for each component of the SIRS criteria [6] and SOFA score [15]. We calculated the maximum SIRS criteria and SOFA score for the time window ranging from 48 h before to 24 h after the onset of infection. Organ dysfunction in patients with sepsis occurring before, near the moment of, or after infection is recognized by clinicians. Thus, for the candidate criteria, we used that time window. From up to 48 h before to up to 24 h after the onset of infection, we calculated changes of ≥2 points in the SOFA score [7, 12].

We defined sepsis or septic shock according to the Sepsis-3 definitions [7]. Organ dysfunction can be identified as an acute change of ≥2 points in the total SOFA score consequent to the infection. The baseline SOFA score can be assumed to be 0 points in patients not known to have pre-existing organ dysfunction. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention if not already being instituted. Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be identified using a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain the mean arterial pressure at ≥65 mmHg and serum lactate concentration at > 2 mmol/L (18 mg/dL) despite adequate volume resuscitation.

Among the Sepsis-3 cohort, the SIRS-positive cohort was defined as patients with SIRS scores of ≥2 points, and the SIRS-negative cohort was defined as patients with SIRS scores of < 2 points, including those with scores of 0 points and 1 point [6].

We collected general information including medical identification numbers, demographic characteristics, vital signs, and laboratory test results from the medical records of patients upon admission to the ICU or during their stay in the ICU. We calculated the SIRS and SOFA scores for each patient using these data. Acute Physiology and Chronic Health Evaluation II (APACHE II) [16] scores were collected to assess the severity of illness among patients admitted to the ICU in the first 24 h.

Researchers who participated in data collection for the study were blinded to the study design, and the study designers did not participate in the data collection.

Data are presented as number and percentage, mean and standard deviation, median and interquartile range, or proportion with 95% confidence interval. The chi-square test for equal proportion, Student’s t-test, or the Wilcoxon rank-sum test was used to test differences. No assumptions were made for missing data, and multivariable analyses were performed for patients with complete data.

To identify independent differences at baseline that may have existed between patients with SIRS-positive sepsis and SIRS-negative sepsis, we applied multivariable logistic regression to the data from all patients with severe sepsis with a SIRS-positive status as the outcome. To further determine the predictive capacity of using two or more SIRS criteria to identify an increase in the risk of death, SIRS was considered first as a dichotomous variable (≥2 SIRS criteria vs. 0 to 1 SIRS criterion) and second as an ordinal variable from 0 to 4, reflecting the number of SIRS criteria met. To determine whether predictors of death differed significantly between SIRS-positive sepsis and SIRS-negative sepsis, we created a multivariable logistic regression model for mortality among all patients with sepsis. All statistical analyses were performed using MedCalc® (version 15.8) statistical software [17] and Empower Stats software [18]. All statistical tests were two-tailed, and p < 0.05 was considered significant.

A flow diagram of the study is shown in Fig. 1. As described in the Methods section, 1243 patients were evaluated in the enrollment period and 873 patients had complete clinical data. We finally enrolled 631 patients with sepsis or septic shock according to the Sepsis-3 definition. In total, 370 patients were excluded because of a < 24-h ICU length of stay (n = 247), secondary admission to the ICU (n = 121), and an age of < 18 years (n = 2). Of 538 patients enrolled in the.

The patients’ baseline characteristics are listed in Table 1. The patients’ age was higher in the SIRS-negative cohort than in the SIRS-positive cohort (p = 0.011). The SIRS scores were higher in the positive than negative cohort. The median APACHE II score for all patients upon ICU arrival was 25. SOFA scores were available for 631 patients, and the median was 9. The SOFA and APACHE II scores were not significantly different between the two cohorts. The median length of ICU stay was 13 days (range, 7–24 days); it was also 13 days in the SIRS-positive and -negative cohorts separately, and pairwise comparison showed no significant difference (p = 0.622). The median length of hospital stay was 22 days (range, 12.5–35 days); it was 22 and 20 days in the SIRS-positive and -negative cohorts, respectively, and pairwise comparison showed no significant difference (p = 0.569). The proportion of male patients was 66.1% (417 of 631), and there was no significant difference in the proportion of male patients between the SIRS-positive and -negative cohorts (p = 0.412). The median 28-day of ventilator-free days and the duration of continuous renal replacement therapy were 8 and 10 days, respectively, with no significant differences between the two SIRS cohorts. The rates of mechanical ventilation and continuous renal replacement therapy in patients with sepsis were not significantly different between the cohorts (both p > 0.05). However, the rate of septic shock in patients with sepsis was higher in the SIRS-positive than SIRS-negative cohort (p = 0.044).

The distributions of hospital mortality according to the SIRS score and subsets of the new Sepsis-3 definition are shown in Fig. 2. An increasing trend of hospital mortality with increasing SIRS scores was not evident (p > 0.05) (Fig. 2a). This held true for both the SIRS-positive and -negative cohorts (Fig. 2b). However, the distribution of hospital mortality was higher in the subgroups of patients with septic shock than in the subgroups of patients with sepsis (p < 0.001) (Fig. 2c). Among all age interval subgroups, the fold changes (ratio) of hospital mortality (SIRS score of ≥2 vs. < 2) were higher in the intervals of 3, 6, and 7 than in the other intervals (Fig. 3).

The distributions of signs meeting the SIRS criteria are shown in Table 2. The most frequent SIRS criterion that was met in patients with SIRS-positive sepsis was an increased heart rate, followed by an increased respiratory rate or a low partial pressure of arterial carbon dioxide and an abnormal white cell count. As in the patients with SIRS-positive sepsis, the most frequent single criterion that was met in patients with SIRS-negative sepsis was an increased heart rate (Table 2). Of patients with SIRS-negative sepsis, 17.2% fulfilled no SIRS criteria, and 82.8% fulfilled one SIRS criterion (Table 2).

The outcomes of the multivariate logistic regression analysis of hospital mortality and SIRS positivity are shown in Table 3. The risk factors for hospital mortality, including the APACHE II score, length of hospital stay, length of ICU stay, 28-day mechanical ventilation, rate of mechanical ventilation, administration of vasopressors, and SOFA score, were statistically significant (p < 0.05). The risk factors for SIRS positivity, including the SOFA score and hospital length of stay, were also statistically significant (p < 0.05).

The areas under the receiver operating characteristic curves (AUROCs) for the baseline risk model (age for mortality), SIRS, SOFA score, and APACHE II score are shown in Fig. 4. The AUROC for the SIRS model was 0.53 for prediction of hospital mortality; this was much lower than those for the baseline risk model, APACHE II score, and SOFA score (SIRS vs. age: 0.53 vs. 0.62, p < 0.01; SIRS vs. APACHE II: 0.53 vs. 0.73, p < 0.01; SIRS vs. SOFA: 0.53 vs. 0.70, p < 0.01).

Our study has several strengths. First, the study is recent, making the data current and relevant. Second, it investigated the effect of the SIRS criteria within the time window of the initial episode of suspected infection during the ICU stay on the diagnosis of sepsis over a period of 1 year. Third, and most importantly, the SIRS data consisted of physiological or laboratory measurements that were retrospectively collected for routine monitoring indicators and are therefore unlikely to be biased.

The first limitation of this study is that symptoms meeting the SIRS criteria were evaluated only during the episode of suspected infection in the ICU as recorded every 1 or 2 h on the observation charts. The second limitation is that we conducted a single-center clinical investigation in a province of southwest China; thus, the characteristics of our study population may lack representativeness. Multicenter prospective studies could address this issue. Finally, the third limitation is the high mortality rate, which had two main causes. First, as a large tertiary teaching hospital, our institution receives numerous patients with severe infections who have been transferred from smaller hospitals and primary healthcare institutions. Second, the limitations of the SOFA system in a retrospective cohort study played an important role in the high morbidity.

Despite the above-described limitations, we investigated the potential prognostic value of the SIRS criteria in a relatively high-risk population and found it to be different from the SOFA criteria.