Septic shock definitions and associated outcomes in blood culture positive critically ill patients

Introduction

In the new Sepsis-3 definition of septic shock, systemic inflammatory response syndrome (SIRS) (1) has been abandoned. Patients have to meet the criteria for organ failure utilizing Sequential Organ Failure Assessment (SOFA) score. According to the Third International Consensus statement providing the definitions for sepsis and septic shock (Sepsis-3), patients with septic shock (requiring vasoactive medication to sustain a mean arterial pressure >65 mmHg and elevated levels of serum lactate, >2 mmol/L) were associated with higher mortality (40%) (2) in comparison to those patients who met the criteria for the old SIRS Sepsis-1 definition. This specific subset of patients is our current work’s interest population.

However, there is still a need for validation of this data in different patient populations (3). For instance, data are lacking in bacteremia patients, which is especially important because only 5% of the subjects included in the study for validating the new Sepsis-3 definition were bacteremic. We addressed this question through a retrospective cohort study comparing the clinical characteristics directly and the outcomes of patients that are critically ill meeting the old Sepsis-1 versus the combined (old and new septic shock) Sepsis-3 definitions of septic shock in a cohort of bacteremic patients admitted to the intensive care unit (ICU) of Mayo Clinic Rochester, MN, USA. We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5147/rc).

Methods

Study design

Our retrospective cohort study was approved by the Mayo Clinic institutional review board (No. 17-009206). It is a subset analysis of the previously published study highlighting the association of the definitions of septic shock with the standardized mortality ratio in critically ill patients (4) and the preliminary work on this manuscript was exhibited in the form of an abstract at the Society of Critical Care Medicine Congress in 2019 (5). Research participants (patients), or their legally authorized representatives had agreed on (informed consent) allowing their medical records and relevant data to be utilized for research in the form of research authorization. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Study patients

All successive adult patients (age ≥18 years) were included who were admitted to all the ICUs (medical, mixed, medical cardiac, surgical cardiac, and the neuroscience intensive care units) at the Mayo Clinic, Rochester, Minnesota, from January 1, 2009, through October 31, 2015. Patients undergoing planned surgeries before the admission to ICU were excluded. Pediatric and Neonatal ICU patients were excluded. We focused on patients needing ICU admission for critical illness, with features of sepsis or septic shock. Patients who had a lower probability of an infection (based on the history and clinical course) as a cause of Critical illness or shock, were excluded. Only the index ICU admission was included for each patient.

Definitions

Positive blood culture was defined as any microbial growth 72 h before or during the index ICU admission. Blood cultures must have been obtained within the first 24 h of admission if the patient had already received antibiotics. Similarly, if the cultures were obtained first, then the antibiotics must have been ordered and administered within 72 h (6). Septic shock was defined as per the new Sepsis 3 definition with patients with suspected infection having persisting hypotension (despite adequate fluid resuscitation) requiring the use of vasoactive medications to sustain a mean arterial pressure (MAP) of ≥65 mmHg and having an elevated serum lactate level (>2 mmol/L or higher) (7). SIRS and severe sepsis were defined per the sepsis guidelines 1991 (1). SIRS was defined as but not limited to, more than one of the following clinical manifestations:

• Body temperature >38 degree centigrade or less than 36 degree centigrade;
• Tachycardia or pulse rate (heart rate) >90 beats per minute;
• Tachypnea or an elevated respiratory rate >20;
• Leucocytosis or leucopenia (elevated white blood cell count >12,000/mm³ or reduced white blood cell count <4,000/mm³).

SIRS in the presence of confirmed infectious process was termed as Sepsis.

Data collection

The patients that were admitted to the intensive care units were identified with the use of a previously validated prospective electronic medical records (EMR) database that recovers the required clinical variables for all the patients that are admitted to the ICU in near real-time, known as the “ICU Data Mart”. The demographic data such as age, sex, vital signs data (hemodynamic data such as mean arterial pressure, systolic and diastolic BP, respiratory rate, pulse), respiratory support in the form of invasive mechanical ventilation (IMV) or noninvasive positive pressure ventilation (NIPPV) or high flow nasal cannula (HFNC), disease severity scores (APACHE III, and SOFA) and the outcomes of hospital and ICU mortality were collected using the Data Mart. The design and working of the Data Mart have been previously described elsewhere (8).

We utilized the Mayo Clinic United data platform (UDP) to collect the data on laboratory values, for variables such as serum lactate levels, date and time of antibiotics administration, and details on obtaining the blood culture before admission to ICU and the code status (full code, DNI/DNR, etc.) (9). To improve the performance of UDP, newer computable phenotypes (automated electronic search strategies) have been devised to expedite data abstraction. Advanced Cohort Explorer (ACE) was utilized to enhance the data retrieval within the UDP. ACE, which is based on Boolean logic, provides a unique free text search approach that the investigators have extensively used at our center to facilitate a rapid search for selected words or phrases in the electronic health records. ACE helps to collate the clinical data from multiple hospital source systems within the Mayo Clinic, Rochester, and is supported by the enterprise endorsed information technology department. Quality control is regulated by means of timely consumer auditing; purpose/protocol inspections are performed to preserve patient data protection and confidentiality. ACE is also HIPAA compliant and is in line with the State law, and the institutional policies of Mayo Clinic for retrieving the patient data securely. Data on 30 random patients were also manually reviewed for quality assurance, including an assessment of individual elements and concepts of both definitions.

Outcomes

The primary outcome of interest was ICU and hospital mortality. Our secondary outcomes of interest included the length of stay measures [both ICU and hospital length of stay (LOS)].

Data analysis

Data were expressed using median (interquartile range, IQR) for quantifiable variables and as frequency (percentage, %) for qualitative variables. Patients who met the new and old criteria for septic shock were analyzed for the above-mentioned outcomes. Differences in the group for categorical records (sex, code status such as DNR/DNI, IMV/NIPPV, ICU/hospital mortality and discharge to home) were assessed by applying the chi-square test. To compare the continuous variables, the two-sample t-test (age) or Kruskal-Wallis test were used.

The standardized mortality ratio (SMR) was calculated for the 2 sepsis definition classes. For this calculation, the numerator was the number of actual hospital deaths, and the denominator was the number of expected deaths. This was extrapolated based on APACHE prediction of the expected mortality. We used the Poisson regression model with a log link for the univariable comparison of the SMRs, among the two comparison groups. The outcome were the observed deaths, whereas, the expected deaths were determined to be an offset term, and an indicator variable represented the four definition classes. The overall P value is centered on the likelihood ratio test, that was utilized to decide if the SMRs were comparable.

Multivariable logistic regression was performed for further analyses to control for the effect of the code status (such as DNR/DNI status) of the patients and the disease severity (APACHE III scores) on the outcome of interest which was ICU and hospital mortality for both old and the combined (old and new) definitions of septic shock. Associations between outcomes of interest and predictors were summarized as odds ratios (ORs) and 95% confidence intervals (CIs). Two-sided tests were used, and P values of <0.05 were deemed to be significant statistically. JMP 14.0.0 (SAS Institute Inc., Cary, NC, USA) was used as the statistical analysis software package.

Results

We started with a cohort of 94, 280 adult ICU admissions starting from the beginning January 2009 through the end of October 2015. The excluded patient consisted of; no prior research authorization, multiple ICU admissions, elective surgeries, and the absence of suspected infections or vasopressor use (Figure 1). We analyzed a total of 19,892 patients as first-time ICU admission with prior research authorization with suspected infection, and after excluding elective surgeries and patients with negative blood culture, we had 477 patients to be studied, with 236 of them meeting the criteria for the old Sepsis-1 septic shock definition and only 21 patients meeting the criteria for the Sepsis-3 definition. Hence, the reason for having the second group comprised of patients who met both the Sepsis-1 and Sepsis-3 criteria. The baseline characteristics and outcomes of the two groups are presented in Table 1. Both groups were similar in terms of gender distribution and age. The patients who met combined-old and new definitions were sicker and had higher chances to have limited resuscitation preferences in terms of the code status (DNI/DNR) compared to the old group alone. They also had higher APACHE III score and were more likely to need invasive mechanical ventilation.

Figure 1 Cohort selection with a total 94,280 adult ICU patients from the beginning of January 2009 through the end of October 2015. ICU, intensive care unit.

Contrasted to patients who met only the old definition (N=206), the group of patients who met the new combined definition (new or both new and old, N=271) had a higher disease severity in the form of APACHE III score, 92 (IQR, 76–112) vs. 76 (IQR, 61–95), P<0.001 and a higher day 1 SOFA score 10 (IQR, 8–13) vs. 7 (IQR, 4–10), P<0.001, although were comparable in age 65.5 years (IQR, 55–74 years) vs. 66 years (IQR, 55–76 years), P=0.47 (Table 1). The patients who met the combined (new or both new and old) definition had higher chances of having conservative resuscitation preferences in the form of code status (DNI/DNR); 77 (28.4) vs. 22 (10.7), P<0.001. The same group likewise had worse outcomes in terms of in-hospital mortality (34.3% vs. 18%, P<0.001) and SMR (0.76 vs. 0.52, P<0.04). Other patient-centered outcomes between the two groups are presented in Table 2.

Discussion

This study showed that bacteremic patients who meet both the new Sepsis-3 and old Sepsis-1 (combined group of both new Sepsis-3 and Sepsis-1) definitions have a higher severity of illness and higher hospital mortality compared to those who meet only the old Sepsis-1 definition. This becomes very important with treatable medical conditions like bacteremia and sepsis in which early therapy and diagnostic testing with multidisciplinary team involvement make a significant impact on patient outcome (10-12).

To the best of our knowledge, there are no studies comparing the sepsis definitions specifically in blood culture-positive sepsis patients. Studies that served as the basis for the third international consensus definitions for sepsis and septic shock (Sepsis-3) (7) had only a small proportion of patients with bacteremia., This makes the generalizability of its results in bacteremic sepsis patients difficult. Before the revelation of the new Sepsis-3 definition, several studies have looked at using the old sepsis definition to predict the patients at higher risk of mortality. A prospective, multicenter, observational study involving 17 ICUs found that the culture-negative patients with sepsis had fewer comorbidities, milder severity of illness, shorter hospitalizations, and lower mortality (13,14). This was further supported by another prospective observational cohort which corroborated the findings that bacteremic patients with sepsis had a higher risk of needing renal replacement therapy when compared with patients without bacteremia (sources like pulmonary and intra-abdominal sources of infection) (15). Time-to-culture positivity has also been associated with earlier death in sepsis patients (16). However, the literature provides heterogeneous evidence with regard to the association of mortality in bacteremic patients with specific infections like urinary tract infections and in patients with sepsis-associated acute respiratory distress syndrome (17-23).

The strength of this study stems from the fact that our study population was distinct from the population which was used to derive the Sepsis-3 definition. The group of investigators were distinct from the experts that were involved in the previous definition’s design or its revision (8,24-27). Thorough manual validation of the newer definition is presented among many subgroups of patients with critical illness. The high quality of the data and granularity ensured the soundness of both septic shock definitions in this large cohort of blood culture-positive patients with sepsis over 6 years.

Limitations to our study include its retrospective design and potential confounding factors that might not have been accounted for. The College of American Pathologists has targeted reducing blood culture contamination rates to 2–3% (28,29). However, in real-world practice, the contamination rates have varied from 0.6% to 6% (30-32). Due to its retrospective nature, we could not identify the falsely positive blood cultures as a result of contamination in this cohort. Our study serves as a piece of hypothesis-generating evidence to plan for more extensive studies with prospective designs to mitigate this flaw. This study protocol did not include other bloodstream infections like fungal bloodstream infections. There is a small possibility that the group of patients that were excluded had positive blood cultures but based on the clinical picture the probability for that remained quite low.

Conclusions

Among blood culture-positive patients with sepsis, the patients who meet both the new sepsis-3 and old sepsis-1 definitions (the combined criteria) have a higher severity of illness and mortality, and a worse SMR when compared to the patients who only satisfy the old sepsis-1 definition of septic shock. This is in line with the purposes of the updated Sepsis-3 definition which offers greater consistency and ability to identify sicker patients that would require more timely and potentially aggressive management early in the course of sepsis.

Acknowledgments

The preliminary work on this project was presented as an abstract at the Society of Critical Care Medicine Congress, 2019 (5).

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5147/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5147/prf

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5147/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5147/coif). AL serves as an unpaid editorial board member of Annals of Translational Medicine from September 2022 to August 2024. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This was a retrospective study approved by the Mayo Clinic institutional review board (No. 17-009206). All included patients, or their legally authorized representatives had provided a prior research authorization (informed consent) allowing their medical records to be used for research purposes.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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