A flow chart of patients is presented in Figure 1. Over the eight study years, 784 patients were treated in the ICU and received a sepsis or septic shock diagnosis. Microbiological samples were not obtained within the predefined time interval in 88 excluded patients. Additionally 52, lacked blood cultures and were excluded. Ninety-five patients were excluded at the medical chart review due to absence of sepsis-3 diagnosis and 549 patients were finally included in the study. Blood cultures were positive in 286 of the patients, 83 had negative blood cultures but a positive culture from another body location classified as the focus of infection. One hundred and eighty patients were sterile without positive cultures. Four sterile patients were positive in polymerase chain reaction assay (PCR); 2 were positive for legionella and 1 for influenza in respiratory tract samples and 1 for meningococci in cerebrospinal fluid and were reclassified as pathogen-detected but non-bacteremic sepsis. Additionally, nine patients with positive blood culture and 3 patients where pathogens were detected from the site of infection, outside the 96-hour time frame surrounding ICU admission, were reclassified as bacteremic and pathogen-detected but non-bacteremic, respectively. This resulted in 54 % (n=295) bacteremic sepsis, 16 % (n=90) pathogen-detected but non-bacteremic sepsis and 30 % (n=164) sterile sepsis, see figure 1.
There were no missing data in the primary analyses. There were no differences in mortality between the groups of different microbiological status, figure 2a. For differences in demography and clinical characteristics between bacteremic and non-bacteremic patients see Table 1and Table 2.
Patients without preceding antibiotic therapy
In 352 patients not treated with antibiotics prior to culture sampling, 63 % (n=223) were bacteremic, 14 % (n=50) were non-bacteremic but with positive microbial samples from foci of infection, and 22 % (n=79) were sterile sepsis.
These patients had similar characteristics except for renal disease being more common among bacteremic patients than non-bacteremic patients, 20 versus 4 patients, respectively, p=0.04. Chronic obstructive pulmonary disease (COPD) was, however, less common among bacteremic patients, 20 patients versus 21 patients, p=0.04, and likewise immunomodulatory medication in 6 bacteremic patients versus 10 non-bacteremic patients, p=0.03.
Escherichia coli was the most common pathogen detected from blood, and non-pneumococcal streptococci were the most common pathogens from other non-blood sites.
Patients from the bacteremic sepsis, pathogen-detected but non-bacteremic sepsis or sterile sepsis groups were compared for proportion of patients with microbial samples from presumed infectious foci. Generally, more microbial samples were sampled from patients with pathogens detected. When compared for proportion of patients with microbial samples from presumed infection foci, the differences between pathogen-detected and sterile sepsis did not remain for respiratory tract, urinary tract, central nervous system, bone and joints and drainage or wound for postoperative infections. A higher number of blood culture pairs were drawn in bacteremic patients, (mean 2.2, 95 % CI 2.1-2.2) compared to non-bacteremic patients (mean 1.9, 95 % CI 1.8-2.0) p<0.01. All patients had at least one pair of blood culture drawn. Bacteremic patients had a higher proportion of a second pair of blood cultures drawn. The additional rate of positivity in the second pair of blood culture was 7.4% for the bacteremic patients. The addition of a second pair of blood culture in the non-bacteremic patients with only one pair of blood culture drawn, with an equal rate of positivity as in the bacteremic sepsis, would be equivalent to 4 more patients becoming bacteremic (Table 2).
As comparisons of mortality between groups of patients with positive respectively negative in microbiological samples are most likely vulnerable to confounders, a propensity score analysis was performed. There were no missing data on the variables in the propensity score analysis.
In the entire cohort 172 matched pairs were retrieved, for clinical characteristics in the matched groups, see table 3. Mortalities were significantly higher among bacteremic patients as were the total SOFA score, the SOFA scores for renal function, liver function, coagulation and lactate, figure 2b.
Since the matching affected the mortality, the mortality was also compared for patients who had received antibiotic therapy prior to blood cultures. Non-bacteremic patients had significantly higher mortality if they received antibiotic therapy prior to blood cultures than if they had not received antibiotic therapy, figure 2c.
Latent Class Analysis
The following baseline variables were categorized and entered into a LCA-model: gender, bacteremia, pathogen-detected but non-bacteremic or sterile sepsis, sepsis-causing pathogen, foci of infection, prior antibiotic treatment, immunomodulatory medications, nosocomial infection, fever (>38°C), hypothermia (<36°C), acidosis (pH<7.35), p-lactate (divided in quartiles; 0-1.8, >1.8-3,>3-5.1,>5.1), and CNS-, respiratory-, cardiovascular-, renal-, liver- or coagulatory organ dysfunction. 469 patients without any missing data on the baseline variables were entered into the LCA. An eight-class model or a nine-class model were the best fit for the cohort, ABIC continued to decrease until 9-classes model, table 4. We inspected the 8- and 9-class models and the 8-class model did yield more clinically meaningful classes and hence was chosen. The representation of class membership for baseline variables are presented in table 5. The eight classes are characterized by:
- Nosocomial, sterile sepsis, in this group all had nosocomial infection and none had a pathogen detected.
- Sepsis with lactic acidosis, this group had the causative pathogen detected in all patients, of those the vast majority (92 %) was bacteremic. In addition, this group had the highest frequency of organ dysfunction at admission to the ICU.
- Community-acquired, sterile sepsis, these patients often suffered from a respiratory tract infection or an abdominal infection.
- Abdominal sepsis with pathogen detected, the infection was community-acquired.
- Nosocomial, pathogen-detected sepsis.
- Sepsis with gram-positive bacteria, the infections were community-acquired, often in the respiratory tract or skin and soft tissue infections.
- Imunosuppressed sepsis, these patients had antibiotic therapy prior to microbial sampling and were yet bacteremic.
- Urinary tract infection sepsis, the pathogen, Enterobacterales, was always detected.
90-day mortality for the different classes was compared in a Kaplan-Meier model, figure 3.
There was a difference in 90-days mortality between classes (p<0.01) with the lowest mortality in class 8, Urinary tract infection sepsis and the highest in class 2, Sepsis with lactic acidosis.