Long-term Mortality and Hospital Readmissions Among Survivors of Sepsis in Sweden: A Population-Based Cohort Study.

Background: Survivors of sepsis may experience long-term risk of increased morbidity and mortality, but estimations of cause-specific effects beyond 1 year after a sepsis episode are lacking. Method: This nationwide population-based cohort study linked data from national registers to compare patients aged ≥18 years in Sweden admitted to an intensive care unit from 2008 to 2019 with severe community-acquired sepsis. Patients were identified through the Swedish Intensive Care Registry, and randomly selected population controls were matched for age, sex, calendar year, and county of residence. Confounding from comorbidities, health care use, and socioeconomic and demographic factors was accounted for by using entropy-balancing methods. Long-term mortality and readmission rates, total and cause specific, were compared for 20 313 patients with sepsis and 396 976 controls via Cox regression. Results: During the total follow-up period, 56% of patients with sepsis died, as opposed to 26% of the weighted controls. The hazard ratio for all-cause mortality was attenuated with time but remained elevated in all periods: 3.0 (95% CI, 2.8-3.2) at 2 to 12 months after admission, 1.8 to 1.9 between 1 and 5 years, and 1.6 (95% CI, 1.5-1.8) at >5 years. The major causes of death and readmission among the sepsis cases were infectious diseases, cancer, and cardiovascular diseases. The hazard ratios were larger among those without underlying comorbidities. Conclusions: Severe community-acquired sepsis was associated with substantial long-term effects beyond 1 year, as measured by mortality and rehospitalization. The cause-specific rates indicate the importance of underlying or undetected comorbidities while suggesting that survivors of sepsis may face increased long-term mortality and morbidity not explained by underlying health factors.

Increasing plasma calprotectin (S100A8/A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients.

BACKGROUND: Calprotectin (S100A8/A9) is a pro-inflammatory mediator primarily released from neutrophils. Previous studies have revealed associations between plasma calprotectin, disease severity and in-hospital mortality in unselected COVID-19 patients. OBJECTIVE: We aimed to assess whether plasma calprotectin dynamics during the first week of intensive care are associated with mortality and functional outcome in critically ill COVID-19 patients. METHODS: This prospective study included 498 COVID-19 patients admitted to six intensive care units (ICUs) in Sweden between May 2020 and May 2021. Blood samples were collected on ICU admission and on day 7. The primary outcome was 12-month mortality. Secondary outcomes were functional outcome of survivors at 3 and 12 months, and the need for invasive mechanical ventilation (IMV) or continuous renal replacement therapy (CRRT) during the ICU stay. Functional outcome was assessed by the Glasgow Outcome Scale Extended (GOSE, range 1-8, with < 5 representing an unfavourable outcome). Associations between plasma calprotectin and outcomes were examined in binary logistic regression analyses adjusted for age, sex, BMI, hypertension, smoking, and creatinine. RESULTS: High plasma calprotectin on admission and day 7 was independently associated with increased 12-month mortality. Increasing calprotectin from admission to day 7 was independently associated with higher mortality at 12 months [OR 2.10 (95% CI 1.18-3.74), p = 0.012], unfavourable functional outcome at 3 months [OR 2.53 (95% CI 1.07-6.10), p = 0.036], and the use of IMV [OR 2.23 (95% CI 1.10-4.53), p = 0.027)] and CRRT [OR 2.07 (95% CI 1.07-4.00), p = 0.031)]. A receiver operator characteristic (ROC) model including day 7 calprotectin and age was a good predictor of 12-month mortality [AUC 0.79 (95% CI 0.74-0.84), p < 0.001]. Day 7 calprotectin alone predicted an unfavourable functional outcome at 3 months [AUC 0.67 (95% CI 0.58-0.76), p < 0.001]. CONCLUSION: In critically ill COVID-19 patients, increasing calprotectin levels after admission to the ICU are associated with 12-month mortality and unfavourable functional outcome in survivors. Monitoring plasma calprotectin dynamics in the ICU may be considered to evaluate prognosis in critical COVID-19. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT04974775, registered April 28, 2020.

Sepsis mimics among presumed sepsis patients at intensive care admission: a retrospective observational study.

BACKGROUND: Diagnosing sepsis remains a challenge because of the lack of gold-standard diagnostics. Since there are no simple, broadly accepted criteria for infection, there is a risk of misclassifying sepsis patients (sepsis mimics) among patients with organ failure. The main objective of this study was to investigate the proportion of non-infected patients (sepsis mimics) in ICU patients with presumed sepsis at intensive care unit (ICU) admission. METHODS: Adult patients were screened retrospectively during 3.5 years in four ICUs in Sweden for fulfilment of the sepsis-3 criteria at ICU admission (presumed sepsis). Proxy criteria for suspected infection were sampled blood culture(s) and concomitant antibiotic administration. Culture-negative presumed sepsis patients were screened for infection according to the Linder-Mellhammar Criteria of Infection (LMCI). Sepsis mimics were defined as without probable infection according to the LMCI. Confirmed sepsis was defined as presumed sepsis after the exclusion of sepsis mimics. RESULTS: In the ICU presumed sepsis cohort (2664 patients), 25% were considered sepsis mimics. The most common reasons for ICU admission among sepsis mimics were acute heart failure and unspecific respiratory failure. Comparing sepsis mimics and confirmed sepsis showed that confirmed sepsis patients were slightly more severely ill but had similar mortality. C-reactive protein had modest discriminatory power (AUROC 0.71) with confirmed sepsis as the outcome. CONCLUSIONS: One-fourth of a presumed ICU sepsis population identified with the sepsis-3 criteria could be considered sepsis mimics. The high proportion of sepsis mimics has a potential dilutional effect on the presumed sepsis population, which threatens the validity of results from sepsis studies using recommended sepsis criteria.

[The Swecrit Biobank, associated clinical registries, and machine learning (artificial intelligence) improve critical care knowledge]. / Provsamlingen Swecrit och AI ger ny kunskap vid intensivvård.

The unique Swecrit Biobank and its associated clinical registries for sepsis, ARDS, cardiac arrest, trauma, and COVID-19 include more than 150,000 blood samples and descriptions of critically ill patients. These assets provide a unique opportunity to research and improve the care of the most seriously ill patients through biomarker analyses, proteomic studies, and genetic and epigenetic studies using modern machine learning techniques (artificial intelligence). Interested researchers are invited to submit their proposals and participate.

A simple mortality prediction model for sepsis patients in intensive care.

Background: Sepsis is common in the intensive care unit (ICU). Two of the ICU's most widely used mortality prediction models are the Simplified Acute Physiology Score 3 (SAPS-3) and the Sequential Organ Failure Assessment (SOFA) score. We aimed to assess the mortality prediction performance of SAPS-3 and SOFA upon ICU admission for sepsis and find a simpler mortality prediction model for these patients to be used in clinical practice and when conducting studies. Methods: A retrospective study of adult patients fulfilling the Sepsis-3 criteria admitted to four general ICUs was performed. A simple prognostic model was created using backward stepwise multivariate logistic regression. The area under the curve (AUC) of SAPS-3, SOFA and the simple model was assessed. Results: One thousand nine hundred eighty four admissions were included. A simple six-parameter model consisting of age, immunosuppression, Glasgow Coma Scale, body temperature, C-reactive protein and bilirubin had an AUC of 0.72 (95% confidence interval (CI) 0.69-0.75) for 30-day mortality, which was non-inferior to SAPS-3 (AUC 0.75, 95% CI 0.72-0.77) (p = 0.071). SOFA had an AUC of 0.67 (95% CI 0.64-0.70) and was inferior to SAPS-3 (p < 0.001) and our simple model (p = 0.0019). Conclusion: SAPS-3 has a lower prognostic value in sepsis than in the general ICU population. SOFA performs less well than SAPS-3. Our simple six-parameter model predicts mortality just as well as SAPS-3 upon ICU admission for sepsis, allowing the design of simple studies and performance monitoring.

Circulating dipeptidyl peptidase 3 on intensive care unit admission is a predictor of organ dysfunction and mortality.

BACKGROUND: Our aim was to investigate the prognostic potential of circulating dipeptidyl peptidase 3 (cDPP3) to predict mortality and development of organ dysfunction in a mixed intensive care unit (ICU) population, and for this reason, we analysed prospectively collected admission blood samples from adult ICU patients at four Swedish hospitals. Blood samples were stored in a biobank for later batch analysis. The association of cDPP3 levels with 30-day mortality and Sequential Organ Failure Assessment (SOFA) scores on day two was investigated before and after adjustment for the simplified acute physiology score III (SAPS-3), using multivariable (ordinal) logistic regression. The predictive power of cDPP3 was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Of 1978 included consecutive patients in 1 year (2016), 632 fulfilled the sepsis 3-criteria, 190 were admitted after cardiac arrest, and 157 because of trauma. Admission cDPP3 was independently (of SAPS-3) associated with 30-day mortality with odds ratios of 1.45 (95% confidence interval (CI) 1.28-1.64) in the entire ICU population, 1.30 (95% CI 1.08-1.57) in the sepsis subgroup and 2.28 (95% CI 1.50-3.62) in cardiac arrest. For trauma, there was no clear association. Circulating DPP3 alone was a moderate predictor of 30-day mortality with AUROCs of 0.68, 0.62, and 0.72 in the entire group, the sepsis subgroup, and the cardiac arrest subgroup, respectively. By adding cDPP3 to SAPS-3, AUROC improved for the entire group, the sepsis subgroup, and the cardiac arrest subgroup (p = 0.023). CONCLUSION: Circulating DPP3 on admission is a SAPS-3 independent prognostic factor of day-two organ dysfunction and 30-day mortality in a mixed ICU population and needs further evaluation.

Plasma proenkephalin A 119-159 on intensive care unit admission is a predictor of organ failure and 30-day mortality.

BACKGROUND: Proenkephalin A 119-159 (penKid) has been suggested as a marker of renal failure and poor outcome. We aimed to investigate the association of penKid on ICU admission with organ dysfunction and mortality in a mixed ICU population. In this retrospective, observational study, admission penKid levels from prospectively collected blood samples of consecutive patients admitted to four Swedish ICUs were analysed. The association of penKid with day-two sequential organ failure assessment (SOFA) scores and 30-day mortality was investigated using (ordinal) logistic regression. The predictive power of penKid for 30-day mortality and dialysis was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: Of 1978 included patients, 632 fulfilled the sepsis 3-criteria, 190 had a cardiac arrest, and 157 had experienced trauma. Admission penKid was positively associated with 30-day mortality with an odds ratio of 1.95 (95% confidence interval 1.75-2.18, p < 0.001), and predicted 30-day mortality in the entire ICU population with an AUC of 0.71 (95% confidence interval 0.68-0.73) as well as in the sepsis, cardiac arrest and trauma subgroups (AUCs of 0.61-0.84). Correction for admission plasma creatinine revealed that penKid correlated with neurological dysfunction. CONCLUSION: Plasma penKid on ICU admission is associated with day-two organ dysfunction and predictive of 30-day mortality in a mixed ICU-population, as well as in sepsis, cardiac arrest and trauma subgroups. In addition to being a marker of renal dysfunction, plasma penKid is associated with neurologic dysfunction in the entire ICU population, and cardiovascular dysfunction in sepsis.

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness.

BACKGROUND: Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis. METHODS: In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis. RESULTS: Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better. CONCLUSIONS: Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Sepsis is underreported in Swedish intensive care units: A retrospective observational multicentre study.

BACKGROUND: Sepsis is a common indication for admission to the intensive care unit (ICU). Since definitions vary across studies, comparisons of prevalence and outcomes have been challenging. We aimed to compare sepsis according to ICU discharge codes with sepsis according to Sepsis-3 criteria and to investigate the epidemiology of sepsis in the ICU. We hypothesized that sepsis using discharge codes is underreported. METHODS: Adult ICU admissions to four ICUs in Sweden between 2015 and 2017 were screened for sepsis according to the Sepsis-3 criteria. Medical records were reviewed and data extracted from the Swedish Intensive Care Registry. RESULTS: Of 5990 adult ICU patients, 28% fulfilled the Sepsis-3 criteria on admission, but only 31% of them had sepsis as the registered main diagnosis at ICU discharge. Of the 1654 Sepsis-3 patients, 38% met the septic shock criteria. The Sepsis-3 in-hospital mortality was 26% compared to 33% in patients with septic shock. The incidence rate for ICU-treated sepsis was 81 cases per 100 000 person-years. One in four had a positive blood culture, and 44% were culture negative. CONCLUSION: This large Swedish multicentre study showed that 28% of adult ICU patients fulfilled the Sepsis-3 criteria, but only one third of them had sepsis according to ICU discharge codes. We could confirm our hypothesis, that sepsis is severely underreported in Swedish ICUs, and we conclude that discharge codes should not be used for quality control or research purposes.

C-reactive protein as a prognostic factor in intensive care admissions for sepsis: A Swedish multicenter study.

PURPOSE: C-reactive protein (CRP) is not included in the major intensive care unit (ICU) prognostic tools such as the Simplified Acute Physiology Score (SAPS). We assessed CRP on ICU admission as a SAPS-3 independent risk marker for short-term mortality and length of stay (LOS) in ICU patients with sepsis. MATERIALS AND METHODS: Adult ICU admissions satisfying the Sepsis-3 criteria to four southern Swedish hospitals were retrospectively identified and divided into a low CRP group (<100 mg/L) and a high CRP group (>100 mg/L) based on the admission CRP level. The standardized mortality ratio (SMR) was calculated. RESULTS: A total of 851 admissions were included. The SMR was higher in the high CRP group (0.85 vs. 0.67, P = .001 in the whole sepsis group and 0.85 vs. 0.59, P = .003 in the culture-positive subgroup). The CRP levels also correlated with ICU and hospital LOS in survivors (P < .001 and P = .002), again independent of SAPS-3. CONCLUSION: An admission CRP level >100 mg/L is associated with an increased risk of ICU and 30-day mortality as well as prolonged LOS in survivors, irrespective of morbidity measured with SAPS-3. Thus, CRP may be a simple, early marker for prognosis in ICU admissions for sepsis.