Design of a national patient-centred clinical pathway for sepsis in Sweden.

BACKGROUND: The World Health Organization has adopted a resolution on sepsis and urged member states to develop national processes to improve sepsis care. In Sweden, sepsis was selected as one of the ten first diagnoses to be addressed, when the Swedish government in 2019 allocated funds for patient-centred clinical pathways in healthcare. A national multidisciplinary working group, including a patient representative, was appointed to develop the patient-centred clinical pathway for sepsis. METHODS: The working group mapped challenges and needs surrounding sepsis care and included a survey sent to all emergency departments (ED) in Sweden, and then designed a patient-centred clinical pathway for sepsis. RESULTS: The working group decided to focus on the following four areas: (1) sepsis alert for early detection and management optimisation for the most severely ill sepsis patients in the ED; (2) accurate sepsis diagnosis coding; (3) structured information to patients at discharge after sepsis care and (4) structured telephone follow-up after sepsis care. A health-economic analysis indicated that the implementation of the clinical pathway for sepsis will most likely not drive costs. An important aspect of the clinical pathway is implementing continuous monitoring of performance and process indicators. A national working group is currently building up such a system for monitoring, focusing on extraction of this information from the electronic health records systems. CONCLUSION: A national patient-centred clinical pathway for sepsis has been developed and is currently being implemented in Swedish healthcare. We believe that the clinical pathway and the accompanying monitoring will provide a more efficient and equal sepsis care and improved possibilities to monitor and further develop sepsis care in Sweden.

A Comparison between Endostatin and Conventional Biomarkers on 30-Day Mortality and Renal Replacement Therapy in Unselected Intensive Care Patients.

Endostatin may predict mortality and kidney impairment in general populations as well as in critically ill patients. We decided to explore the possible role of endostatin as a predictor of 30-day mortality, acute kidney injury (AKI), and renal replacement therapy (RRT) in a cohort of unselected intensive care unit (ICU) patients. Endostatin and creatinine in plasma were analyzed and SAPS3 was determined in 278 patients on ICU arrival at admission to a Swedish medium-sized hospital. SAPS3 had the highest predictive value, 0.85 (95% C.I.: 0.8-0.90), for 30-day mortality. Endostatin, in combination with age, predicted 30-day mortality by 0.76 (95% C.I.: 0.70-0.82). Endostatin, together with age and creatinine, predicted AKI with 0.87 (95% C.I.: 0.83-0.91). Endostatin predicted AKI with [0.68 (0.62-0.74)]. Endostatin predicted RRT, either alone [0.82 (95% C.I.: 0.72-0.91)] or together with age [0.81 (95% C.I.: 0.71-0.91)]. The predicted risk for 30-day mortality, AKI, or RRT during the ICU stay, predicted by plasma endostatin, was not influenced by age. Compared to the complex severity score SAPS3, circulating endostatin, combined with age, offers an easily managed option to predict 30-day mortality. Additionally, circulating endostatin combined with creatinine was closely associated with AKI development.

TNFR1, TNFR2, neutrophil gelatinase-associated lipocalin and heparin binding protein in identifying sepsis and predicting outcome in an intensive care cohort.

To date no biomarkers can aid diagnosing sepsis with adequate accuracy. We set out to assess the ability of Tumor necrosis factor receptor (TNFR) 1 and 2, Neutrophil gelatinase-associated lipocalin (NGAL) and Heparin binding protein (HBP) to discriminate sepsis from non-infected critically ill patients in a large ICU cohort, and to evaluate their value to predict mortality at 30 days. Adult patients admitted to the ICU with an arterial catheter were included. Clinical data and blood samples were prospectively recorded daily. Diagnoses were set retrospectively. Descriptive statistics and logistic regression models were used. NGAL, TNFR1 and TNFR2 were higher in sepsis patients compared to other diagnoses, as well as in non-survivors compared to survivors. In addition, these biomarkers increased with increasing stages of acute kidney injury. TNFR1 and TNFR2 performed similarly to NGAL and CRP in identifying sepsis patients, but they performed better than CRP in predicting 30-day mortality in this ICU cohort. Thus, TNFR1 and TNFR2 may be particularly useful in identifying high risk sepsis patients and facilitate relevant health care actions in this group of sepsis patients.

Calprotectin is superior to procalcitonin as a sepsis marker and predictor of 30-day mortality in intensive care patients.

Sepsis is the most frequent cause of death in the intensive care unit (ICU). A rapid and correct diagnosis and initiation of therapy is crucial for improving patient outcomes. The aim of this study was to compare the performance of calprotectin with the more widely used sepsis biomarker procalcitonin (PCT) in ICU patients. The performance of calprotectin and PCT as sepsis and prognostic markers for 30-d mortality was compared in a prospective, observational study in an eight-bed ICU. We investigated concentrations of the biomarkers in plasma collected at admission from all ICU patients admitted during a year (2012-2013, n = 271) together with simplified acute physiology 3 scores (SAPS3) and sequential organ failure assessment (SOFA) scores. The receiver operating characteristic (ROC) analysis showed a higher area under the curve (AUC) value for calprotectin (0.79) than for PCT (0.49) when used as a sepsis marker. The calprotectin concentrations at admission were higher in non-survivors than in survivors at day 30. In our study, calprotectin was superior to PCT for distinguishing between ICU patients with sepsis and non-sepsis patients. Calprotectin also had higher predictive ability regarding 30-d mortality.

Renal clearance of heparin-binding protein and elimination during renal replacement therapy: Studies in ICU patients and healthy volunteers.

BACKGROUND: Heparin-binding protein (HBP) is released by neutrophils upon activation, and elevated plasma levels are seen in inflammatory states like sepsis, shock, cardiac arrest, and burns. However, little is known about the elimination of HBP. We wanted to study renal clearance of HBP in healthy individuals and in burn patients in intensive care units (ICUs). We also wished to examine the levels of HBP in the effluent of renal replacement circuits in ICU patients undergoing continuous renal replacement therapy (CRRT). METHODS: We measured plasma and urine levels of HBP and urine flow rate in 8 healthy individuals and 20 patients in a burn ICU. In 32 patients on CRRT, we measured levels of HBP in plasma and in the effluent of the CRRT circuit. RESULTS: Renal clearance of HBP (median (IQR) ml/min) was 0.19 (0.08-0.33) in healthy individuals and 0.30 (0.01-1.04) in burn ICU patients. In ICU patients with cystatin C levels exceeding 1.44 mg/l, clearance was 0.45 (0.15-2.81), and in patients with cystatin C below 1.44 mg/l clearance was lower 0.28 (0.14-0.55) (p = 0.04). Starting CRRT did not significantly alter plasma levels of HBP (p = 0.14), and the median HBP level in the effluent on CRRT was 9.1 ng/ml (IQR 7.8-14.4 ng/ml). CONCLUSION: In healthy individuals and critically ill burn patients, renal clearance of HBP is low. It is increased when renal function is impaired. Starting CRRT in critically ill patients does not alter plasma levels of HBP significantly, but HBP can be found in the effluent. It seems unlikely that impaired kidney function needs to be considered when interpreting concentrations of HBP in previous studies. Starting CRRT does not appear to be an effective way of reducing HBP concentrations.

Heparin-binding protein in ventilator-induced lung injury.

BACKGROUND: Although mechanical ventilation is often lifesaving, it can also cause injury to the lungs. The lung injury is caused by not only high pressure and mechanical forces but also by inflammatory processes that are not fully understood. Heparin-binding protein (HBP), released by activated granulocytes, has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis. We investigated if HBP levels were increased in the bronchoalveolar lavage fluid (BALF) or plasma in a pig model of ventilator-induced lung injury (VILI). We also investigated if HBP was present in BALF from healthy volunteers and in intubated patients in the intensive care unit (ICU). METHODS: Anaesthetized pigs were randomized to receive ventilation with either tidal volumes of 8 ml/kg (controls, n = 6) or 20 ml/kg (VILI group, n = 6). Plasma and BALF samples were taken at 0, 1, 2, 4, and 6 h. In humans, HBP levels in BALF were sampled from 16 healthy volunteers and from 10 intubated patients being cared for in the ICU. RESULTS: Plasma levels of HBP did not differ between pigs in the control and VILI groups. The median HBP levels in BALF were higher in the VILI group after 6 h of ventilation compared to those in the controls (1144 ng/ml (IQR 359-1636 ng/ml) versus 89 ng/ml (IQR 33-191 ng/ml) ng/ml, respectively, p = 0.02). The median HBP level in BALF from healthy volunteers was 0.90 ng/ml (IQR 0.79-1.01 ng/ml) as compared to 1959 ng/ml (IQR 612-3306 ng/ml) from intubated ICU patients (p < 0.001). CONCLUSIONS: In a model of VILI in pigs, levels of HBP in BALF increased over time compared to controls, while plasma levels did not differ between the two groups. HBP in BALF was high in intubated ICU patients in spite of the seemingly non-harmful ventilation, suggesting that inflammation from other causes might increase HBP levels.

Circulating syndecans during critical illness.

Circulating syndecans are proposed to be markers of glycocalyx degradation and previous investigations have found higher plasma levels of syndecan-1 among patients with different pathological conditions. We wanted to investigate if levels of other syndecans (-2,-3 and -4) are altered during critical illness and compare the levels to syndecan-1. In 137 consecutive intensive care unit (ICU) patients with sepsis, cardiac arrest, gastrointestinal bleeding, intoxication or trauma, plasma levels of syndecan-1, -2, -3 and -4 were measured using ELISA. Syndecan-1 and syndecan-3 levels were similar among the different ICU patient groups but higher than controls. No differences in plasma levels of syndecan-2 or syndecan-4 were found neither among the different ICU patient groups nor compared to controls. All syndecans showed an association with mortality and the levels of syndecan-1 and -3 and correlated with each other. The results indicate that syndecan release is triggered by the physiological stress of critical illness in general and involves several subtypes such as syndecan-1 and syndecan-3.

Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure.

PURPOSE: Heparin-binding protein (HBP) is released by granulocytes and has been shown to increase vascular permeability in experimental investigations. Increased vascular permeability in the lungs can lead to fluid accumulation in alveoli and respiratory failure. A generalized increase in vascular permeability leads to loss of circulating blood volume and circulatory failure. We hypothesized that plasma concentrations of HBP on admission to the intensive care unit (ICU) would be associated with decreased oxygenation or circulatory failure. METHODS: This is a prospective, observational study in a mixed 8-bed ICU. We investigated concentrations of HBP in plasma at admission to the ICU from 278 patients. Simplified acute physiology score (SAPS) 3 was recorded on admission. Sequential organ failure assessment (SOFA) scores were recorded daily for three days. RESULTS: Median SAPS 3 was 58.8 (48-70) and 30-day mortality 64/278 (23%). There was an association between high plasma concentrations of HBP on admission with decreased oxygenation (p<0.001) as well as with circulatory failure (p<0.001), after 48-72 hours in the ICU. There was an association between concentrations of HBP on admission and 30-day mortality (p = 0.002). ROC curves showed areas under the curve of 0,62 for decreased oxygenation, 0,65 for circulatory failure and 0,64 for mortality. CONCLUSIONS: A high concentration of HBP in plasma on admission to the ICU is associated with respiratory and circulatory failure later during the ICU care period. It is also associated with increased 30-day mortality. Despite being an interesting biomarker for the composite ICU population it's predictive value at the individual patient level is low.