Predicting sepsis using a combination of clinical information and molecular immune markers sampled in the ambulance.

Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-classified in our prediction models, due to milder symptoms as well as lower expression levels of the investigated immune mediators. This indicates a need of stratifying septic patients with a priori knowledge of certain clinical and molecular parameters in order to improve prediction for early sepsis diagnosis.Trial registration: NCT03249597. Registered 15 August 2017.

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.

Presentation of the septic patient to the emergency department with respect to age and sex - a retrospective cross-sectional study.

OBJECTIVE: It is challenging to identify sepsis in the emergency department, in part due to the non-specific presentation of septic patients. Current clinical sepsis screening tools rely on vital signs but many patients present with near normal vital signs and are therefore not identified as septic. This suggests that variables, e.g. signs and symptoms, need to be included to improve sepsis detection in the emergency department. Our hypothesis was that the presentation of sepsis differs based age and sex. The potential differences in presentation could be used to apply to future sepsis screening tools. The aim was to analyze the prevalence of keywords reflecting the presentation of septic patients in the emergency department in relation to age and sex. METHOD: Retrospective cross-sectional study. Keywords reflecting sepsis presentation to the emergency department were quantified and compared between age categories and the sex. 479 patients admitted to the emergency department of Södersjukhuset, Stockholm during 2013 and discharged with an ICD-10 code consistent with sepsis were included. We adjusted for multiple comparisons by applying Bonferroni-adjusted significance levels for all comparisons. RESULT: "Pain" and "risk factors for sepsis" were significantly more common among patients younger than 65 years as compared with those 75 years and older: (n = 87/137; 63.5% vs n = 99/240; 41.3%, P-value < 0.000) and (n = 74/137; 54.0% vs 55/240; 22.9%, P-value < 0.000) respectively. "Risk factors for sepsis" was also significantly more common among patients between 65 and 74 years as compared with those 75 years and older: (n = 43/102; 42.2% vs 55/240; 22.9%, P-value < 0.000). "Pain" and "gastrointestinal symptoms" were significantly more common among women as compared with men: (n = 128/224; 57.1% vs n = 102/255; 40.0%, P-value < 0.000) and (n = 82/244; 36.6% vs n = 55/255; 21.6%, P-value < 0.000) respectively. CONCLUSION: The keywords "pain" and "risk factors for sepsis" were more common among younger patients and "pain" and "gastrointestinal symptoms" were more common among women. However, most keywords had a similar prevalence irrespective of age and sex. The results could potentially be used to augment sepsis screening tools or clinical decision tools.

Association between variables measured in the ambulance and in-hospital mortality among adult patients with and without infection: a prospective cohort study.

BACKGROUND: Patients presenting with infection to the ambulance are common, but risk factors for poor outcome are not known. The primary aim of the current study was to study the association between variables measured in the ambulance and mortality among adult patients with and without infection. The secondary aim was to study the association between these variables and mortality in a subgroup of patients who developed sepsis within 36 h. METHODS: Prospective cohort study of 553 ambulance patients with, and 318 patients without infection, performed in Stockholm during 2017-2018. The association between 21 variables (8 keywords related to medical history, 6 vital signs, 4 blood tests, and age, gender, comorbidity) and in-hospital mortality was analysed using logistic regression. RESULTS: Among patients with infection, inability of the patient to answer questions relating to certain symptoms such as pain and gastrointestinal symptoms was significantly associated with mortality in univariable analysis, in addition to oxygen saturation < 94%, heart rate > 110 /min, Glasgow Coma Scale (GCS) < 15, soluble urokinase Plasminogen Activator Receptor (suPAR) 4.0-7.9 ng/mL, suPAR ≥ 8.0 ng/mL and a Charlson comorbidity score ≥ 5. suPAR ≥ 8.0 ng/mL remained significant in multivariable analysis (OR 25.4; 95% CI, 3.2-199.8). Among patients without infection, suPAR ≥ 8.0 ng/mL and a Charlson comorbidity score ≥ 5 were significantly associated with mortality in univariable analysis, while suPAR ≥ 8.0 ng/mL remained significant in multivariable analysis (OR 56.1; 95% CI, 4.5-700.0). Among patients who developed sepsis, inability to answer questions relating to pain remained significant in multivariable analysis (OR 13.2; 95% CI, 2.2-78.9), in addition to suPAR ≥ 8.0 ng/mL (OR 16.1; 95% CI, 2.0-128.6). CONCLUSIONS: suPAR ≥ 8.0 ng/mL was associated with mortality in patients presenting to the ambulance both with and without infection and in those who developed sepsis. Furthermore, the inability of the ambulance patient with an infection to answer questions relating to specific symptoms was associated with a surprisingly high mortality. These results suggest that suPAR and medical history are valuable tools with which to identify patients at risk of poor outcome in the ambulance and could potentially signal the need of enhanced attention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03249597. Registered 15 August 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03249597 .

Keywords reflecting sepsis presentation based on mode of emergency department arrival: a retrospective cross-sectional study.

BACKGROUND: Current sepsis screening tools are predominantly based on vital signs. However, patients with serious infections frequently present with normal vital signs and there has been an increased interest to include other variables such as symptoms in screening tools to detect sepsis. The majority of patients with sepsis arrive to the emergency department by emergency medical services. Our hypothesis was that the presentation of sepsis, including symptoms, may differ between patients arriving to the emergency department by emergency medical services and patients arriving by other means. This information is of interest to adapt future sepsis screening tools to the population in which they will be implemented. The aim of the current study was to compare the prevalence of keywords reflecting the clinical presentation of sepsis based on mode of arrival among septic patients presenting to the emergency department. METHODS: Retrospective cross-sectional study of 479 adult septic patients. Keywords reflecting sepsis presentation upon emergency department arrival were quantified and analyzed based on mode of arrival, i.e., by emergency medical services or by other means. We adjusted for multiple comparisons by applying Bonferroni-adjusted significance levels for all comparisons. Adjustments for age, gender, and sepsis severity were performed by stratification. All patients were admitted to the emergency department of Södersjukhuset, Stockholm, and discharged with an ICD-10 code compatible with sepsis between January 1, and December 31, 2013. RESULTS: "Abnormal breathing" (51.8% vs 20.5%, p value < 0.001), "abnormal circulation" (38.4% vs 21.3%, p value < 0.001), "acute altered mental status" (31.1% vs 13.1%, p value < 0.001), and "decreased mobility" (26.1% vs 10.7%, p value < 0.001) were more common among patients arriving by emergency medical services, while "pain" (71.3% vs 40.1%, p value < 0.001) and "risk factors for sepsis" (50.8% vs 30.8%, p value < 0.001) were more common among patients arriving by other means. CONCLUSIONS: The distribution of most keywords related to sepsis presentation was similar irrespective of mode of arrival; however, some differences were present. This information may be useful in clinical decision tools or sepsis screening tools.

Performance of NEWS2, RETTS, clinical judgment and the Predict Sepsis screening tools with respect to identification of sepsis among ambulance patients with suspected infection: a prospective cohort study.

BACKGROUND: There is little evidence of which sepsis screening tool to use in the ambulance setting. The primary aim of the current study was to compare the performance of NEWS2 (National Early Warning score 2) and RETTS (Rapid Emergency Triage and Treatment System) with respect to identification of sepsis among ambulance patients with clinically suspected infection. The secondary aim was to compare the performance of the novel Predict Sepsis screening tools with that of NEWS2, RETTS and clinical judgment. METHODS: Prospective cohort study of 323 adult ambulance patients with clinically suspected infection, transported to hospitals in Stockholm, during 2017/2018. The sensitivity, specificity, and AUC (Area Under the receiver operating Curve) were calculated and compared by using McNemar´s test and DeLong's test. RESULTS: The prevalence of sepsis in the current study population was 44.6% (144 of 323 patients). No significant difference in AUC was demonstrated between NEWS2 ≥ 5 and RETTS ≥ orange. NEWS2 ≥ 7 demonstrated a significantly greater AUC than RETTS red. The Predict Sepsis screening tools ≥ 2 demonstrated the highest sensitivity (range 0.87-0.91), along with RETTS ≥ orange (0.83), but the lowest specificity (range 0.39-0.49). The AUC of NEWS2 (0.73) and the Predict Sepsis screening tools (range 0.75-0.77) was similar. CONCLUSIONS: The results indicate that NEWS2 could be the better alternative for sepsis identification in the ambulance, as compared to RETTS. The Predict Sepsis screening tools demonstrated a high sensitivity and AUCs similar to that of NEWS2. However, these results need to be interpreted with caution as the Predict Sepsis screening tools require external validation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03249597. Registered 15 August 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03249597 .

Predicting mortality among septic patients presenting to the emergency department-a cross sectional analysis using machine learning.

BACKGROUND: Sepsis is a life-threatening condition, causing almost one fifth of all deaths worldwide. The aim of the current study was to identify variables predictive of 7- and 30-day mortality among variables reflective of the presentation of septic patients arriving to the emergency department (ED) using machine learning. METHODS: Retrospective cross-sectional design, including all patients arriving to the ED at Södersjukhuset in Sweden during 2013 and discharged with an International Classification of Diseases (ICD)-10 code corresponding to sepsis. All predictions were made using a Balanced Random Forest Classifier and 91 variables reflecting ED presentation. An exhaustive search was used to remove unnecessary variables in the final model. A 10-fold cross validation was performed and the accuracy was described using the mean value of the following: AUC, sensitivity, specificity, PPV, NPV, positive LR and negative LR. RESULTS: The study population included 445 septic patients, randomised to a training (n = 356, 80%) and a validation set (n = 89, 20%). The six most important variables for predicting 7-day mortality were: "fever", "abnormal verbal response", "low saturation", "arrival by emergency medical services (EMS)", "abnormal behaviour or level of consciousness" and "chills". The model including these variables had an AUC of 0.83 (95% CI: 0.80-0.86). The final model predicting 30-day mortality used similar six variables, however, including "breathing difficulties" instead of "abnormal behaviour or level of consciousness". This model achieved an AUC = 0.80 (CI 95%, 0.78-0.82). CONCLUSIONS: The results suggest that six specific variables were predictive of 7- and 30-day mortality with good accuracy which suggests that these symptoms, observations and mode of arrival may be important components to include along with vital signs in a future prediction tool of mortality among septic patients presenting to the ED. In addition, the Random Forests appears to be a suitable machine learning method on which to build future studies.

The predictive value of variables measurable in the ambulance and the development of the Predict Sepsis screening tools: a prospective cohort study.

BACKGROUND: Despite sepsis being a time critical condition with a high mortality, it is often not identified in a timely fashion. The aim of the current study was to create a screening tool based on bedside measurable variables predictive of sepsis among ambulance patients with infection according to clinical judgment by ambulance personnel. METHODS: Prospective cohort study of 551 adult patients presenting with suspected infection, performed in the ambulance setting of Stockholm during 2017-2018. 18 variables were measured in the ambulance (8 keywords related to medical history, 6 vital signs, 4 point-of-care blood tests, in addition to age, gender, and comorbidity. Logistic regression, area under the curve (AUC) and classification trees were used to study the association with sepsis. The AUC, sensitivity, specificity, predictive values and likelihood ratios were used to evaluate the predictive ability of sepsis screening models. RESULTS: The six variables with the strongest association with sepsis were: systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status. These were combined into the Predict Sepsis screening tool 1, with a sensitivity of 0.90, specificity 0.41, AUC 0.77; 95% confidence interval [CI] 0.73-0.81, PPV 0.52, and NPV 0.86. Combining a history of acute altered mental status with GCS < 15 and excluding lactate in the Predict Sepsis screening tool 2 did not noticeably affect the AUC. In addition, the AUCs of these models did not differ noticeably when compared to a model including vital signs alone, with novel calculated cut-offs; the Predict Sepsis screening tool 3. CONCLUSIONS: Systolic blood pressure ≤ 100 mmHg, temperature > 38.5 °C, GCS < 15, lactate > 4 mmol/L, gastrointestinal symptoms, and a history of acute altered mental status demonstrated the strongest association with sepsis. We present three screening tools to predict sepsis with similar sensitivity. The results indicated no noticeable increase of predictive ability by including symptom-variables and blood tests to a sepsis screening tool in the current study population. TRIAL REGISTRATION: NCT03249597.

Presentations of adult septic patients in the prehospital setting as recorded by emergency medical services: a mixed methods analysis.

BACKGROUND: Current sepsis screening tools rely on vital parameters which are, however, normal in one third of patients with serious infections. Therefore, there is a need to include other variables than vital parameters to identify septic patients. Our primary aim was to identify and quantify keywords related to the septic patients' symptom presentation in the prehospital setting. The secondary aims were to compare keywords in relation to in-hospital mortality and the distribution of keywords in relation to age categories, survivors/ deceased and severe/ non-severe sepsis. METHODS: A mixed methods analysis using a sequential exploratory design was performed, starting with a content analysis of presentations of septic patients as documented in Emergency Medical Services (EMS) records (n = 80) from 2012, to identify keywords related to sepsis presentation. Thereafter, the identified keywords were quantified among 359 septic patients from 2013. All patients were adults, admitted to Södersjukhuset and discharged with an ICD-10-code (International Classification of Diseases, Tenth Revision) compatible with sepsis. RESULTS: The most common keywords related to septic patients' symptom presentation were: abnormal/ suspected abnormal temperature (64.1.%), pain (38.4%), acute altered mental status (38.2%), weakness of the legs (35.1%), breathing difficulties (30.4%), loss of energy (26.2%) and gastrointestinal symptoms (24.0%). There was an association between keywords and in-hospital mortality. Symptoms varied between age categories, survivors/ deceased and severe/ non-severe sepsis. DISCUSSION: This is, to the best of our knowledge, the first study exploring the symptom presentation as documented by EMS, of septic patients in the prehospital setting. Keywords related to patients´ symptom presentation recurred in the EMS records of septic patients, so that a pattern was discernible. In addition, certain symptom presentations were associated with increased in-hospital mortality CONCLUSIONS: Information relating to symptom presentation is not included in current sepsis screening tools. We suggest that keywords related to patients´ symptom presentation could be integrated into screening tools and may thus increase the identification of sepsis, and potentially also identify high-risk patients. However, as a first step, the specificity of these keywords, with respect to sepsis, needs to be examined.

Longer time to antibiotics and higher mortality among septic patients with non-specific presentations--a cross sectional study of Emergency Department patients indicating that a screening tool may improve identification.

BACKGROUND: The presentation of sepsis is varied and our hypotheses were that septic patients with non-specific presentations such as decreased general condition (DGC) have a less favourable outcome, and that a screening tool could increase identification of these patients. We aimed to: 1) assess time to antibiotics and in-hospital mortality among septic patients with ED chief complaint DGC, as compared with septic patients with other ED chief complaints, and 2) determine whether a screening tool could improve identification of septic patients with non-specific presentations such as DGC. METHODS: Cross sectional study comparing time to antibiotics (Mann Whitney and Kaplan-Meier tests), and in-hospital mortality (logistic regression), between 61 septic patients with ED chief complaint DGC and 516 septic patients with other ED chief complaints. The sensitivity and specificity of the modified Robson screening tool was compared with that of ED doctor clinical judgment (McNemar's two related samples test) among 122 patients presenting to the ED with chief complaint DGC, of which 61 were discharged with ICD code sepsis. RESULTS: Septic patients presenting to the ED with the chief complaint DGC had a longer median time to antibiotics (05:26 h:minutes; IQR 4:00-10:40, vs. 03:56 h:minutes; IQR 2:21-7:32) and an increased in-hospital mortality (crude OR = 4.01; 95% CI, 2.19-7.32), compared to septic patients with other ED chief complaints. This association remained significant when adjusting for sex, age, priority, comorbidity and fulfilment of the Robson score (OR 4.31; 95% CI, 2.12-8.77). The modified Robson screening tool had a higher sensitivity (63.0 vs. 24.6%, p < 0.001), but a lower specificity (68.3 vs. 100.0%, p < 0.001), as compared to clinical judgment. DISCUSSION: This is, to the best of our knowledge, the first study comparing outcome of septic patients according to ED chief complaint. Septic patients presenting with a non-specific ED presentation, here exemplified as the chief complaint DGC, have a less favourable outcome. Our results indicate that implementation of a screening tool may increase the identification of septic patients. CONCLUSIONS: The results indicate that septic patients presenting with ED chief complaint DGC constitute a vulnerable patient group with delayed time to antibiotics and high in-hospital mortality. Furthermore, the results support that implementation of a screening tool may be beneficial to improve identification of these patients.

Identification of adult septic patients in the prehospital setting: a comparison of two screening tools and clinical judgment.

BACKGROUND: Timely identification and treatment of sepsis is crucial for patient outcome. The aim of this study was to compare two previously unvalidated prehospital sepsis screening tools with clinical judgment by emergency medical services (EMS) personnel with respect to identification of septic patients. PATIENTS AND METHODS: We carried out a retrospective cross-sectional study of 353 adult patients, transported by the EMS, with a hospital discharge International Classification of Diseases code consistent with sepsis. We analyzed EMS records for the identification of sepsis according to two screening tools and clinical judgment by EMS providers. The Robson screening tool includes temperature, heart rate, respiratory rate, altered mental status, plasma glucose, and a history suggestive of a new infection. BAS 90-30-90 refers to the vital signs: oxygen saturation, respiratory rate, and systolic blood pressure. McNemar's two related samples test was used to compare the sensitivity of the two screening tools with the sensitivity of clinical judgment. RESULTS: The Robson screening tool had a sensitivity of 75% (18 out of 24 patients for whom all parameters were documented, P<0.001, as compared with clinical judgment). BAS 90-30-90 had a sensitivity of 43% (76 out of 175 patients, P<0.001). EMS personnel documented suspected sepsis in 42 out of 353 (12%) patients with sepsis. CONCLUSION: The Robson screening tool had a sensitivity superior to both BAS 90-30-90 and clinical judgment. This supports our hypothesis that the implementation of a screening tool could lead to increased prehospital identification of sepsis, which may enable a more timely treatment of these patients.