Development of a clinical prediction rule for sepsis in primary care: protocol for the TeSD-IT study

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Loots, Rogier Hopstaken, Kevin Jenniskens, Geert W.J. Frederix, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.24104/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Aug, 2020 Read the published version in Diagnostic and Prognostic Research → Version 2 posted 9 You are reading this latest preprint version Show more versions Abstract Background Early recognition and treatment of sepsis is crucial to prevent detrimental outcomes. General practitioners (GPs) are often the first healthcare providers to encounter seriously-ill patients. The aim of this study is to assess the value of clinical information and additional tests to develop a clinical prediction rule to support early diagnosis and management of sepsis by GPs. Methods We will perform a diagnostic study in the setting of out-of-hours home visits in four GP cooperatives in the Netherlands. Acutely ill adult patients suspected of a serious infection will be screened for eligibility by the GP. The following candidate predictors will be prospectively recorded: 1) age; 2) body temperature; 3) systolic blood pressure; 4) heart rate; 5) respiratory rate; 6) peripheral oxygen saturation; 7) mental status; 8) history of rigors and 9) rate of progression. After clinical assessment by the GP, blood samples will be collected in all patients to measure C-reactive protein, lactate and procalcitonin. All patients will receive care as usual. The primary outcome is presence or absence of sepsis within 72 hours after inclusion, according to an expert panel. The need for hospital treatment for any indication will be assessed by the expert panel as a secondary outcome. Multivariable logistic regression will be used to design an optimal prediction model first, and subsequently derive a simplified clinical prediction rule that enhances feasibility of using the model in daily clinical practice. Bootstrapping will be performed for internal validation of both the optimal model and simplified prediction rule. Performance of both models will be compared to existing clinical prediction rules for sepsis. Discussion This study will enable us to develop a clinical prediction rule for the recognition of sepsis in a high-risk primary care setting to aid in the decision which patients have to be immediately referred to a hospital and who can be safely treated at home. As clinical signs and blood samples will be obtained prospectively, near complete data will be available for analyses. External validation will be needed before implementation in routine care and to determine in which pre-hospital settings care can be improved using the prediction rule. Trial registration The study is registered in the Netherlands Trial Registry (registration number NTR7026). General Practice Preventive Medicine sepsis clinical prediction rule diagnosis primary care general practice out-of-hours medical care practitioner cooperative point-of-care testing Figures Figure 1 Background Sepsis is a life-threatening complication of an infection. Early detection and initiation of adequate treatment is the key factor influencing outcome. 1-4 It is estimated that annually 49 million people suffer from sepsis worldwide, of which 11 million do not survive. 5 In 2017, the WHO declared sepsis a global healthcare priority and urged member states to improve recognition and treatment of sepsis. 6 Global efforts to reduce mortality and morbidity from sepsis have focused on hospital settings, but patients often present in primary care in the early stages of sepsis. General practitioners (GPs) are confronted with acutely ill patients with a variety of symptoms, signs and potential diagnoses. Within minutes they have to decide whether a patient can safely be treated at home or should be referred to a hospital for further assessment. In the Netherlands, out-of-hours primary care is provided by large GP cooperatives. 7 Patients are only assessed by a GP if the medical complaint cannot wait until the following working day. In contrast to other common time-critical conditions such as stroke and myocardial infarction, patients with sepsis are more likely to contact a GP cooperative instead of an emergency medical service prior to hospital treatment. 8 Data from our preliminary research on patients admitted to an intensive care unit (ICU) due to community acquired sepsis, showed that about half of the patients had prior contact with a GP cooperative. Two thirds of these patients were referred to the hospital after the first contact. 9 The majority of the patients were assessed during a home visit. In the hospital setting, vital signs are used to screen for sepsis in patient with suspected infections. The Systemic Inflammatory Response Syndrome (SIRS) was introduced in 1992 to define sepsis. 10 Besides the white blood count, the SIRS criteria are a heart rate 20/min, and a body temperature 38°C. As SIRS criteria are often present in patients without serious infections and one in eight patients admitted to the ICU with sepsis were found to lack positive SIRS criteria, a new consensus definition was formulated in 2016. In the “Sepsis-3” definition, the Sequential Organ Failure Assessment (SOFA) score was proposed to diagnose sepsis. 1 As this score is not easy to apply outside the ICU, the quick SOFA (qSOFA) was introduced for rapid bedside assessment. The criteria used in the qSOFA are an altered mental status, systolic blood pressure ≤100 mmHg, and a respiratory rate ≥ 22/min. A positive score on two or more parameters predicts an increased risk of mortality. However, the qSOFA is not suitable as a screening tool as it lacks sensitivity. 11-12 C-reactive protein (CRP), lactate and procalcitonin (PCT) have all been shown to increase the sensitivity and overall diagnostic performance of the qSOFA. 13-15 To our knowledge, no study has assessed the contribution to the accurate early detection of sepsis in primary care of factors such as symptoms, signs, and biomarkers potentially available as point-of-care tests (POCT) such as CRP, lactate, and PCT. The aim of the TeSD-IT study ( Te sting for S epsis in primary care: D iagnostic and prognostic study I nvestigating the potential benefits of point of care T esting) is to develop a clinical prediction rule to improve the detection of sepsis while limiting unnecessary referrals in acutely ill patients presenting at the GP cooperative home visits. Clinical signs and symptoms as well as blood tests will be considered as candidate predictors. Methods Setting, and design We will perform a prospective diagnostic cohort study in the Netherlands in four GP cooperatives (Ede,’s-Hertogenbosch, Uden and Oss) for out-of-hours primary care. The cooperatives serve a total of approximately 830,000 inhabitants in a mixed urban, suburban and rural area. The cooperatives are based in or adjacent to regional hospitals. Patients Patients will be recruited during out-of-hours home visits by GPs. Patients only receive home visits when they have acute medical complaints that cannot wait until the next working day and they are not able to visit the GP cooperative location for a clinic consultation. This is decided after telephone assessment by a triage nurse based on the Netherlands Triage System (NTS). 16 Inclusion criteria: 1) Acutely ill adult patients (≥18 years), receiving a home visit by a GP during OOH And 2) Fever, confusion or general deterioration or otherwise suspected of a serious infection. Exclusion criteria: 1) Non-infectious cause of the acute complaints ( e.g. stroke or myocardial infarction) 2) Hospitalisation within seven days before the home visit 3) Condition that requires secondary care assessment if there are any signs of systemic infection ( e.g. chemotherapy with possible neutropenia) 4) Terminal illness or other reason not to refer the patient to a hospital despite presence of a life-threatening condition. Candidate predictors We selected nine clinical features and three blood tests as candidate predictors for the development of the clinical prediction model (Table 1). Parameters of widely used scoring systems such as the SIRS, qSOFA and National Early Warning Score (NEWS) 17 were considered, as well as clinical features used in guidelines such as the Netherlands Triage Standard (NTS) and NICE Sepsis guideline. 18 Candidate predictors were selected if there was evidence to suggest that they might usefully contribute to the diagnosis of sepsis, and if they can be easily and objectively measured by GPs. Candidate blood tests had to be currently used in the hospital setting for the diagnosis and/or prognosis of sepsis, and, preferably, to be available as a point-of-care (POC) test for reasons of implementation. CRP and lactate measurement are part of the standard care in patients with suspected sepsis during assessment in the Emergency Department (ED) in the Netherlands. Procalcitonin (PCT) is not routinely measured in most hospitals, but we decided to include PCT as a candidate predictor as PCT might be superior to CRP, 19 and the NICE sepsis guideline recommends research to further evaluate the use of PCT POCT for diagnosing serious bacterial infection and initiating antibiotic therapy. CRP, lactate and PCT are currently available as POC tests. Outcome measures The primary outcome measure is sepsis within 72 hours after inclusion. This will be determined by an expert panel using the Sepsis-3 criteria. 1 The operational definition of sepsis is the presence of infection and a SOFA score (Table 2) of at least two above the baseline (which can be assumed to be zero in patients not known to have preexisting organ dysfunction). To limit the workload for the experts, we will appoint three expert panels, each comprising a GP, an emergency physician, and an internist(-intensivist). Each case will be assessed by one panel. All relevant information from medical records from the GP and the hospital when applicable will be presented to the panel (see additional file 1). If there is no consensus on the primary outcome, the case will be discussed in a face-to-face consensus meeting with all three experts to determine the final outcome. Interobserver agreement between the three panels will be assessed in a selection of 10% of the cases that will be assessed by all panels. Besides the dichotomous primary outcome “sepsis within 72 hours”, the likelihood of sepsis will be assigned a numerical score between 0 and 10. This gives information on remaining uncertainty regarding sepsis classification, providing insight in the degree of bias that may be introduced when calculating diagnostic accuracy measures using dichotomous sepsis classification. 20 Furthermore, the need for hospital treatment is scored between 0 and 10 by the expert panel as a secondary outcome. An average score above 5 will be regarded as a patient that should best be referred to the hospital immediately by the GP and a score ≤ 5 as a patient that does not have to be referred immediately. Other outcome measures are hospitalisation (length of stay and type of care: ICU or regular ward), maximum SOFA score in the first 72 hours, 30 day all-cause mortality, final diagnosis, and medical costs. Study procedures Study period The inclusion period is from June 2018 until April 2020. If in April 2020 the required sample size is not reached, the patients will continue to be recruited until the minimum required number of events has been reached. Follow-up of the patients is 30 days. Procedure during home visit All patients will receive usual care. Patients will be screened for eligibility during home visits by the attending GP of the GP cooperative. Verbal informed consent will be obtained from the patient or his legal representative. The GP will be (routinely) accompanied by a chauffeur during the home visit. The chauffeurs are used to practically assist the GP during the visit. Portable monitors (Philips intelliVue MP2 or X2) will be available to record peripheral oxygen saturation, automated blood pressure and heart- and respiratory rate by three lead electrodes on the chest. The GP will record the assessment of the candidate predictors in a case report form. In addition, the GP will record if he/she has a gut feeling that “something is wrong” and will provide the likelihood of presence of sepsis at inclusion on a scale from 0 to 10. All study materials will be taken to the patient’s home in a study bag. The venous samples will be collected by either the GP or an on-call laboratory assistant or nurse within one hour after inclusion, with a maximum of eight hours. Written informed consent will be obtained prior to the collection of the blood samples. In case the patient is referred to the hospital and the blood samples are not collected by the GP, the study bag will be transported with the patient to the ED. Subsequently, the laboratory assistant on call will visit the patient in the hospital and collect the blood samples. Three blood tubes will be collected: 10 ml for serum, 10 ml for EDTA plasma and a 2 ml heparin tube. Lactate will be measured immediately afterwards from a single drop of blood taken from the heparin tube, using the StatStrip Xpress (Nova Biomedical) POC test. The remaining blood samples will be taken to the hospital laboratory and divided into six samples of serum and six samples of EDTA plasma. The aliquots will be temporarily stored at the local laboratory at <-70°C. Two samples (1 ml serum and 1 ml EDTA plasma) will be transported to the Jeroen Bosch Hospital for CRP and PCT analyses, and the remaining samples (5x 0.5 ml serum and 5x 0.5 ml EDTA plasma) will be stored for 15 years at <-80°C at the UMC Utrecht for potential future testing. Training and remuneration of personnel Chauffeurs of the GP cooperatives will be trained in using portable monitors for vital sign measurement and other study procedures. At the GP cooperative in Ede the chauffeurs will also be trained in the measurement of POC-lactate, as GPs will collect the venous blood samples themselves occasionally. The laboratory assistants and nurses who will be on call for the collection of the blood samples will also be trained in the POC–lactate measurement and other study procedures, including the obtaining of written informed consent. Attending GPs will be informed by an information letter by mail and hard copy at the GP cooperative. Leaflets with a summary of the study procedures will also be available. Follow-up The total follow-up time is 30 days (see figure 1). Patients will be asked to complete the EQ5D-5L questionnaire 22 at the end of follow-up (1) at the day of completion of the questionnaire; (2) before the onset of the recent disease episode (i.e. their health status of at least one month ago); and (3) for the worst day they remember from their recent disease episode. Furthermore, patients will be asked to report on consumption of medical resources during the 30-day follow-up period.. In case of no response to the questionnaire after one week, patients will be contacted once by telephone as a reminder. Data-extraction Relevant medical information will be obtained from the patient’s (regular) GP, the GP cooperative, and the hospital. Information from all hospital admissions in the 30-day follow-up will be retrieved, first by digital search in the local hospital and secondly by manual screening of the GP record for admissions in other hospitals. Medication use and comorbidities before inclusion will be retrieved from GP electronic records, as well as information on any subsequent contacts. The medical record of the assessment at the time of inclusion will be retrieved from the GP cooperative. The following data from the electronic medical record of the hospital will be collected: full reports from ED and hospital discharge; date and time of ED visit, hospital admittance and discharge (including type of ward); vital signs, EMV score, leucocyte count, thrombocyte count, creatinine, bilirubin, CRP and lactate measured in the first 72 hours after inclusion; cultures taken in the first 72 hours after inclusion; radiodiagnostic procedures in the first seven days after inclusion; antibiotic prescriptions during hospitalisation; intravenous volume therapy in the first 72 hours (defined as more than 1.5 litres of fluids in 24 hours). Sample size In total, 12 candidate predictors are chosen for the development of the prediction model (table 1). Using the rule of thumb of 10 events per variable, 23 we need 120 patients reaching the primary outcome “sepsis within 72 hours after inclusion” in the final dataset. Prior to the start, the prevalence of sepsis based on previous research and literature was estimated to be around 12%. However, preliminary data analysis from the patients included in the study so far, indicates the prevalence of sepsis in the study cohort to be around 30-40%. After the first 100 cases will be assessed by the expert panel, we will determine the final target sample size. Statistical analyses Descriptive statistics We will use a combination of IBM SPSS Statistics and R Statistical Software for all analyses. We will start with descriptive analyses on baseline characteristics (age, sex, comorbidities, vital sign measurements and other clinical features, blood tests results, baseline EQ5D-5L score), final diagnosis, hospital admission, ICU admission, length of stay, EQ5D-5L compared to baseline, and 30-day mortality. Results will be stratified based on whether patients do or do not meet the primary outcome sepsis. Data cleaning Range and distribution of all continuous variables will be graphically inspected, and any outliers (more than three standard deviations from the mean) will be discussed and corrected or removed in case of a data recording error. Any missing data on clinical features or blood tests, will be accounted for by applying multiple imputation techniques. Prediction model development and performance will be analysed using the imputed datasets. Development of the prediction model A multivariable penalized logistic regression model will be developed, based on the variables listed in table 1, for predicting the primary outcome (sepsis within 72 hours after inclusion). We will use a two-stepped approach entering and selecting clinical features first, and blood tests second. In both steps the selection of predictors will be based on a stepwise backward selection, using change in Akaike information criterion (AIC) for selecting the preferred model. 24 The goal is to generate an efficient model by eliminating variables that contribute little to the model’s performance, requiring only measurement of the most important variables in clinical practice. Continuous predictors in the model will be assessed for linear relationship with the logit of the primary outcome. Transformation of the data and splines will be used if deemed appropriate based on distribution of the data. The resulting prediction model that will be the most accurate prediction model, by making use of continuous measurements of predictors and reflecting non-linear relationships by transformations or splines (optimal model). To make this model workable in daily clinical practice without electronic aids, a second model will be derived (clinical practice model) by categorising or stratifying predictors. Cut-offs for categorisation will be based on a combination of known and commonly used thresholds in clinical practice and optimal thresholds based on the data. This model simplification is likely to induce a performance drop with regard to the full model, which will be assessed during the analysis. The above procedures will result in the following three models: 1) Optimal model with clinical features only; 2) Optimal model with clinical features and blood tests; 3) Simplified model (with clinical features and blood tests). Performance of the prediction model The performance of all three models will be determined based on their discrimination and calibration. Discrimination will be evaluated based on the area under the receiver-operator characteristic (AUROC). Calibration will be assessed by plotting observed and expected probabilities and inspecting this plot graphically. Measures of calibration will include calibration slope, calibration in the large, observed/expected (O/E) ratio, and the Brier score. 25 We will perform internal validation for all three models by using a bootstrap simulation. The resulting distribution will reflect optimism and the degree of overfitting. 26 The SIRS criteria, NEWS score, and qSOFA score will be calculated for all individuals in the TeSD-IT study. Diagnostic performance of the existing models will be determined by calculating the same measures of discrimination and calibration as described in the sections above, and comparing these with the three models that were developed. To assess the added value of the prediction models on top of usual care, other outcomes than sepsis will be considered. This is crucial for gaining insight in the net benefit of using the clinical prediction rule in daily practice. For example, when a patient is predicted as non-sepsis by the model, but the patient was referred by the GP, improvement compared to care as usual is only the case if hospital treatment was not needed according to the expert panel. To assess the added value, the proportion of reclassifications within the original contingency tables will be presented for the following outcomes: 1) the gut feeling of the visiting GP that “something is wrong” 2) the assessment of the visiting GP for the likelihood of sepsis, and 3) the decision of the visiting GP whether or not to refer the patient to the hospital. Cost-effectiveness and budget impact analysis We will measure costs from a societal perspective, including health care costs and patient costs within and outside the hospital (see additional file 2 for detailed information). Productivity costs will be ignored as the average age of patients participating will exceed the age of pensioning in the Netherlands. The patient questionnaire as well as follow-up data from hospital and GP medical records will be used for the calculation of total and per patient costs. The EQ5D-5L scores retrieved from the questionnaire will be used to calculate QALYs. Our patient outcome analysis will generate QALYs for different health states that will be used in health economic modelling, such as a complicated sepsis case (including ICU admission), hospital admittance for a suspicion of sepsis, and an infectious disease episode without hospital admission. Different scenarios with different levels of implementation of POCT for sepsis in general practice will be analysed and compared to standard of care: 100% use of the best performing testing strategy; 70%, 30% and 0% use of POCT for suspicion of sepsis (the latter representing usual care). The budget impact will be assessed using the health economic model that will be built for the economic evaluation and results will be analysed in a probabilistic way. Discussion The TeSD-IT study is a diagnostic and prognostic study, designed for the development of a clinical prediction rule for the early recognition of sepsis in primary care. A limited number of nine clinical parameters and three blood tests were selected. This will enable us to construct the model using multivariable logistic regression techniques with 120 events included in the dataset. We realise the validity of rule of thumb of 10 event per variable is debated. 27 However, using an alternative sample size calculation suggested by van Smeden, 28 results in a similar identical sample size of about 350 patients in case of 12 variables, an outcome rate of 0.35 and rMPSE set at 0.09. We have chosen to recruit patients in the setting of out-of-hours home visits performed by a GP. In this setting GPs frequently encounter seriously ill patients in whom they instantly have to decide whether or not to refer the patient (immediately) to the hospital. A methodological advantage is that the required sample size is substantially lower than in other primary care settings with a lower incidence of sepsis. However, external validation in other settings and populations will be needed before implementing the clinical prediction rule more broadly. The diagnosis of sepsis is not straightforward. In 2016, new consensus definitions for sepsis were published, which we try to implement as well as possible. As both the presence of infection as well as organ failure can be equivocal, we will use expert panels to determine the final outcome. The outcome should be clinically relevant for the GP. The rationale of the timeframe of 72 hours is that patients who are found septic within this period after GP assessment would likely benefit from immediate hospital referral. Not all patients with organ failure need hospital treatment to recover, and not all patients with severe infections that are treated with intravenous antibiotic therapy have signs of organ failure. However, we believe the diagnosis of sepsis based on the Sepsis-3 definitions is the most relevant endpoint for GPs to differentiate between patients who are likely to benefit from immediate hospital treatment and patients who might be treated at home successfully. The expert panel will also rate the need for hospital treatment for every patient, regardless of the diagnosis. This will enable us to evaluate the effect of the new clinical prediction rule on medically unnecessary referrals. The expert panels will be instructed to use the SOFA score (increase, due to infection, of ≥2 points from baseline) to define the primary outcome “sepsis within 72 hours after inclusion”. This is consistent with the Sepsis-3 consensus definition and leads to an objective and reproducible endpoint in absence of a gold standard. However, this approach introduces the risk of incorporation bias. Parameters included in the SOFA score are more likely to be predictive of sepsis in our model. However, the blood tests (CRP, lactate and procalcitonin) are not included in the SOFA score, which limits the risk of incorporation bias for these tests. Furthermore, vital signs measured in the first 72 hours will be used to calculate the SOFA score and not only at the time of inclusion. Patients will receive a questionnaire at day 30 measuring EQ5D-5L. The results may be biased due to selective response and poor recall due to sepsis- or age-related cognitive impairment. Imputation of the missing answers on the questionnaires will reduce this form of bias as much as possible. Furthermore, the development of the clinical prediction rule is not affected, as the patient questionnaires will only be used for the cost-effectiveness analyses To compare the performance of the new clinical prediction rule with usual care, not only the decision to refer the patient to the ED, but also the assessment of the GP of the likelihood of sepsis on a scale from 0-10 and the presence of a “gut-feeling something is wrong” will be used. We will examine if the prediction rule will outperform those assessments of the GP in order to likely improve the usual care. Only three candidate blood tests were selected for the development of the prediction rule. Various other biomarkers have promising diagnostic and/or prognostic properties in patients with suspected sepsis. 29-30 At the start of this study, sufficient evidence of the additional diagnostic and/or prognostic value above lactate, CRP and PCT was lacking. However, sufficient blood samples will be stored for retrospective testing of multiple additional biomarkers. Although to our best knowledge no clinical prediction rules for sepsis in primary care were previously developed, several sepsis screening tools were published for the ambulance setting. 31 However, none of those have adequate inclusion criteria, data collection and clinically relevant endpoints for use in the primary care setting. Availability of Data and Materials Data will be made available from the corresponding author on reasonable request after completion of the study. Abbreviations AIC: Akaike information criterion CRP: C-reactive protein ED: Emergency department GP: General Practitioner ICU: Intensive care unit NEWS: National Early Warning Score NTS: Netherlands Triage Standard PCT: Procalcitonin POC(T): Point-of-care (testing) AUROC: Area under the receiver-operator characteristic SIRS: Systemic inflammatory response syndrome (q)SOFA: (quick) Sequential organ failure assessment score QALY: Quality-adjusted life year References 1. Singer M, Deutschman CS, Seymour CW, et al . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8):801-10. 2. Rhodes A, Evans LE, Alhazzani W, et al . Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. 3. Sherwin R, Winters ME, Vilke GM, Wardi G. Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock? J Emerg Med. 2017 Oct;53(4):588-95. doi:10.1016/j.jemermed.2016.12.009. 4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369(9): 840-51. 5. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020 Jan 18;395(10219):200-11. doi:10.1016/S0140-6736(19)32989-7. 6. Reinhart K, Daniels R, Kissoon N, et al. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017 Aug 3;377(5):414-17. doi:10.1056/NEJMp1707170. 7. Smits M, Rutten M, Keizer E, et al.The development and performance of after-hours primary care in the Netherlands: a narrative review. Ann Intern Med 2017;166(10):737-42. 8. Søvsø MB, Christensen MB, Bech BH, et al. Contacting out-of-hours primary care or emergency medical services for time-critical conditions - impact on patient outcomes. BMC Health Serv Res. 2019 Nov 7;19(1):813. doi: 10.1186/s12913-019-4674-0. 9. Loots FJ, Smits M, van Steensel C, et al. Management of sepsis in out-of-hours primary care: a retrospective study of patients admitted to the intensive care unit. BMJ Open. 2018 Sep 17;8(9):e022832. doi: 10.1136/bmjopen-2018-022832. 10. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101(6):1644-55. 11. Williams JM, Greenslade JH, McKenzie JV, et al. Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and Organ Dysfunction: Insights From a Prospective Database of ED Patients With Infection. Chest. 2017 Mar;151(3):586-96. doi: 10.1016/j.chest.2016.10.057. 12. Fernando SM, Tran A, Taljaard M, et al. Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis. Ann Intern Med. 2018 Feb 20;168(4):266-75. doi: 10.7326/M17-2820. 13. Dimitrov E, Minkov G, Enchev E, et al. A combination of C-reactive protein and quick sequential organ failure assessment (qSOFA) score has better prognostic accuracy than qSOFA alone in patients with complicated intra-abdominal infections. Acta Chir Belg. 2019 Jul 16:1-5. doi: 10.1080/00015458.2019.1642579. 14. Yu H, Nie L, Liu A, et al. Combining procalcitonin with the qSOFA and sepsis mortality prediction. Medicine (Baltimore). 2019 Jun;98(23):e15981. doi: 10.1097/MD.00000000000159813-14 15. Baumann BM, Greenwood JC, Lewis K, et al. Combining qSOFA criteria with initial lactate levels: Improved screening of septic patients for critical illness. Am J Emerg Med. 2019 Jul 4. pii: S0735-6757(19)30450-4. doi:10.1016/j.ajem.2019.07.003. 16. Nederlands Triage Systeem [Dutch Triage System]. 2017. www.de-nts.nl. Accessed 16 January 2020. 17. Physicians RCo. National Early Warning Score (NEWS) 2: Standardising the Assessment of Acute-Illness Severity in the NHS; RCP: London, UK, 2017. 18. National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. 2017. https://www.nice.org.uk/guidance/ng51 . Accessed 16 January 2020. 19. Tan M, Lu Y, Jiang H, Zhang L. The diagnostic accuracy of procalcitonin and C-reactive protein for sepsis: A systematic review and meta-analysis. J Cell Biochem. 2019 Apr;120(4):5852-59. doi: 10.1002/jcb.27870. 20. Jenniskens K, Naaktgeboren CA, Reitsma JB, et al. Forcing dichotomous disease classification from reference standards leads to bias in diagnostic accuracy estimates: A simulation study. J Clin Epidemiol. 2019 Jul;111:1-10. doi: 10.1016/j.jclinepi.2019.03.002. 21. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. 22. EQ-5D instruments. https://euroqol.org/ . Accessed 16 January 2020. 23. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49(12):1373–79. 24. Sakamoto Y, Ishiguro M, Kitagawa G. Akaike information criterion statistics. Dordrecht, The Netherlands: D. Reidel. 1986;81. 25. Steyerberg EW, Vickers AJ, Cook NR, et al. Assessing the performance of prediction models: a framework for some traditional and novel measures. Epidemiology (Cambridge, Mass.). 2010 Jan;21(1):128. 26. Moons KG, Kengne AP, Woodward M, et al. Risk prediction models: I. Development, internal validation, and assessing the incremental value of a new (bio) marker. Heart. 2012 May 1;98(9):683-90. 27. van Smeden M, Moons KG, de Groot JA, et al. Sample size for binary logistic prediction models: Beyond events per variable criteria. Stat Methods Med Res. 2019 Aug;28(8):2455-74. doi:10.1177/0962280218784726. 28. https://mvansmeden.shinyapps.io/BeyondEPV/ . Accessed 31 March 2020 29. Vincent JL, Beumier M. Diagnostic and prognostic markers in sepsis. Anti Infect Ther. 2013 Mar;11(3):265-75. doi: 10.1586/eri.13.9. 30. van Engelen TSR, Wiersinga WJ, Scicluna BP, van der Poll T. Biomarkers in Sepsis. Crit Care Clin. 2018 Jan;34(1):139-52. doi: 10.1016/j.ccc.2017.08.010. 31. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: a systematic review. BMJ Open 2016;6:e011218. doi:10.1136/bmjopen-2016-011218. Declarations Ethics approval and consent to participate The study was approved by the Ethical Research Committee of the UMC Utrecht, and is registered under number 18/169. Written informed consent will be obtained before the collection of blood samples and after initial verbal informed consent. In mentally incapacitated patients, consent will be provided by the legal representative. In case written informed consent is not feasible prior to the collection of blood samples due to an acute life-threatening condition, the written consent will be asked as soon as possible afterwards. All collected data - including the blood results - will be stored without identifying information under a study number. Personal details of the patient which are needed for the data collection will be store in an secured online environment until the data collection is completed. The data and excess blood samples will be stored for 15 years afterwards. Additional test of stored blood samples will only be done in patients who opted in in the written informed consent. Availability of data and materials Not applicable. Competing interests Non declared. Funding The study was financially supported by ZonMw, grant number 843001811. In kind support for material costs were provided by ThermoFischer (procalcitonin analyses), Nova Biomedical (POC lactate measurement) and Philips (portable monitoring devices). Neither funding party had a role in the design of this study, interpretation of the data, or decision to submit results. Authors' contributions FL contributed to the study conceptualisation and design, and drafted the manuscript. RH contributed to the study conceptualisation and design and revised the manuscript critically for important intellectual content. KJ and MS contributed to the design of the statistical analyses and co-drafted the manuscript. GF, AP, AB, JJO and AZ contributed to the study design and revised the manuscript critically for important intellectual content. TV supervised the study, contributed to the study design and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript and 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. Acknowledgements The authors would like to thank all staff of the GP cooperatives Gelderse Vallei and Oost-Brabant for their support and cooperation. Tables Table 1. Candidate predictors eligible for the selection in the prediction model Type of predictor Candidate predictor Measurement method Measurement unit Used in Clinical feature Age Inclusion date minus date of birth years NICE guideline 18 Body temperature Tympanic measurement °C SIRS, 10 NEWS, 17 NICE guideline Heart rate IntelliVue MP2/ X2 beats/min SIRS, NEWS, NICE guideline Respiratory rate IntelliVue MP2/ X2 or GP assessment breaths/min SIRS, qSOFA, NICE guideline, NEWS Systolic blood pressure IntelliVue MP2/ X2 mmHg qSOFA, NEWS, NICE guideline Peripheral oxygen saturation IntelliVue MP2/ X2 % NEWS, NICE guideline Mental status GP assessment normal/altered qSOFA, NEWS, NICE guideline Rapid progression of illness in last 24h GP assessment yes/no NICE guideline (History of) rigors in last 24h GP assessment yes/no NTS 16 Blood test C-reactive protein (CRP) Siemens, ADVIA Chemistry XPT mg/l Lactate StatStrip Xpress mmol/l Procalcitonin (PCT) Siemens, ADVIA Centaur XPT ng/ml Table 2. SOFA score a Score System 1 2 3 4 Respiration PaO 2 /FiO 2 , mmHg 300-440 > 440 <200 with respiratory support < 100 with respiratory support Coagulation Platelets, x10 3 /µL <150 <100 <50 204 Cardiovascular Hypotension MAP < 70 mmHg Dopamine 15 or epinephrine >0.1 or norepinephrine >0.1 Central nervous system Glasgow Coma Score 13-14 10-12 6-9 440 Urine output, mL/d <500 <200 a Adapted from Vincent et al. 21 b Adrenergic agents administered for at least one hour (doses given in µg/kg/min). PaO 2 , partial pressure of arterial oxygen. FiO 2 , fraction of inspired oxygen. MAP, mean arterial pressure. Supplementary Files Additionalfile2.docx Additionalfile1v2clean.docx Cite Share Download PDF Status: Published Journal Publication published 06 Aug, 2020 Read the published version in Diagnostic and Prognostic Research → Version 2 posted Review # 2 received at journal 30 Apr, 2020 Editorial decision: Accept 30 Apr, 2020 Reviewer # 2 agreed at journal 22 Apr, 2020 Editor assigned by journal 16 Apr, 2020 Reviewers invited by journal 16 Apr, 2020 Reviewer # 1 agreed at journal 16 Apr, 2020 Review # 1 received at journal 16 Apr, 2020 Submission checks completed at journal 15 Apr, 2020 Editor invited by journal 15 Apr, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-14664","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Protocol","associatedPublications":[],"authors":[{"id":497105,"identity":"e286aa77-27ed-4a06-94bc-ad3f87dc110b","order_by":1,"name":"Feike J. 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Early detection and initiation of adequate treatment is the key factor influencing outcome.\u003csup\u003e1-4\u003c/sup\u003e It is estimated that annually 49 million people suffer from sepsis worldwide, of which 11 million do not survive.\u003csup\u003e5\u003c/sup\u003e In 2017, the WHO declared sepsis a global healthcare priority and urged member states to improve recognition and treatment of sepsis.\u003csup\u003e6\u003c/sup\u003e Global efforts to reduce mortality and morbidity from sepsis have focused on hospital settings, but patients often present in primary care in the early stages of sepsis. General practitioners (GPs) are confronted with acutely ill patients with a variety of symptoms, signs and potential diagnoses. Within minutes they have to decide whether a patient can safely be treated at home or should be referred to a hospital for further assessment.\u003c/p\u003e\n\u003cp\u003eIn the Netherlands, out-of-hours primary care is provided by large GP cooperatives.\u003csup\u003e7\u003c/sup\u003e Patients are only assessed by a GP if the medical complaint cannot wait until the following working day. In contrast to other common time-critical conditions such as stroke and myocardial infarction, patients with sepsis are more likely to contact a GP cooperative instead of an emergency medical service prior to hospital treatment.\u003csup\u003e8\u003c/sup\u003e Data from our preliminary research on patients admitted to an intensive care unit (ICU) due to community acquired sepsis, showed that about half of the patients had prior contact with a GP cooperative. Two thirds of these patients were referred to the hospital after the first contact.\u003csup\u003e9\u003c/sup\u003e The majority of the patients were assessed during a home visit.\u003c/p\u003e\n\u003cp\u003eIn the hospital setting, vital signs are used to screen for sepsis in patient with suspected infections. The Systemic Inflammatory Response Syndrome (SIRS) was introduced in 1992 to define sepsis.\u003csup\u003e10\u003c/sup\u003e Besides the white blood count, the SIRS criteria are a heart rate \u0026lt;90/min, respiratory rate \u0026gt;20/min, and a body temperature \u0026lt;36\u0026deg;C or \u0026gt;38\u0026deg;C. As SIRS criteria are often present in patients without serious infections and one in eight patients admitted to the ICU with sepsis were found to lack positive SIRS criteria, a new consensus definition was formulated in 2016. In the \u0026ldquo;Sepsis-3\u0026rdquo; definition, the Sequential Organ Failure Assessment (SOFA) score was proposed to diagnose sepsis.\u003csup\u003e1\u003c/sup\u003e As this score is not easy to apply outside the ICU, the quick SOFA (qSOFA) was introduced for rapid bedside assessment. The criteria used in the qSOFA are an altered mental status, systolic blood pressure \u0026le;100 mmHg, and a respiratory rate \u0026ge; 22/min. A positive score on two or more parameters predicts an increased risk of mortality. However, the qSOFA is not suitable as a screening tool as it lacks sensitivity.\u003csup\u003e11-12\u003c/sup\u003e C-reactive protein (CRP), lactate and procalcitonin (PCT) have all been shown to increase the sensitivity and overall diagnostic performance of the qSOFA.\u003csup\u003e13-15\u003c/sup\u003e To our knowledge, no study has assessed the contribution to the accurate early detection of sepsis in primary care of factors such as symptoms, signs, and biomarkers potentially available as point-of-care tests (POCT) such as CRP, lactate, and PCT.\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe aim of the TeSD-IT study (\u003cstrong\u003eTe\u003c/strong\u003esting for \u003cstrong\u003eS\u003c/strong\u003eepsis in primary care: \u003cstrong\u003eD\u003c/strong\u003eiagnostic and prognostic study \u003cstrong\u003eI\u003c/strong\u003envestigating the potential benefits of point of care \u003cstrong\u003eT\u003c/strong\u003eesting) is to develop a clinical prediction rule to improve the detection of sepsis while limiting unnecessary referrals in acutely ill patients presenting at the GP cooperative home visits. Clinical signs and symptoms as well as blood tests will be considered as candidate predictors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSetting, and design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will perform a prospective diagnostic cohort study in the Netherlands in four GP cooperatives (Ede,\u0026rsquo;s-Hertogenbosch, Uden and Oss) for out-of-hours primary care. The cooperatives serve a total of approximately 830,000 inhabitants in a mixed urban, suburban and rural area. The cooperatives are based in or adjacent to regional hospitals.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will be recruited during out-of-hours home visits by GPs. Patients only receive home visits when they have acute medical complaints that cannot wait until the next working day and they are not able to visit the GP cooperative location for a clinic consultation. This is decided after telephone assessment by a triage nurse based on the Netherlands Triage System (NTS).\u003csup\u003e16 \u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eInclusion criteria:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e1) Acutely ill adult patients (\u0026ge;18 years), receiving a home visit by a GP during OOH\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; And\u003c/p\u003e\n\u003cp\u003e2) Fever, confusion or general deterioration or otherwise suspected of a serious infection.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eExclusion criteria: \u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e1) Non-infectious cause of the acute complaints (\u003cem\u003ee.g.\u003c/em\u003e stroke or myocardial infarction)\u003c/p\u003e\n\u003cp\u003e2) Hospitalisation within seven days before the home visit\u003c/p\u003e\n\u003cp\u003e3) Condition that requires secondary care assessment if there are any signs of systemic infection (\u003cem\u003ee.g.\u003c/em\u003e chemotherapy with possible neutropenia)\u003c/p\u003e\n\u003cp\u003e4) Terminal illness or other reason not to refer the patient to a hospital despite presence of a life-threatening condition.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCandidate predictors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe selected nine clinical features and three blood tests as candidate predictors for the development of the clinical prediction model (Table 1). Parameters of widely used scoring systems such as the SIRS, qSOFA and National Early Warning Score (NEWS)\u003csup\u003e17\u003c/sup\u003e were considered, as well as clinical features used in guidelines such as the Netherlands Triage Standard (NTS) and NICE Sepsis guideline.\u003csup\u003e18\u003c/sup\u003e Candidate predictors were selected if there was evidence to suggest that they might usefully contribute to the diagnosis of sepsis, and if they can be easily and objectively measured by GPs. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCandidate blood tests had to be currently used in the hospital setting for the diagnosis and/or prognosis of sepsis, and, preferably, to be available as a point-of-care (POC) test for reasons of implementation. CRP and lactate measurement are part of the standard care in patients with suspected sepsis during assessment in the Emergency Department (ED) in the Netherlands. Procalcitonin (PCT) is not routinely measured in most hospitals, but we decided to include PCT as a candidate predictor as PCT might be superior to CRP,\u003csup\u003e19\u003c/sup\u003e and the NICE sepsis guideline recommends research to further evaluate the use of PCT POCT for diagnosing serious bacterial infection and initiating antibiotic therapy. CRP, lactate and PCT are currently available as POC tests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure is sepsis within 72 hours after inclusion. This will be determined by an expert panel using the Sepsis-3 criteria.\u003csup\u003e1\u003c/sup\u003e The operational definition of sepsis is the presence of infection and a SOFA score (Table 2) of at least two above the baseline (which can be assumed to be zero in patients not known to have preexisting organ dysfunction).\u003c/p\u003e\n\u003cp\u003eTo limit the workload for the experts, we will appoint three expert panels, each comprising a GP, an emergency physician, and an internist(-intensivist). Each case will be assessed by one panel. All relevant information from medical records from the GP and the hospital when applicable will be presented to the panel (see additional file 1). If there is no consensus on the primary outcome, the case will be discussed in a face-to-face consensus meeting with all three experts to determine the final outcome. Interobserver agreement between the three panels will be assessed in a selection of 10% of the cases that will be assessed by all panels. Besides the dichotomous primary outcome \u0026ldquo;sepsis within 72 hours\u0026rdquo;, the likelihood of sepsis will be assigned a numerical score between 0 and 10. This gives information on remaining uncertainty regarding sepsis classification, providing insight in the degree of bias that may be introduced when calculating diagnostic accuracy measures using dichotomous sepsis classification.\u003csup\u003e20\u003c/sup\u003e Furthermore, the need for hospital treatment is scored between 0 and 10 by the expert panel as a secondary outcome. An average score above 5 will be regarded as a patient that should best be referred to the hospital immediately by the GP and a score \u0026le; 5 as a patient that does not have to be referred immediately. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOther outcome measures are hospitalisation (length of stay and type of care: ICU or regular ward), maximum SOFA score in the first 72 hours, 30 day all-cause mortality, final diagnosis, and medical costs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy period\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion period is from June 2018 until April 2020. If in April 2020 the required sample size is not reached, the patients will continue to be recruited \u0026nbsp;until the minimum required number of events has been reached. Follow-up of the patients is 30 days.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProcedure during home visit\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll patients will receive usual care. Patients will be screened for eligibility during home visits by the attending GP of the GP cooperative. Verbal informed consent will be obtained from the patient or his legal representative. The GP will be (routinely) accompanied by a chauffeur during the home visit. The chauffeurs are used to practically assist the GP during the visit. Portable monitors (Philips intelliVue MP2 or X2) will be available to record peripheral oxygen saturation, automated blood pressure and heart- and respiratory rate by three lead electrodes on the chest.\u003c/p\u003e\n\u003cp\u003eThe GP will record the assessment of the candidate predictors in a case report form. In addition, the GP will record if he/she has a gut feeling that \u0026ldquo;something is wrong\u0026rdquo; and will provide the likelihood of presence of sepsis at inclusion on a scale from 0 to 10.\u003c/p\u003e\n\u003cp\u003eAll study materials will be taken to the patient\u0026rsquo;s home in a study bag. The venous samples will be collected by either the GP or an on-call laboratory assistant or nurse within one hour after inclusion, with a maximum of eight hours. Written informed consent will be obtained prior to the collection of the blood samples. In case the patient is referred to the hospital and the blood samples are not collected by the GP, the study bag will be transported with the patient to the ED. Subsequently, the laboratory assistant on call will visit the patient in the hospital and collect the blood samples. Three blood tubes will be collected: 10 ml for serum, 10 ml for EDTA plasma and a 2 ml heparin tube. Lactate will be measured immediately afterwards from a single drop of blood taken from the heparin tube, using the StatStrip Xpress (Nova Biomedical) POC test. The remaining blood samples will be taken to the hospital laboratory and divided into six samples of serum and six samples of EDTA plasma. The aliquots will be temporarily stored at the local laboratory at \u0026lt;-70\u0026deg;C. Two samples (1 ml serum and 1 ml EDTA plasma) will be transported to the Jeroen Bosch Hospital for CRP and PCT analyses, and the remaining samples (5x 0.5 ml serum and 5x 0.5 ml EDTA plasma) will be stored for 15 years at \u0026lt;-80\u0026deg;C at the UMC Utrecht for potential future testing. \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTraining and remuneration of personnel\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eChauffeurs of the GP cooperatives will be trained in using portable monitors for vital sign measurement and other study procedures. At the GP cooperative in Ede the chauffeurs will also be trained in the measurement of POC-lactate, as GPs will collect the venous blood samples themselves occasionally. The laboratory assistants and nurses who will be on call for the collection of the blood samples will also be trained in the POC\u0026ndash;lactate measurement and other study procedures, including the obtaining of written informed consent. Attending GPs will be informed by an information letter by mail and hard copy at the GP cooperative. Leaflets with a summary of the study procedures will also be available.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFollow-up\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe total follow-up time is 30 days (see figure 1). Patients will be asked to complete the EQ5D-5L \u0026nbsp;questionnaire\u003csup\u003e22\u003c/sup\u003e at the end of follow-up (1) at the day of completion of the questionnaire; (2) before the onset of the recent disease episode (i.e. their health status of at least one month ago); and (3) for the worst day they remember from their recent disease episode. Furthermore, patients will be asked to report on consumption of medical resources during the 30-day follow-up period.. In case of no response to the questionnaire after one week, patients will be contacted once by telephone as a reminder. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData-extraction\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRelevant medical information will be obtained from the patient\u0026rsquo;s (regular) GP, the GP cooperative, and the hospital. Information from all hospital admissions in the 30-day follow-up will be retrieved, first by digital search in the local hospital and secondly by manual screening of the GP record for admissions in other hospitals.\u0026nbsp; Medication use and comorbidities before inclusion will be retrieved from GP electronic records, as well as information on any subsequent contacts. The medical record of the assessment at the time of inclusion will be retrieved from the GP cooperative. The following data from the electronic medical record of the hospital will be collected: full reports from ED and hospital discharge; date and time of ED visit, hospital admittance and discharge (including type of ward); vital signs, EMV score, leucocyte count, thrombocyte count, creatinine, bilirubin, CRP and lactate measured in the first 72 hours after inclusion; cultures taken in the first 72 hours after inclusion; radiodiagnostic procedures in the first seven days after inclusion; antibiotic prescriptions during hospitalisation; intravenous volume therapy in the first 72 hours (defined as more than 1.5 litres of fluids in 24 hours).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 12 candidate predictors are chosen for the development of the prediction model (table 1). Using the rule of thumb of 10 events per variable,\u003csup\u003e23\u003c/sup\u003e we need 120 patients reaching the primary outcome \u0026ldquo;sepsis within 72 hours after inclusion\u0026rdquo; in the final dataset. Prior to the start, the prevalence of sepsis based on previous research and literature was estimated to be around 12%. However, preliminary data analysis from the patients included in the study so far, indicates the prevalence of sepsis in the study cohort to be around 30-40%. After the first 100 cases will be assessed by the expert panel, we will determine the final target sample size.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003ca name=\"_Toc326702356\"\u003e\u003c/a\u003e\u003cem\u003eDescriptive statistics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe will use a combination of IBM SPSS Statistics and R Statistical Software for all analyses. We will start with descriptive analyses on baseline characteristics (age, sex, comorbidities, vital sign measurements and other clinical features, blood tests results, baseline EQ5D-5L score), final diagnosis, hospital admission, ICU admission, length of stay, EQ5D-5L compared to baseline, and 30-day mortality. Results will be stratified based on whether patients do or do not meet the primary outcome sepsis.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData cleaning\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRange and distribution of all continuous variables will be graphically inspected, and any outliers (more than three standard deviations from the mean) will be discussed and corrected or removed in case of a data recording error. Any missing data on clinical features or blood tests, will be accounted for by applying multiple imputation techniques. Prediction model development and performance will be analysed using the imputed datasets.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDevelopment of the prediction model\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA multivariable penalized logistic regression model will be developed, based on the variables listed in table 1, for predicting the primary outcome (sepsis within 72 hours after inclusion). We will use a two-stepped approach entering and selecting clinical features first, and blood tests second. In both steps the selection of predictors will be based on a stepwise backward selection, using change in Akaike information criterion (AIC) for selecting the preferred model.\u003csup\u003e24\u003c/sup\u003e The goal is to generate an efficient model by eliminating variables that contribute little to the model\u0026rsquo;s performance, requiring only measurement of the most important variables in clinical practice.\u003c/p\u003e\n\u003cp\u003eContinuous predictors in the model will be assessed for linear relationship with the logit of the primary outcome. Transformation of the data and splines will be used if deemed appropriate based on distribution of the data.\u003c/p\u003e\n\u003cp\u003eThe resulting prediction model that will be the most accurate prediction model, by making use of continuous measurements of predictors and reflecting non-linear relationships by transformations or splines (optimal model). To make this model workable in daily clinical practice without electronic aids, a second model will be derived (clinical practice model) by categorising or stratifying predictors. Cut-offs for categorisation will be based on a combination of known and commonly used thresholds in clinical practice and optimal thresholds based on the data. This model simplification is likely to induce a performance drop with regard to the full model, which will be assessed during the analysis.\u003c/p\u003e\n\u003cp\u003eThe above procedures will result in the following three models: 1) Optimal model with clinical features only; 2) Optimal model with clinical features and blood tests; 3) Simplified model (with clinical features and blood tests).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePerformance of the prediction model\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe performance of all three models will be determined based on their discrimination and calibration. Discrimination will be evaluated based on the area under the receiver-operator characteristic (AUROC). Calibration will be assessed by plotting observed and expected probabilities and inspecting this plot graphically. Measures of calibration will include calibration slope, calibration in the large, observed/expected (O/E) ratio, and the Brier score.\u003csup\u003e25 \u003c/sup\u003eWe will perform internal validation for all three models by using a bootstrap simulation. The resulting distribution will reflect optimism and the degree of overfitting.\u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe SIRS criteria, NEWS score, and qSOFA score will be calculated for all individuals in the TeSD-IT study. Diagnostic performance of the existing models will be determined by calculating the same measures of discrimination and calibration as described in the sections above, and comparing these with the three models that were developed.\u003c/p\u003e\n\u003cp\u003eTo assess the added value of the prediction models on top of usual care, other outcomes than sepsis will be considered. This is crucial for gaining insight in the net benefit of using the\u0026nbsp; clinical prediction rule in daily practice. For example, when a patient is predicted as non-sepsis by the model, but the patient was referred by the GP, improvement compared to care as usual is only the case if hospital treatment was not needed according to the expert panel. To assess the added value, the proportion of reclassifications within the original contingency tables will be presented for the following outcomes: 1) the gut feeling of the visiting GP that \u0026ldquo;something is wrong\u0026rdquo; 2) the assessment of the visiting GP for the likelihood of sepsis, and 3) the decision of the visiting GP whether or not to refer the patient to the hospital.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCost-effectiveness and budget impact analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe will measure costs from a societal perspective, including health care costs and patient costs within and outside the hospital (see additional file 2 for detailed information). Productivity costs will be ignored as the average age of patients participating will exceed the age of pensioning in the Netherlands. The patient questionnaire as well as follow-up data from hospital and GP medical records will be used for the calculation of total and per patient costs. The EQ5D-5L scores retrieved from the questionnaire will be used to calculate QALYs. Our patient outcome analysis will generate QALYs for different health states that will be used in health economic modelling, such as a complicated sepsis case (including ICU admission), hospital admittance for a suspicion of sepsis, and an infectious disease episode without hospital admission. Different scenarios with different levels of implementation of POCT for sepsis in general practice will be analysed and compared to standard of care: 100% use of the best performing testing strategy; 70%, 30% and 0% use of POCT for suspicion of sepsis (the latter representing usual care). The budget impact will be assessed using the health economic model that will be built for the economic evaluation and results will be analysed in a probabilistic way.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe TeSD-IT study is a diagnostic and prognostic study, designed for the development of a clinical prediction rule for the early recognition of sepsis in primary care. A limited number of nine clinical parameters and three blood tests were selected. This will enable us to construct the model using multivariable logistic regression techniques with 120 events included in the dataset. We realise the validity of rule of thumb of 10 event per variable is debated.\u003csup\u003e27\u003c/sup\u003e However, using an alternative sample size calculation suggested by van Smeden,\u003csup\u003e28\u003c/sup\u003e results in a similar identical sample size of about 350 patients\u0026nbsp; in case of 12 variables, an outcome rate of 0.35 and rMPSE set at 0.09. \u0026nbsp;We have chosen to recruit patients in the setting of out-of-hours home visits performed by a GP. In this setting GPs frequently encounter seriously ill patients in whom they instantly have to decide whether or not to refer the patient (immediately) to the hospital. A methodological advantage is that the required sample size is substantially lower than in other primary care settings with a lower incidence of sepsis. However, external validation in other settings and populations will be needed before implementing the clinical prediction rule more broadly.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of sepsis is not straightforward. In 2016, new consensus definitions for sepsis were published, which we try to implement as well as possible. As both the presence of infection as well as organ failure can be equivocal, we will use expert panels to determine the final outcome. The outcome should be clinically relevant for the GP. The rationale of the timeframe of 72 hours is that patients who are found septic within this period after GP assessment would likely benefit from immediate hospital referral. Not all patients with organ failure need hospital treatment to recover, and not all patients with severe infections that are treated with intravenous antibiotic therapy have signs of organ failure. However, we believe the diagnosis of sepsis based on the Sepsis-3 definitions is the most relevant endpoint for GPs to differentiate between patients who are likely to benefit from immediate hospital treatment and patients who might be treated at home successfully. The expert panel will also rate the need for hospital treatment for every patient, regardless of the diagnosis. This will enable us to evaluate the effect of the new clinical prediction rule on medically unnecessary referrals.\u003c/p\u003e\n\u003cp\u003eThe expert panels will be instructed to use the SOFA score (increase, due to infection, of \u0026ge;2 points from baseline) to define the primary outcome \u0026ldquo;sepsis within 72 hours after inclusion\u0026rdquo;.\u0026nbsp; This is consistent with the Sepsis-3 consensus definition and leads to an objective and reproducible endpoint in absence of a gold standard. However, this approach introduces the risk of incorporation bias. Parameters included in the SOFA score are more likely to be predictive of sepsis in our model. However, the blood tests (CRP, lactate and procalcitonin) are not included in the SOFA score, which limits the risk of incorporation bias for these tests. Furthermore, vital signs measured in the first 72 hours will be used to calculate the SOFA score and not only at the time of inclusion.\u003c/p\u003e\n\u003cp\u003ePatients will receive a questionnaire at day 30 measuring EQ5D-5L. The results may be biased due to selective response and poor recall due to sepsis- or age-related cognitive impairment. Imputation of the missing answers on the questionnaires will reduce this form of bias as much as possible. Furthermore, the development of the clinical prediction rule is not affected, as the patient questionnaires will only be used for the cost-effectiveness analyses \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo compare the performance of the new clinical prediction rule with usual care, not only the decision to refer the patient to the ED, but also the assessment of the GP of the likelihood of sepsis on a scale from 0-10 and the presence of a \u0026ldquo;gut-feeling something is wrong\u0026rdquo; will be used. We will examine if the prediction rule will outperform those assessments of the GP in order to likely improve the usual care.\u003c/p\u003e\n\u003cp\u003eOnly three candidate blood tests were selected for the development of the prediction rule. Various other biomarkers have promising diagnostic and/or prognostic properties in patients with suspected sepsis.\u003csup\u003e29-30 \u003c/sup\u003eAt the start of this study, sufficient evidence of the additional diagnostic and/or prognostic value above lactate, CRP and PCT was lacking. However, sufficient blood samples will be stored for retrospective testing of multiple additional biomarkers.\u003c/p\u003e\n\u003cp\u003eAlthough to our best knowledge no\u0026nbsp; clinical prediction rules for sepsis in primary care were previously developed, several sepsis screening tools were published for the ambulance setting.\u003csup\u003e31\u003c/sup\u003e However, none of those have adequate inclusion criteria, data collection and clinically relevant endpoints for use in the primary care setting. \u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Availability of Data and Materials","content":"\u003cp\u003e\u0026nbsp;Data will be made available from the corresponding author on reasonable request after completion of the study.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAIC: \u003c/em\u003e\u003c/strong\u003eAkaike information criterion\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCRP: \u003c/em\u003e\u003c/strong\u003eC-reactive protein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eED: \u003c/em\u003e\u003c/strong\u003eEmergency department\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGP: \u003c/em\u003e\u003c/strong\u003eGeneral Practitioner\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eICU: \u003c/em\u003e\u003c/strong\u003eIntensive care unit\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNEWS: \u003c/em\u003e\u003c/strong\u003eNational Early Warning Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNTS: \u003c/em\u003e\u003c/strong\u003eNetherlands Triage Standard\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePCT: \u003c/em\u003e\u003c/strong\u003eProcalcitonin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePOC(T): \u003c/em\u003e\u003c/strong\u003ePoint-of-care (testing)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAUROC:\u003c/em\u003e\u003c/strong\u003e Area under the receiver-operator characteristic\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSIRS: \u003c/em\u003e\u003c/strong\u003eSystemic inflammatory response syndrome\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e(q)SOFA: \u003c/em\u003e\u003c/strong\u003e(quick) Sequential organ failure assessment score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eQALY: \u003c/em\u003e\u003c/strong\u003eQuality-adjusted life year\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Singer M, Deutschman CS, Seymour CW, \u003cem\u003eet al\u003c/em\u003e. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8):801-10.\u003c/p\u003e\n\n\u003cp\u003e2. Rhodes A, Evans LE, Alhazzani W, \u003cem\u003eet al\u003c/em\u003e. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77.\u003c/p\u003e\n\n\u003cp\u003e3. Sherwin R, Winters ME, Vilke GM, Wardi G. Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock? J Emerg Med. 2017 Oct;53(4):588-95. doi:10.1016/j.jemermed.2016.12.009.\u003c/p\u003e\n\n\u003cp\u003e4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369(9): 840-51. \u003c/p\u003e\n\n\u003cp\u003e5. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020 Jan 18;395(10219):200-11. doi:10.1016/S0140-6736(19)32989-7.\u003c/p\u003e\n\n\u003cp\u003e6. Reinhart K, Daniels R, Kissoon N, et al. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017 Aug 3;377(5):414-17. doi:10.1056/NEJMp1707170.\u003c/p\u003e\n\n\u003cp\u003e7. Smits M, Rutten M, Keizer E, et al.The development and performance of after-hours primary care in the Netherlands: a narrative review. Ann Intern Med 2017;166(10):737-42.\u003c/p\u003e\n\n\u003cp\u003e8. Søvsø MB, Christensen MB, Bech BH, et al. Contacting out-of-hours primary care or emergency medical services for time-critical conditions - impact on patient outcomes. BMC Health Serv Res. 2019 Nov 7;19(1):813. doi: 10.1186/s12913-019-4674-0.\u003c/p\u003e\n\n\u003cp\u003e9. Loots FJ, Smits M, van Steensel C, et al. Management of sepsis in out-of-hours primary care: a retrospective study of patients admitted to the intensive care unit. BMJ Open. 2018 Sep 17;8(9):e022832. doi: 10.1136/bmjopen-2018-022832.\u003c/p\u003e\n\n\u003cp\u003e10. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101(6):1644-55.\u003c/p\u003e\n\n\u003cp\u003e11. Williams JM, Greenslade JH, McKenzie JV, et al. Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and Organ Dysfunction: Insights From a Prospective Database of ED Patients With Infection. Chest. 2017 Mar;151(3):586-96. doi: 10.1016/j.chest.2016.10.057. \u003c/p\u003e\n\n\u003cp\u003e12. Fernando SM, Tran A, Taljaard M, et al. Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis. Ann Intern Med. 2018 Feb 20;168(4):266-75. doi: 10.7326/M17-2820.\u003c/p\u003e\n\n\u003cp\u003e13. Dimitrov E, Minkov G, Enchev E, et al. A combination of C-reactive protein and quick sequential organ failure assessment (qSOFA) score has better prognostic accuracy than qSOFA alone in patients with complicated intra-abdominal infections. Acta Chir Belg. 2019 Jul 16:1-5. doi: 10.1080/00015458.2019.1642579.\u003c/p\u003e\n\n\u003cp\u003e14. Yu H, Nie L, Liu A, et al. Combining procalcitonin with the qSOFA and sepsis mortality prediction. Medicine (Baltimore). 2019 Jun;98(23):e15981. doi: 10.1097/MD.00000000000159813-14\u003c/p\u003e\n\n\u003cp\u003e15. Baumann BM, Greenwood JC, Lewis K, et al. Combining qSOFA criteria with initial lactate levels: Improved screening of septic patients for critical illness. Am J Emerg Med. 2019 Jul 4. pii: S0735-6757(19)30450-4. doi:10.1016/j.ajem.2019.07.003.\u003c/p\u003e\n\n\u003cp\u003e16. Nederlands Triage Systeem [Dutch Triage System]. 2017. www.de-nts.nl. Accessed 16 January 2020.\u003c/p\u003e\n\n \u003cpre \u003e17. Physicians RCo. National Early Warning Score (NEWS) 2: Standardising the Assessment of Acute-Illness Severity in the NHS; RCP: London, UK, 2017.\u003c/pre\u003e\u003cp\u003e18. National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. 2017. \u003ca href=\"https://www.nice.org.uk/guidance/ng51\"\u003ehttps://www.nice.org.uk/guidance/ng51\u003c/a\u003e. Accessed 16 January 2020.\u003c/p\u003e\n\n\u003cp\u003e19. Tan M, Lu Y, Jiang H, Zhang L. The diagnostic accuracy of procalcitonin and C-reactive protein for sepsis: A systematic review and meta-analysis. J Cell Biochem. 2019 Apr;120(4):5852-59. doi: 10.1002/jcb.27870. \u003c/p\u003e\n\n\u003cp\u003e20. Jenniskens K, Naaktgeboren CA, Reitsma JB, et al. Forcing dichotomous disease classification from reference standards leads to bias in diagnostic accuracy estimates: A simulation study. J Clin Epidemiol. 2019 Jul;111:1-10. doi: 10.1016/j.jclinepi.2019.03.002.\u003c/p\u003e\n\n\u003cp\u003e21. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. \u003c/p\u003e\n\n\u003cp\u003e22. EQ-5D instruments. \u003ca href=\"https://euroqol.org/\"\u003ehttps://euroqol.org/\u003c/a\u003e. Accessed 16 January 2020.\u003c/p\u003e\n\n\u003cp\u003e23. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49(12):1373–79.\u003c/p\u003e\n\n\u003cp\u003e24. Sakamoto Y, Ishiguro M, Kitagawa G. Akaike information criterion statistics. Dordrecht, The Netherlands: D. Reidel. 1986;81.\u003c/p\u003e\n\n\u003cp\u003e25. Steyerberg EW, Vickers AJ, Cook NR, et al. Assessing the performance of prediction models: a framework for some traditional and novel measures. Epidemiology (Cambridge, Mass.). 2010 Jan;21(1):128.\u003c/p\u003e\n\n\u003cp\u003e26. Moons KG, Kengne AP, Woodward M, et al. Risk prediction models: I. Development, internal validation, and assessing the incremental value of a new (bio) marker. Heart. 2012 May 1;98(9):683-90.\u003c/p\u003e\n\n \u003cpre \u003e \u003c/pre\u003e\u003cpre \u003e27. van Smeden M, Moons KG, de Groot JA, et al. Sample size for binary logistic prediction models: Beyond events per variable criteria. Stat Methods Med Res. 2019 Aug;28(8):2455-74. doi:10.1177/0962280218784726.\u003c/pre\u003e\u003cpre \u003e \u003c/pre\u003e\u003cpre \u003e28. \u003ca href=\"https://mvansmeden.shinyapps.io/BeyondEPV/\"\u003ehttps://mvansmeden.shinyapps.io/BeyondEPV/\u003c/a\u003e . Accessed 31 March 2020\u003c/pre\u003e\u003cp\u003e29. Vincent JL, Beumier M. Diagnostic and prognostic markers in sepsis. Anti Infect Ther. 2013 Mar;11(3):265-75. doi: 10.1586/eri.13.9.\u003c/p\u003e\n\n\u003cp\u003e30. van Engelen TSR, Wiersinga WJ, Scicluna BP, van der Poll T. Biomarkers in Sepsis. Crit Care Clin. 2018 Jan;34(1):139-52. doi: 10.1016/j.ccc.2017.08.010. \u003c/p\u003e\n\n\u003cp\u003e31. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: a systematic review. BMJ Open 2016;6:e011218. doi:10.1136/bmjopen-2016-011218.\u003c/p\u003e\n\n "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003cbr /\u003e \u003c/strong\u003eThe study was approved by the Ethical Research Committee of the UMC Utrecht, and is registered under number 18/169. Written informed consent will be obtained before the collection of blood samples and after initial verbal informed consent. In mentally incapacitated patients, consent will be provided by the legal representative. In case written informed consent is not feasible prior to the collection of blood samples due to an acute life-threatening condition, the written consent will be asked as soon as possible afterwards. All collected data - including the blood results - will be stored without identifying information under a study number. Personal details of the patient which are needed for the data collection will be store in an secured online environment until the data collection is completed. The data and excess blood samples will be stored for 15 years afterwards. Additional test of stored blood samples will only be done in patients who opted in in the written informed consent.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003cbr /\u003e \u003c/strong\u003eNon declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr /\u003e The study was financially supported by ZonMw, grant number 843001811. In kind support for material costs were provided by ThermoFischer (procalcitonin analyses), Nova Biomedical (POC lactate measurement) and Philips (portable monitoring devices). Neither funding party had a role in the design of this study, interpretation of the data, or decision to submit results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003cbr /\u003e \u003c/strong\u003eFL contributed to the study conceptualisation and design, and drafted the manuscript. RH contributed to the study conceptualisation and design and revised the manuscript critically for important intellectual content. KJ and MS contributed to the design of the statistical analyses and co-drafted the manuscript. GF, AP, AB, JJO and AZ contributed to the study design and revised the manuscript critically for important intellectual content. TV supervised the study, contributed to the study design and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript and 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.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003cbr /\u003e \u003c/strong\u003eThe authors would like to thank all staff of the GP cooperatives Gelderse Vallei and Oost-Brabant for their support and cooperation.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp style=\"line-height: 150%; text-autospace: none; margin: 0in 0in .0001pt 14.2pt;\"\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e \u003cstrong\u003eCandidate predictors eligible for the selection in the prediction model\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 595.35pt; margin-left: -63.0pt; border-collapse: collapse; border: none;\" width=\"794\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\u003cspan style=\"font-size: 11.0pt; line-height: 150%; font-family: 'Segoe UI',sans-serif;\"\u003e\u003cbr style=\"page-break-before: always;\" /\u003e\u003c/span\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cstrong\u003eType of predictor\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cstrong\u003eCandidate predictor\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cstrong\u003eMeasurement method\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cstrong\u003eMeasurement unit\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border-top: solid windowtext 1.0pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cstrong\u003eUsed in \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eClinical feature\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eInclusion date minus date of birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eyears\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eNICE guideline\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eBody temperature\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eTympanic measurement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026deg;C\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSIRS,\u003csup\u003e10\u003c/sup\u003e NEWS,\u003csup\u003e17\u003c/sup\u003e NICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eHeart rate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eIntelliVue MP2/ X2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003ebeats/min\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSIRS, NEWS, NICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eRespiratory rate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eIntelliVue MP2/ X2 or GP assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003ebreaths/min\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSIRS, qSOFA, NICE guideline, NEWS\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSystolic blood pressure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eIntelliVue MP2/ X2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003emmHg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eqSOFA, NEWS, NICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003ePeripheral oxygen saturation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eIntelliVue MP2/ X2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eNEWS, NICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eMental status\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eGP assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003enormal/altered\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eqSOFA, NEWS, NICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eRapid progression of illness in last 24h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eGP assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eyes/no\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eNICE guideline\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e(History of) rigors in last 24h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eGP assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eyes/no\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eNTS\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eBlood test\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eC-reactive protein (CRP)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSiemens, ADVIA Chemistry XPT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003emg/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eLactate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eStatStrip Xpress\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003emmol/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cu\u003e\u003cspan style=\"text-decoration: none;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 69.2pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"92\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 150.55pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"201\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eProcalcitonin (PCT)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 170.1pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"227\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eSiemens, ADVIA Centaur XPT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 85.15pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"114\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003eng/ml\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 120.35pt; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"160\"\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u003cu\u003e\u003cspan style=\"text-decoration: none;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin-bottom: .0001pt; line-height: 150%;\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; text-decoration-style: initial; text-decoration-color: initial;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003eTable 2. SOFA score\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"box-sizing: border-box; border-collapse: collapse; color: #212529; font-family: 'Source Sans Pro', sans-serif; font-size: 16px; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; text-decoration-style: initial; text-decoration-color: initial; width: 494.45pt; border: none;\" border=\"0\" width=\"659\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n\u003ctbody style=\"box-sizing: border-box;\"\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 22pt; vertical-align: bottom;\" colspan=\"2\" valign=\"bottom\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: bottom;\" valign=\"bottom\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003eScore\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: bottom;\" colspan=\"2\" valign=\"bottom\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003eSystem\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e1\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e2\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e3\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 22pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003e4\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; border: none; padding: 0in 5.4pt; height: 12.2pt; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eRespiration\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; border: none; padding: 0in 5.4pt; height: 12.2pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; border: none; padding: 0in 5.4pt; height: 12.2pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; border: none; padding: 0in 5.4pt; height: 12.2pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; border: none; padding: 0in 5.4pt; height: 12.2pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003ePaO\u003csub style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; bottom: -0.25em;\"\u003e2\u003c/sub\u003e/FiO\u003csub style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; bottom: -0.25em;\"\u003e2\u003c/sub\u003e, mmHg\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e300-440\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026gt; 440\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;200\u003cbr style=\"box-sizing: border-box;\" /\u003ewith respiratory support\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt; 100\u003cbr style=\"box-sizing: border-box;\" /\u003ewith respiratory support\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 11.05pt; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eCoagulation\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 11.05pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 11.05pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 11.05pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 11.05pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003ePlatelets, x10\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003e3\u003c/sup\u003e/\u0026micro;L\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;150\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;100\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;50\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 11pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;20\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 16.7pt; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eLiver\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 16.7pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 16.7pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 16.7pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 16.7pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eBilirubin,\u0026nbsp;\u0026micro;mol/L\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e20-32\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e33-101\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e102-204\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 5.3pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026gt;204\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 0.2in; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eCardiovascular\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 0.2in; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 0.2in; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 0.2in; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 0.2in; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: normal; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003eHypotension\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: normal; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003eMAP\u0026nbsp;\u0026lt;\u0026nbsp;70 mmHg\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: normal; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003eDopamine \u0026lt;5 or dobutamine (any dose)\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: normal; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003eDopamine 5.1-15\u003cbr style=\"box-sizing: border-box;\" /\u003eor epinephrine\u0026nbsp;\u0026le;0.1\u003cbr style=\"box-sizing: border-box;\" /\u003eor norepinephrine\u0026nbsp;\u0026le;0.1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 7.6pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: normal; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003eDopamine \u0026gt;15\u003cbr style=\"box-sizing: border-box;\" /\u003eor epinephrine\u0026nbsp;\u0026gt;0.1\u003cbr style=\"box-sizing: border-box;\" /\u003eor norepinephrine\u0026nbsp;\u0026gt;0.1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 15.2pt; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eCentral nervous system\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 15.2pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 15.2pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 15.2pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 15.2pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eGlasgow Coma Score\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e13-14\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e10-12\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e6-9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 6.85pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 1.65in; padding: 0in 5.4pt; height: 12.9pt; vertical-align: top;\" colspan=\"2\" valign=\"top\" width=\"24.012158054711247%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eRenal\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 12.9pt; vertical-align: top;\" valign=\"top\" width=\"17.173252279635257%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 12.9pt; vertical-align: top;\" valign=\"top\" width=\"18.693009118541035%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 12.9pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 12.9pt; vertical-align: top;\" valign=\"top\" width=\"20.060790273556233%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eCreatinine,\u0026nbsp;\u0026micro;mol/L\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e110-170\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e171-299\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e300-440\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; padding: 0in 5.4pt; height: 12.15pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026gt; 440\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"box-sizing: border-box;\"\u003e\n\u003ctd style=\"box-sizing: border-box; width: 12.5pt; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"2.579666160849772%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 106.3pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"21.547799696509863%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 18px;\"\u003eUrine output, mL/d\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 85.05pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"17.147192716236724%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 92.15pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"18.66464339908953%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cstrong style=\"box-sizing: border-box; font-weight: bolder;\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.25pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;500\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"box-sizing: border-box; width: 99.2pt; border-style: none none solid; border-bottom-width: 1pt; border-bottom-color: windowtext; padding: 0in 5.4pt; height: 9.3pt; vertical-align: top;\" valign=\"top\" width=\"20.030349013657055%\"\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 16px;\"\u003e\u0026lt;200\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; text-decoration-style: initial; text-decoration-color: initial;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003ea\u0026nbsp;\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003eAdapted from Vincent et al.\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003e21\u003c/sup\u003e\u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; text-decoration-style: initial; text-decoration-color: initial;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003csup style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; top: -0.5em;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003eb\u0026nbsp;\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003eAdrenergic agents administered for at least one hour (doses given in\u0026nbsp;\u0026micro;g/kg/min).\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"box-sizing: border-box; color: #616161; font-family: 'Segoe UI', sans-serif; font-size: 15px; line-height: 22px; letter-spacing: 0.5px; font-weight: 400; margin: 0in 0in 0.0001pt; font-style: normal; font-variant-ligatures: normal; font-variant-caps: normal; orphans: 2; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px; -webkit-text-stroke-width: 0px; background-color: #ffffff; text-decoration-style: initial; text-decoration-color: initial;\"\u003e\u003cspan style=\"box-sizing: border-box; font-family: Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"box-sizing: border-box; font-size: 11px;\"\u003e\u003cspan style=\"box-sizing: border-box;\"\u003e\u003cspan style=\"box-sizing: border-box; line-height: 20px;\"\u003ePaO\u003csub style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; bottom: -0.25em;\"\u003e2\u003c/sub\u003e,\u003csub style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; bottom: -0.25em;\"\u003e\u0026nbsp;\u0026nbsp;\u003c/sub\u003epartial pressure of arterial oxygen. FiO\u003csub style=\"box-sizing: border-box; position: relative; font-size: 8.25px; line-height: 0; vertical-align: baseline; bottom: -0.25em;\"\u003e2\u003c/sub\u003e, fraction of inspired oxygen. MAP, mean arterial pressure.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"diagnostic-and-prognostic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dapr","sideBox":"Learn more about [Diagnostic and Prognostic Research](https://diagnprognres.biomedcentral.com/)","snPcode":"41512","submissionUrl":"https://submission.springernature.com/new-submission/41512/3","title":"Diagnostic and Prognostic Research","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sepsis, clinical prediction rule, diagnosis, primary care, general practice, out-of-hours medical care, practitioner cooperative, point-of-care testing ","lastPublishedDoi":"10.21203/rs.2.24104/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.24104/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground Early recognition and treatment of sepsis is crucial to prevent detrimental outcomes. General practitioners (GPs) are often the first healthcare providers to encounter seriously-ill patients. The aim of this study is to assess the value of clinical information and additional tests to develop a clinical prediction rule to support early diagnosis and management of sepsis by GPs. \u003c/p\u003e\u003cp\u003eMethods We will perform a diagnostic study in the setting of out-of-hours home visits in four GP cooperatives in the Netherlands. Acutely ill adult patients suspected of a serious infection will be screened for eligibility by the GP. The following candidate predictors will be prospectively recorded: 1) age; 2) body temperature; 3) systolic blood pressure; 4) heart rate; 5) respiratory rate; 6) peripheral oxygen saturation; 7) mental status; 8) history of rigors and 9) rate of progression. After clinical assessment by the GP, blood samples will be collected in all patients to measure C-reactive protein, lactate and procalcitonin. All patients will receive care as usual. The primary outcome is presence or absence of sepsis within 72 hours after inclusion, according to an expert panel. The need for hospital treatment for any indication will be assessed by the expert panel as a secondary outcome. Multivariable logistic regression will be used to design an optimal prediction model first, and subsequently derive a simplified clinical prediction rule that enhances feasibility of using the model in daily clinical practice. Bootstrapping will be performed for internal validation of both the optimal model and simplified prediction rule. Performance of both models will be compared to existing clinical prediction rules for sepsis. \u003c/p\u003e\u003cp\u003eDiscussion This study will enable us to develop a clinical prediction rule for the recognition of sepsis in a high-risk primary care setting to aid in the decision which patients have to be immediately referred to a hospital and who can be safely treated at home. As clinical signs and blood samples will be obtained prospectively, near complete data will be available for analyses. External validation will be needed before implementation in routine care and to determine in which pre-hospital settings care can be improved using the prediction rule. \u003c/p\u003e\u003cp\u003eTrial registration The study is registered in the Netherlands Trial Registry (registration number NTR7026).\u003c/p\u003e","manuscriptTitle":"Development of a clinical prediction rule for sepsis in primary care: protocol for the TeSD-IT study","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-04-23 16:02:07","doi":"10.21203/rs.2.24104/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-04-30T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept\nForm responses:\n---\n\nComments to Author:\n---\nI am satisfied with the changes made to the protocol and believe they have strengthened the dissemination of the study team's research.\nI also welcome the addition of the a priori health economics plan as part of the submission.\n\nGood luck with your analyses. I look forward to seeing the results of this study.\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"decision","content":"Accept","date":"2020-04-30T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-22T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-04-16T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-04-16T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-16T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-04-16T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept\nForm responses:\n---\n\nComments to Author:\n---\nJust one comment: I think there is a typographical mistake in line 277 \"The resulting prediction model that will be the most accurate prediction model, by..\"\n\nShould this be \"The resulting prediction model will be the most accurate prediction model, by\"\n\n?* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"checksComplete","content":"","date":"2020-04-15T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-04-15T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"diagnostic-and-prognostic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dapr","sideBox":"Learn more about [Diagnostic and Prognostic Research](https://diagnprognres.biomedcentral.com/)","snPcode":"41512","submissionUrl":"https://submission.springernature.com/new-submission/41512/3","title":"Diagnostic and Prognostic Research","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-02-20 21:30:05","doi":"10.21203/rs.2.24104/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-03-18T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-03-05T12:00:00+00:00","index":2,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nMy comments, with much better formatting, are also in the Word file that has been emailed separately to the editorial office.\n\n\nReview of TeSD-IT study\nLINE TEXT COMMENTS\n2 protocol of the TeSD-IT study Prepositions are almost arbitrary, but \"protocol for\" is easier on my ear. Google finds 3 times as many \"protocol for\"-s.\n34 We will … Tenses go backwards and forwards rather randomly.\nConsider using the future, present, or past tense consistently.\n34 The following candidate predictors are prospectively recorded It is a pity that GP's did not record the most likely site of infection and their confidence in their guess.\n\nPerhaps the discussion section could explain why this was not done?\n35-36 1) age; 2) body temperature; 3) systolic blood pressure; 4) heart rate; 5) respiratory rate; 6)\n36 peripheral oxygen saturation; 7) altered mental status; 8) rigors and 9) rapid illness progression. Items 1 - 6 are parameters\nItems 7 - 9 are values of parameters\n\nFor precision and consistency, for 7 - 9 consider mental status, history of rigors, rate of progression\n50 samples will be retrieved samples will be obtained?\n52 validation is needed validation will be needed\n69-70 but patients' early stages of sepsis are often presented\n70 in primary care. But patients often present in primary care in the earlt stages of sepsis\n72 patients can be treated at home or have to be referred to a hospital A patient can safely be treated at home or should be referred to a hospital\n84-85 Besides the white blood count, the SIRS parameters are heart rate \u003c90/min,\n85 respiratory rate \u003e20/min, and a body temperature \u003c36°C or \u003e38°C. In this sentence, and in a the subsequent text, the meanings of parameter and criterion are confused.\nA parameter is a variable that can take a range of values.\nA criterion is a specified value of a parameter, and it is used as a threshold for some decision about classification or action.\nIn this example, \"heart rate\" is a parameter, while \"heart rate \u003c90/min\" is a criterion used in the definition of SIRS.\nSo, this senetence should be: \"…the SIRS criteria are …\"\n90 The parameters used in the qSOFA As above: The criteria used in the qSOFA\n94 have all shown to increase have all been shown to increase\n95 Both signs and symptoms as well as additional biomarkers like CRP, lactate and PCT are however not evaluated for early detection of sepsis in primary care. Do you mean to say \"No study has (to our knowledge) assessed the contribution to the accurate early detection of sepsis in primary care of factors such as symptoms, signs, and biomarkers potentially available as point of care tests such as CRP, lactate, and PCT\".\n?\n\nThe name of the study implies that CRP, lactate, and PCT are available as point of care tests, but this is not stated explicitly anywhere. This is a good place to do so.\n119 - 120 Condition that requires secondary care assessment in case of … A condition that requires secondary care assessment if there are …\n129 Candidate predictors were considered when they were expected to … Candidate predictors were selected if there was evidence to suggest that they might usefully contribute to the diagnosis of sepsis, and if they can be easily and objectively measured by GPs\n137 -138 the NICE sepsis guideline specifically recommends to further evaluate PCT in sepsis research The NICE sepsis guideline recommends research to further evaluate the use of PCT point of care tests for diagnosing serious bacterial infection and initiating antibiotic therapy.\n\nThis is a wider brief than sepsis research.\n143 - 144 In this consensus definition, sepsis is defined by an increase of two SOFA-points The operational definition of sepsis is the presence of infection and a SOFA score of at least two above the baseline (which can be assumed to be zero in patients not known to have preexisting organ dysfunction).\n\nOr, if brevity is important, and most patients triaged by GPs have baseline SOFA scores of zero:\n\nThe operational definition of sepsis is the presence of infection and a SOFA score of at least two.\n146 we will install three expert panels we will appoint three expert panels\n170 the patient inclusion will be prolonged Patients will continue to be recruited\n171 End of follow-up is 30 days after inclusion of the last patient. Does \"follow-up\" mean that patients were seen for the study up to 30 days after the inclusion of the last patient?\n234 Using the rule of thumb of 10 events per variable Some picky reader could say that there is no good rationale for this rule of thumb\n\nhttps://pubmed.ncbi.nlm.nih.gov/27881078-no-rationale-for-1-variable-per-10-events-criterion-for-binary-logistic-regression-analysis/\n\nMaybe discuss this in the discussion section?\n331 sepsis were published, which we try to implement are good as possible sepsis were published (which we try to implement) are as good as possible\n343 - 345 (increase of ≥2 points from\n344 baseline due to infection) (increase, due to infection, of ≥2 points from baseline)\n\n\n\n\n\nImputation of SOFA points:\n\nPeripheral oxygen saturation (SpO2) and supplemented oxygen are used to estimate respectively the pO2 and FiO2 for calculation of the pO2/FiO2 ratio. Results from blood gas analyses are (outside the ICU) are not taken into account as the amount of oxygen supplied at the time of blood collection is unknown. For the estimation of the pO2 and FiO2, the following conversion tables are used: Replace pO2 by the conventional abbreviation, PaO2.\n\nThe table uses PaO2 as the column header.\nSOFA points are adopted from the electronic medical records from the ICU SOFA points are obtained from …\n\n\n\n\n\n\n\n\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Needs some language corrections before being published**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"editorInvitedReview","content":"","date":"2020-03-05T12:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nLoots et. al present a protocol for a community based study to collect data to develop a clinical prediction rule for identification of sepsis in the Netherlands. This is commendable and in line with recent efforts for transparency and improved quality over diagnostic test evaluation research. Sepsis recognition is a worldwide unmet need and is particularly complex within primary care. It is noted that the study is in progress and close to completion. Therefore, the below comments regarding potential improvements to the protocol aim to improve the quality and detail presented, in order to aid transferability to other investigators in this area as well as inform the subsequent data analysis.\n\nGeneral comments:\n- CPR is commonly used acronym in healthcare for cardiopulmonary resuscitation. Suggest that the authors consider a differ acronym to avoid confusion.\n- While the title of the study includes the words diagnostic and prognostic study. The protocol describes a study which is developing models therefore it is not strictly diagnostic nor prognostic (even though the intention for these models will be to diagnose sepsis and predict admission to hospital). Further external validation would be needed to measure diagnostic and prognostic accuracy. Consider revising.\n- The TRIPOD (and potentially the STARD) checklist should be followed and all relevant changes made throughout the protocol.\n\nMajor comments:\n- It is difficult to follow the study processes from patient screening to participant follow up. A study flowchart would help the reader. A lot of the information presented in the discussion should be moved to the methods section for\n- The protocol does not adequately describe the process of data collection and follow up of the patients not referred to hospital. If these patients were subsequently referred to hospital, would this data be captured? This is important as they are false negatives in the current care pathway and so, a potential improvement over current care would be to ensure these patients were referred sooner.\n- Could the authors make it clear their a priori rules for the expert panel diagnosis? It is unclear what data they will be presented with when, and in which patients in order to form their diagnosis. For example, in line 343 it states that the expert panel will be instructed to use the SOFA score. The supplementary material suggested that the SOFA score will be inputted for those patients where it is not available i.e. those not admitted to hospital, is this the case. Imputation based on this data risks bias within the development of the model. In general, more clarity is needed on the analysis plan in the protocol. An appended statistical analysis plan could add strength to this protocol and aid other investigators in this complex area.\n- Within the data cleaning section (lines 251 - 255): the explanation of removal of outliers 'more than three standard deviations from the mean' is worrying as it could lead to selection bias. By nature of sepsis, these patients may have extremely high or extremely low clinical test results. A more appropriate plan would be to look for statistical outliers and explore whether these are data recording errors. If so, they could be removed. If not, they should be included as they may represent the most important data of all. Failure to include these data points could results in selection bias. Please see reference: Rousseeuw, P.J. and Hubert, M. (2011), Robust statistics for outlier detection. WIREs Data Mining Knowl Discov, 1: 73-79. doi:10.1002/widm.2\n- Do you have a health economic evaluation plan? If so, please add to the supplementary material as it will be useful for other researchers.\n\nMinor comments:\n- Presentation of the inclusion and exclusion criteria could be improved and separated on individual lines to help the reader. Further clarity could be added to also help the reader from other countries understand the exact patient group which are eligible.\n- The protocol is inconsistent in the description of the QoL instrument (EQ-5D or EQ-5D-5L) which will be used. Please choose appropriate tool and make consistent.\n- How the data regarding confidence in diagnosis was going to be analysis was not clear. Please clarify analysis plan.\n- Line 89: propose changing diagnosis to recognise…\n- Line 155: Change \"in\" to \"into\".\n- Lines 186-188: there is an apparent time delay in taking blood samples from those patients who are referred to hospital and now. Will this be accounted for in the analysis?\n- Lines 213-214: Asking patients to complete an EQ-5D-5L questionnaire from recall for the worst day they remember from their recent sepsis episode is going to produce results of questionable accuracy. A symptom of sepsis is acute confusion, and this, coupled with the duration of time from their sepsis episode to the end of follow-up when they are asked to complete the questionnaire (30 days), would lead to poor accuracy of recall in this largely elderly population. This should be discussed as a limitation.\n- Line 226: EMV not defined.\n- Lines 232 - 234: It is important to note the evidence advocating 10 events per variable in binary logistic regression analysis is weak. Further explanation should be provided why you are using this rule. The authors may find this paper helpful: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710621/pdf/10.1177_0962280218784726.pdf\n- Line 248: primary outcome should read ''sepsis within 72 hours''\n- Table 1 - add references to the sources in order to future proof this publication.\n- Line 289 - Using AUROC to compare between different models should be used with caution, please see reference: https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/1471-2288-11-13\n- Line 331 - try to implement as good as possible: reword to ' try to implement as much/well as possible'\n- Line 360 - change retroactive to retrospective.\n- Are the investigators planning to make the data available for other investigators? It would add strength to make their intentions clear in like 367.\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n"},{"type":"reviewerAgreed","content":"","date":"2020-02-29T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-02-26T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-02-23T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-02-18T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-02-18T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-02-17T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-02-17T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"diagnostic-and-prognostic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dapr","sideBox":"Learn more about [Diagnostic and Prognostic Research](https://diagnprognres.biomedcentral.com/)","snPcode":"41512","submissionUrl":"https://submission.springernature.com/new-submission/41512/3","title":"Diagnostic and Prognostic Research","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"409df07b-8561-4b7d-bc8d-8cd2f2d8e3d4","owner":[],"postedDate":"April 23rd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":60983,"name":"General Practice"},{"id":60984,"name":"Preventive Medicine"}],"tags":[],"updatedAt":"2020-08-09T15:01:49+00:00","versionOfRecord":{"articleIdentity":"rs-14664","link":"https://doi.org/10.1186/s41512-020-00080-5","journal":{"identity":"diagnostic-and-prognostic-research","isVorOnly":false,"title":"Diagnostic and Prognostic Research"},"publishedOn":"2020-08-06 12:00:00","publishedOnDateReadable":"August 6th, 2020"},"versionCreatedAt":"2020-04-23 16:02:07","video":"","vorDoi":"10.1186/s41512-020-00080-5","vorDoiUrl":"https://doi.org/10.1186/s41512-020-00080-5","workflowStages":[]},"version":"v2","identity":"rs-14664","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-14664","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}