Introduction - University of Manchester
Title: Incidence and outcomes of sepsis after cardiac surgery as defined by the Sepsis-3 guidelinesKeywords: Thoracic Surgery; Cardiac Surgical Procedures, SepsisRunning Title: Sepsis following cardiac surgeryAuthors: Samuel H. Howitt 1,2, Matthew Herring3, Ignacio Malagon 1,2, Charles N McCollum 1,4, Stuart W. Grant 1Institute of Cardiovascular Sciences, University of Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, M23 9LT, UK. Department of Cardiothoracic Anaesthesia and Critical Care, University Hospital of South Manchester, Manchester, M23 9LT, UK. Faculty of Biology, Medicine and Health, University Hospital of South Manchester, Manchester, M23 9LT, UK.Department of Vascular Surgery, University Hospital of South Manchester, Manchester, M23 9LT, UK. Corresponding Author: Stuart W. Grant. Institute of Cardiovascular Sciences, University of Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, M23 9LT, UK. Tel (0044)161 291 58420 email:stuart.grant@manchester.ac.uk Summary (Abstract)Background The Sepsis-3 guidelines diagnose sepsis based on organ dysfunction in patients with either proven or suspected infection. The objective of this study was to assess the incidence and outcomes of sepsis diagnosed using these guidelines in patients on the Cardiac Intensive Care Unit (CICU) after cardiac surgery. MethodsDaily Sequential Organ Failure Assessment (SOFA) scores were calculated for 2230 consecutive adult cardiac surgery patients between January 2013 and May 2015. Patients with a rise in SOFA score of ≥2 and suspected or proven infection were identified. The length of CICU stay, 30-day mortality and 2-year survival were compared between groups. Multivariable linear regression, multivariable logistic regression and Cox proportional hazards regression were used to adjust for possible confounders. ResultsSepsis with suspected or proven infection was diagnosed in 104 (4.7%) and 107 (4.8%) patients respectively. After adjustment for confounding variables, sepsis with suspected infection was associated with an increased length of CICU stay of 134.1 (95%CI 99.0-168.2) hours (p<0.01) and increased 30-day mortality risk (odds ratio 3.7, 95%CI 1.1-10.2, p=0.02). Sepsis with proven infection was associated with an increased length of CICU stay of 266.1 (95%CI 231.6-300.7) hours (p<0.01) and increased 30-day mortality risk (odds ratio 6.6, 95%CI 2.6-15.7, p<0.01). ConclusionsApproximately half of sepsis diagnoses were based on proven infection and half on suspected infection. Patients diagnosed with sepsis using the Sepsis-3 guidelines have significantly worse outcomes after cardiac surgery. The Sepsis-3 guidelines are a potentially useful tool in the management of sepsis following cardiac surgery.Word count 250IntroductionThe Sepsis-3 guidelines were introduced in 2016 and define sepsis as organ dysfunction in the presence of proven or suspected infection. ADDIN EN.CITE <EndNote><Cite><Author>Singer</Author><Year>2016</Year><RecNum>2096</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>2096</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2096</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singer, M.</author><author>Deutschman, C. S.</author><author>Seymour, C.</author><author>et al.,</author></authors></contributors><titles><title>THe third international consensus definitions for sepsis and septic shock (sepsis-3)</title><secondary-title>Jama</secondary-title></titles><periodical><full-title>Jama</full-title></periodical><pages>801-810</pages><volume>315</volume><number>8</number><dates><year>2016</year></dates><isbn>0098-7484</isbn><urls><related-urls><url> In the critical care setting, organ dysfunction identified using the Sequential Organ Failure Assessment (SOFA) score (Table 1) ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>1996</Year><RecNum>1968</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>1968</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">1968</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Moreno, R.</author><author>Takala, J.</author><author>Willatts, S.</author><author>De Mendonca, A.</author><author>Bruining, H.</author><author>Reinhart, C. K.</author><author>Suter, P. M.</author><author>Thijs, L. G.</author></authors></contributors><auth-address>Erasme University Hospital, Brussels, Belgium.</auth-address><titles><title>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</title><secondary-title>Intensive Care Med</secondary-title><alt-title>Intensive care medicine</alt-title></titles><alt-periodical><full-title>Intensive care medicine</full-title></alt-periodical><pages>707-10</pages><volume>22</volume><number>7</number><edition>1996/07/01</edition><keywords><keyword>Humans</keyword><keyword>Multiple Organ Failure/ classification/diagnosis/microbiology/mortality</keyword><keyword>Reproducibility of Results</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Sepsis/ complications</keyword><keyword>Severity of Illness Index</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0342-4642 (Print)
0342-4642 (Linking)</isbn><accession-num>8844239</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>2 replaces the Systemic Inflammatory Response Syndrome (SIRS) as the means by which the adverse physiological effects of infection are identified. ADDIN EN.CITE <EndNote><Cite><Author>Bone</Author><Year>1992</Year><RecNum>2171</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>2171</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bone, R. C.</author><author>Balk, R. A.</author><author>Cerra, F. B.</author><author>Dellinger, R. P.</author><author>Fein, A. M.</author><author>Knaus, W. A.</author><author>Schein, R. M.</author><author>Sibbald, W. J.</author></authors></contributors><titles><title>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</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1644-1655</pages><volume>101</volume><number>6</number><dates><year>1992</year></dates><isbn>0012-3692</isbn><urls><related-urls><url> According to the new guideline, suspected or proven infection with proven organ dysfunction (defined as an increase of ≥2 in SOFA score) results in the diagnosis of sepsis. In previous definitions, suspected infection could only result in a diagnosis of suspected sepsis until infection was proven on microbiological culture.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXZ5PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 3 4 There is limited published data on the frequency of sepsis following cardiac surgery. Previous studies often limited their investigations to patients with positive microbiological cultures from specific sites such as the wound or the respiratory tract. Such studies used previous definitions of sepsis and identified sepsis in 0.5% -2% of cardiac surgery patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWNoYWxvcG91bG9zPC9BdXRob3I+PFllYXI+MTk5ODwv
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ADDIN EN.CITE.DATA 5-7 In these studies, sepsis was associated with mortality rates in the range of 17%-79%. As organ dysfunction is frequent following cardiac surgery due to the inflammatory response to surgery and cardiopulmonary bypass, Sepsis-3 criteria could potentially diagnose sepsis in patients with transient organ dysfunction due to surgery and coincidental minor infection. The objective of this study was to ensure that adoption of the Sepsis-3 guidelines is appropriate for patients undergoing cardiac surgery. To achieve this objective we have assessed the incidence of sepsis as defined by the new guidelines and also investigated whether diagnosis with proven or suspected infection influences short and mid-term clinical outcomes. MethodsPatients and Data collectionAll relevant clinical and monitoring data were collected prospectively from consecutive adult patients admitted to the Cardiac Intensive Care Unit (CICU) after cardiac surgery at University Hospital of South Manchester (UHSM) between January 2013 and May 2015. Patients undergoing cardiac transplantation were excluded from the study. Data were collected for the duration of the patients’ first CICU admission following cardiac surgery from three sources. i) Patient demographics, preoperative morbidity and outcome data were collected from the hospital’s clinical governance database. ii) Physiological variables, medication data, and case note data regarding the suspicion or diagnosis of infection were collected from the electronic patient record (EPR). iii) Haematology and biochemistry results together with all microbiology reports were collected from the hospital’s pathology database. Hourly recordings of physiological variables, medication administrated and all available biochemical and haematological results were cleaned using cleaning algorithms in R Studio (R Foundation for statistical computing) ADDIN EN.CITE <EndNote><Cite><Author>R Core Team</Author><Year>2015</Year><RecNum>2174</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>2174</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2174</key></foreign-keys><ref-type name="Computer Program">9</ref-type><contributors><authors><author>R Core Team,</author></authors></contributors><titles><title>R: A Language and Environment for Statistical Computing</title></titles><dates><year>2015</year></dates><pub-location>Vienna, Austria</pub-location><publisher>R Foundation for Statistical Computing </publisher><urls><related-urls><url>. Daily SOFA scores (Table 1) were calculated for each patient using the most abnormal value recorded for each variable on each day. ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>1996</Year><RecNum>1968</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>1968</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">1968</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Moreno, R.</author><author>Takala, J.</author><author>Willatts, S.</author><author>De Mendonca, A.</author><author>Bruining, H.</author><author>Reinhart, C. K.</author><author>Suter, P. M.</author><author>Thijs, L. G.</author></authors></contributors><auth-address>Erasme University Hospital, Brussels, Belgium.</auth-address><titles><title>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</title><secondary-title>Intensive Care Med</secondary-title><alt-title>Intensive care medicine</alt-title></titles><alt-periodical><full-title>Intensive care medicine</full-title></alt-periodical><pages>707-10</pages><volume>22</volume><number>7</number><edition>1996/07/01</edition><keywords><keyword>Humans</keyword><keyword>Multiple Organ Failure/ classification/diagnosis/microbiology/mortality</keyword><keyword>Reproducibility of Results</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Sepsis/ complications</keyword><keyword>Severity of Illness Index</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0342-4642 (Print)
0342-4642 (Linking)</isbn><accession-num>8844239</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>2 For all patients who experienced a SOFA score increase of ≥2, the clinical notes were examined to identify suspected or proven infection. Proven infection was confirmed by microbiological cultures (excluding isolated c.albicans-positive sputum cultures, mixed growth urine samples or screening swabs which indicated colonisation). Infection was classified as suspected if antibiotics other than those given as standard prophylaxis were administered or suspicion of infection was documented in the clinical notes section of the EPR. All indicators of suspected or proven infection recorded within 24 hours of the day of the SOFA ≥2 rise were included to ensure that no suspected or proven infection was missed.Missing DataWhere blood analyses necessary for calculation of daily SOFA scores were missing, the last known appropriate result recorded for that patient was substituted. Bilirubin concentrations were not routinely measured for low risk patients, so there were 340 occasions (5.2% of all SOFA score calculations) when there was no bilirubin level available for the SOFA score calculation. In 257 of these cases a bilirubin level subsequently measured for that patient was used. In the remaining 83 calculations (total of 39 patients), SOFA was calculated incorporating the median bilirubin concentration for all patients. In the one patient with no available creatinine level and two with no available platelet count, the median for the missing variable was used. All other data were complete.Statistical analysisNormally distributed data were described using the mean and standard deviation; data with non-parametric distributions were described using the median and interquartile range (IQR). Outcome measures were length of CICU stay (hours), 30-day mortality (defined as death due to any cause within the first 30 days after cardiac surgery) and 2-year survival. The relationship between sepsis and length of CICU stay was analysed using the Kruskal-Wallis test as length of stay was not normally distributed. Univariate analyses of the relationship between sepsis and 30-day mortality were conducted using Fisher’s exact test due to the low observed mortality rate. Two year survival rates were compared using the log-rank test. Logistic EuroSCORE and cardiopulmonary bypass (CPB) time were adjusted for using linear regression analyses for the multivariable length of CICU stay analysis. Multivariable logistic regression analyses were performed to adjust for the effect of logistic EuroSCORE on 30-day mortality. The low number of deaths prevented the inclusion of additional confounders in these analyses. ADDIN EN.CITE <EndNote><Cite><Author>Peduzzi</Author><Year>1996</Year><RecNum>2225</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>2225</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Peduzzi, P.</author><author>Concato, J.</author><author>Kemper, E.</author><author>Holford, T. R.</author><author>Feinstein, A. R.</author></authors></contributors><auth-address>Cooperative Studies Program Coordinating Center, Veterans Affairs Medical Center, West Haven Connecticut 06516, USA.</auth-address><titles><title>A simulation study of the number of events per variable in logistic regression analysis</title><secondary-title>J Clin Epidemiol</secondary-title><alt-title>Journal of clinical epidemiology</alt-title></titles><periodical><full-title>J Clin Epidemiol</full-title></periodical><alt-periodical><full-title>Journal of Clinical Epidemiology</full-title></alt-periodical><pages>1373-9</pages><volume>49</volume><number>12</number><edition>1996/12/01</edition><keywords><keyword>Bias (Epidemiology)</keyword><keyword>Computer Simulation</keyword><keyword>Coronary Artery Bypass</keyword><keyword>Coronary Disease/ mortality/surgery</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Monte Carlo Method</keyword><keyword>Regression Analysis</keyword><keyword>Reproducibility of Results</keyword></keywords><dates><year>1996</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0895-4356 (Print)
0895-4356 (Linking)</isbn><accession-num>8970487</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>9 Finally, Cox proportional hazards analyses were performed to adjust for the influence of logistic EuroSCORE and CPB time, on 2-year survival. The Logistic EuroSCORE HYPERLINK \l "_ENREF_10" \o "Roques, 2003 #2180" ADDIN EN.CITE <EndNote><Cite><Author>Roques</Author><Year>2003</Year><RecNum>2180</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>2180</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2180</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roques, F.</author><author>Michel, P.</author><author>Goldstone, A. R.</author><author>Nashef, S. A.</author></authors></contributors><titles><title>The logistic EuroSCORE</title><secondary-title>Eur Heart J</secondary-title><alt-title>European heart journal</alt-title></titles><alt-periodical><full-title>European Heart Journal</full-title></alt-periodical><pages>881-2</pages><volume>24</volume><number>9</number><edition>2003/05/03</edition><keywords><keyword>Coronary Disease/ surgery</keyword><keyword>Europe</keyword><keyword>Humans</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Thoracic Surgical Procedures</keyword></keywords><dates><year>2003</year><pub-dates><date>May</date></pub-dates></dates><isbn>0195-668X (Print)
0195-668X (Linking)</isbn><accession-num>12727160</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>10 is an extensively validated preoperative risk prediction model for perioperative mortality that includes patient co-morbidities, variables reflecting cardiac function and operative risk factors. It demonstrates good discriminative ability for UK cardiac surgery.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaWNrZXk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 11 Data collection was approved by the National Research Ethics Service–Haydock as part of the Vascular Governance Northwest Project (09/H 1000 10/2+5) and all analyses were performed using R. ADDIN EN.CITE <EndNote><Cite><Author>R Core Team</Author><Year>2015</Year><RecNum>2174</RecNum><DisplayText><style face="superscript">8</style></DisplayText><record><rec-number>2174</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2174</key></foreign-keys><ref-type name="Computer Program">9</ref-type><contributors><authors><author>R Core Team,</author></authors></contributors><titles><title>R: A Language and Environment for Statistical Computing</title></titles><dates><year>2015</year></dates><pub-location>Vienna, Austria</pub-location><publisher>R Foundation for Statistical Computing </publisher><urls><related-urls><url> ResultsDuring the study period, 2230 patients were admitted to CICU after cardiac surgery. The mean (range) age was 66.1 (18-93) years and the majority of patients were men (1615, 72.4%). Full patient characteristics for the study population are shown in Table 2. Median length of CICU stay (IQR) was 48.8 (40.1-93.0) hours. Overall 30-day mortality was 1.5% and 2 year survival was 93.0%. SOFA rises of ≥2 were identified on 710 occasions in 323 patients. A total of 573 patients were discharged from the CICU on the first postoperative day. In these patients only one SOFA score was available preventing the calculation of a difference between the daily SOFA scores. As a result these patients were classified as not suffering sepsis during the CICU admission. SepsisThe Sepsis-3 criteria for sepsis were met by 211 (9.5%) of the 2230 patients. Sepsis with suspected infection occurred in 104 patients (4.7%) and sepsis with proven infection was demonstrated in 107 (4.8%). The respiratory tract was the most frequent source of both proven (72.1%) and suspected infection (55.4%). Other sources of infection are shown in Table 3. The median length of CICU stay (IQR) was 145.2 (114.5-261.7) hours for those with sepsis due to suspected infection, 211.5 (117.2-478.1) hours for those with sepsis due to proven infection, and 47.0 (28.8-72.6) hours for those without sepsis (p <0.01 for both). After controlling for the logistic EuroSCORE and CPB time using linear regression modelling, patients with sepsis had significantly longer CICU stays than those without. The increase in length of CICU stay (95% CI) was 134.1 (99.0-168.2) hours for those with suspected infection and 266.1 (231.6-300.7) hours for those with proven infection (p<0.01 for both). The linear regression model is detailed in the Appendix. To ensure the length of stay analysis was not skewed by the 573 patients discharged on the first post-operative day, a sensitivity analysis using the same linear regression model on data taken exclusively from patients with two or more daily SOFA scores (n=1657) was performed. The increase in length CICU of stay (95%CI) attributed to a diagnosis of sepsis with suspected infection in this subgroup remained significant at 135.7 (99.1-172.3) hours; the increase related to proven infection was 265.8 (229.7-301.9) hours (p<0.01 for both). The 30-day mortality was 6.6% for those who suffered sepsis compared with 1.0% for those who did not (p<0.01). The mortality rates for sepsis with suspected infection (5.8%) and sepsis with proven infection (7.5%) were both significantly higher than the rate of 1.0% for those without sepsis (p<0.01 for both). After adjusting for pre-and intraoperative confounders using the logistic EuroSCORE (full model detailed in the Appendix), the odds ratio associated with sepsis was 3.7 (95%CI 1.1-10.2, p=0.02) for suspected infection and 6.6 (95% CI 2.6-15.7, p <0.01) for proven infection. Among those who suffered from sepsis, the main differences between survivors and those who died were that those who died had a higher median logistic EuroSCORE (16.7 vs 6.7, p<0.01) and were less likely to have undergone isolated CABG or valve surgery (21.4% vs 60.4%, p=0.01). Rates of renal replacement therapy (71.4% vs 28.4%, p<0.01) and prolonged mechanical ventilation (92.9% vs 33.5%, p<0.01) were higher in non-survivors than survivors. Among patients with sepsis the 2-year survival was 87.5% for those with suspected infection and 73.8% for those with proven infection compared with 94.3% for those without sepsis (p<0.01 for both). As seen in Figure 1 the greatest difference in mortality rates was seen in the first 12 postoperative months. A second log-rank analysis which included only those patients alive one year post surgery showed a smaller difference in the rates of survival to two years between those who had suffered sepsis (98.1%) and those who had not (96.0%) which was no longer statistically significant(p=0.06). The confounding effects of preoperative logistic EuroSCORE and CPB time on 2-year survival were adjusted for using Cox proportional hazards regression. For those with sepsis due to suspected infection the hazard ratio was 1.1 and the effect on survival was not statistically significant (95%CI 0.5-2.4, p=0.76). However, for sepsis due to proven infection compared with those without sepsis the hazard ratio was 3.6 (95%CI 2.2-5.9 p<0.01). The model is detailed in the Appendix.SOFA rise ≥2 in the absence of sepsis112 patients developed a SOFA rise ≥2 in the absence of proven or suspected infection. The median length of CICU stay (IQR) for these patients was 83.2 (48.5-124.9) hours. This was significantly shorter than the median CICU stay of 211.5 hours for both those with sepsis due to proven infection and 145.2 hours for those with suspected infection (p<0.01 for both). On multivariable analysis (full model detailed in the Appendix), a SOFA rise ≥2 without sepsis was associated with a statistically insignificant difference in length of stay of 6.9 hours (95%CI -28.2-41.9, p=0.70). The 30-day mortality rate for those with a SOFA rise ≥2 in the absence of sepsis was 2.7%. This was higher than that for patients with lesser increases in SOFA scores and lower than that for those with sepsis and suspected or proven infection but none of these differences was statistically significant. (p=0.10, p=0.32 and p=0.13 respectively). After adjusting for pre-and intraoperative confounders using the logistic EuroSCORE (full model detailed in the Appendix), a SOFA rise≥2 in the absence of sepsis was not significantly associated with 30-day mortality (odds ratio 2.1 (95% CI 0.5-6.2, p =0.23). The 2-year survival rate for patients who suffered a SOFA rise ≥2 without sepsis was 91.1%. This was not significantly different to the rate of 94.3% for patients with stable or small rises (<2) in the SOFA score (p=0.13) neither was it significantly different from the 87.5% in those with suspected infection (p=0.38). It was however, significantly higher than the 73.8% for those with proven infection and sepsis (p<0.01). Septic ShockOf the 211 patients diagnosed with sepsis, 159 patients (75.4%) met criteria relating to serum lactate concentration and use of vasopressors compatible with a diagnosis of septic shock. For this subgroup, median (IQR) length of CICU stay was 193.2 (139.5-364.0) hours, thirty day mortality was 8.8%, and the 2-year survival rate was 76.7%. All of these results were significantly worse than for patients with sepsis who did not suffer septic shock (p<0.02 for all).Discussion This is the first study to validate the Sepsis-3 guidelines in a cohort of patients after cardiac surgery. The new guidelines allow patients with only suspected infection to be diagnosed with sepsis. This may be one reason why the incidence of sepsis following cardiac surgery in this study (9.5%) is higher than that reported in studies which only included those with infection proven by microbiological culture.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWNoYWxvcG91bG9zPC9BdXRob3I+PFllYXI+MTk5ODwv
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ADDIN EN.CITE.DATA 5 7 14 15 Sepsis based on the Sepsis-3 guidelines was a significant risk factor for adverse outcomes in our cohort. 30-day mortality risk increased 6-fold in patients who met the Sepsis-3 criteria. Patients who suffered sepsis also had significantly longer CICU stays compared with patients who did not. Overall 2-year survival rates were lower for patients with sepsis, although our secondary analysis including only those who survived to 1 year illustrates that most of the impact of sepsis on mortality risk appears to be observed in the first 12 months. This relatively short term effect on risk is different to that reported in patients from general ICUs which detected impact on survival in the longer term. ADDIN EN.CITE <EndNote><Cite><Author>Winters</Author><Year>2010</Year><RecNum>2222</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>2222</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Winters, B. D.</author><author>Eberlein, M.</author><author>Leung, J.</author><author>Needham, D. M.</author><author>Pronovost, P. J.</author><author>Sevransky, J. E.</author></authors></contributors><auth-address>Departments of Anesthesiology and Critical Care Medicine and Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. bwinters@jhmi.edu</auth-address><titles><title>Long-term mortality and quality of life in sepsis: a systematic review</title><secondary-title>Crit Care Med</secondary-title><alt-title>Critical care medicine</alt-title></titles><alt-periodical><full-title>Critical Care Medicine</full-title></alt-periodical><pages>1276-83</pages><volume>38</volume><number>5</number><edition>2010/03/24</edition><keywords><keyword>Comorbidity</keyword><keyword>Hospital Mortality</keyword><keyword>Humans</keyword><keyword>Quality of Life</keyword><keyword>Sepsis/ mortality/psychology</keyword><keyword>Severity of Illness Index</keyword><keyword>Time Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>1530-0293 (Electronic)
0090-3493 (Linking)</isbn><accession-num>20308885</accession-num><urls></urls><electronic-resource-num>10.1097/CCM.0b013e3181d8cc1d</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>16 This difference may be due to the cohort of patients included in our study. In the cardiac surgery patients studied, the organ dysfunction that triggered the diagnosis of sepsis often progressed to organ failure in patients who had already been physiologically stressed by their surgery. 31% of those with sepsis required renal replacement therapy and 37% required prolonged mechanical ventilation. Patients either recovered from these critical complications or died as a result of them within a relatively short period. Studies in general ICU populations found that when Sepsis-3 criteria and SIRS-related sepsis criteria were applied to the same patients with suspected infection, the Sepsis-3 criteria identified fewer patients than SIRS-related criteria. They also showed that patients identified by the Sepsis-3 criteria were likely to suffer worse outcomes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25uZWxseTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA 17 18 However, the variables included in the SIRS criteria are influenced by the inflammatory response to major surgery as well as treatments such as mechanical ventilation, patient warming and perioperative beta-blockade which are frequently employed following cardiac surgery. Importantly, unlike the SOFA-related definitions, the SIRS criteria cannot recognise the effects of interventions on the absolute values of these parameters. Moreover, in our cohort, 88% of patients fulfilled the criteria for SIRS postoperatively. Therefore, using SIRS-related criteria to diagnose sepsis would have led to the vast majority of suspected infections resulting in a diagnosis of sepsis, even where inflammation did not progress above the postoperative baseline. Consequently, the Sepsis-3 definitions seem to provide the most appropriate means for detecting sepsis after cardiac surgery. This may be also true for patient groups who require critical care treatments after undergoing other types of major surgery or suffering from conditions which result in non-infective, inflammatory responses such as pancreatitis or severe burns. A significant proportion of the patients diagnosed with sepsis in this study went on to meet the criteria for septic shock. The length of CICU stay, 30-day mortality and 2-year survival rate associated with septic shock were significantly worse than those for patients who suffered sepsis without septic shock. Further work to identify patients at the highest risk of developing septic shock would therefore be of clinical importance. Approximately half of the patients diagnosed with sepsis in our study had proven infection and half had suspected infection; a proportion similar to that documented in the general ICU population. ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>2006</Year><RecNum>2173</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>2173</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Sakr, Y.</author><author>Sprung, C. L.</author><author>Ranieri, V. M.</author><author>Reinhart, K.</author><author>Gerlach, H.</author><author>Moreno, R.</author><author>Carlet, J.</author><author>Le Gall, J. R.</author><author>Payen, D.</author><author>Sepsis Occurrence in Acutely Ill Patients, Investigators</author></authors></contributors><auth-address>Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.</auth-address><titles><title>Sepsis in European intensive care units: results of the SOAP study</title><secondary-title>Crit Care Med</secondary-title><alt-title>Critical care medicine</alt-title></titles><alt-periodical><full-title>Critical Care Medicine</full-title></alt-periodical><pages>344-53</pages><volume>34</volume><number>2</number><edition>2006/01/21</edition><keywords><keyword>Apache</keyword><keyword>Aged</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Europe/epidemiology</keyword><keyword>Female</keyword><keyword>Hospital Mortality</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Intensive Care Units</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Sepsis/drug therapy/ epidemiology/mortality</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0090-3493 (Print)
0090-3493 (Linking)</isbn><accession-num>16424713</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>19 The new Sepsis-3 guidelines include suspicion of infection to ensure all patients with sepsis were identified and treated early. ADDIN EN.CITE <EndNote><Cite><Author>Singer</Author><Year>2016</Year><RecNum>2096</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>2096</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2096</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singer, M.</author><author>Deutschman, C. S.</author><author>Seymour, C.</author><author>et al.,</author></authors></contributors><titles><title>THe third international consensus definitions for sepsis and septic shock (sepsis-3)</title><secondary-title>Jama</secondary-title></titles><periodical><full-title>Jama</full-title></periodical><pages>801-810</pages><volume>315</volume><number>8</number><dates><year>2016</year></dates><isbn>0098-7484</isbn><urls><related-urls><url> This analysis demonstrates that patients with suspected infection suffered outcomes more similar to those with proven infection than to those with no sepsis. While outcomes for patients with proven infection were worse than for those with suspected infection, it is clearly appropriate to adopt Sepsis-3 as this improves the early identification of patients at a high risk of adverse short term outcomes. LimitationsThe new Sepsis-3 criteria identify worsening organ function by the change in the daily SOFA score rather than absolute values. The guidelines state that the baseline SOFA should be assumed to be 0 unless a patient has “pre-existing organ dysfunction (acute or chronic)”. Following cardiac surgery, the mean day one SOFA score was 5.4 and over 90% of patients had a day one SOFA score >2. Consequently, assuming a baseline SOFA score of 0 for patients undergoing this major surgery would be inappropriate. As a result, we required two daily postoperative scores in order to calculate the change in SOFA score and were therefore unable to diagnose sepsis before the second postoperative day. 26% of our patients were discharged on the first post-operative day and therefore could not be classified as having sepsis. The median CICU stay in these early discharge patients was 22.6 hours and their 30-day mortality was only 0.7%. Although sepsis would be unusual on the first day following cardiac surgery we have performed a sensitivity analysis excluding these patients and the conclusions from the analysis are unchanged. The small 30-day mortality rate in the study (34 deaths) prevented the inclusion of additional confounders into the logistic regression analyses for 30-day mortality. ADDIN EN.CITE <EndNote><Cite><Author>Peduzzi</Author><Year>1996</Year><RecNum>2225</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>2225</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">2225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Peduzzi, P.</author><author>Concato, J.</author><author>Kemper, E.</author><author>Holford, T. R.</author><author>Feinstein, A. R.</author></authors></contributors><auth-address>Cooperative Studies Program Coordinating Center, Veterans Affairs Medical Center, West Haven Connecticut 06516, USA.</auth-address><titles><title>A simulation study of the number of events per variable in logistic regression analysis</title><secondary-title>J Clin Epidemiol</secondary-title><alt-title>Journal of clinical epidemiology</alt-title></titles><periodical><full-title>J Clin Epidemiol</full-title></periodical><alt-periodical><full-title>Journal of Clinical Epidemiology</full-title></alt-periodical><pages>1373-9</pages><volume>49</volume><number>12</number><edition>1996/12/01</edition><keywords><keyword>Bias (Epidemiology)</keyword><keyword>Computer Simulation</keyword><keyword>Coronary Artery Bypass</keyword><keyword>Coronary Disease/ mortality/surgery</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Monte Carlo Method</keyword><keyword>Regression Analysis</keyword><keyword>Reproducibility of Results</keyword></keywords><dates><year>1996</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0895-4356 (Print)
0895-4356 (Linking)</isbn><accession-num>8970487</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>9 Logistic EuroSCORE was chosen to be the sole confounder entered into the model as it was considered the most clinically relevant variable. As with any observational study there were missing data. The incidence of missing data was however very low and SOFA scores were calculated using imputed bilirubin values for less than two percent of patients. In three of these patients creatinine concentration or platelet count were also imputed. A further potential limitation of this study is that it was conducted at a single centre. Although our centre performs almost all aspects of adult cardiac surgery, a larger, multicentre study would be the optimal method to validate these findings further. ConclusionThis is the first study exploring how Sepsis-3 criteria influence the diagnosis of sepsis in cardiac surgery patients. Patients with sepsis due to both proven and suspected infection suffered prolonged CICU stays and increased 30-day mortality justifying the adoption of Sepsis-3 guidelines in cardiac surgery.Declaration of interestsNo author has a conflict of interest.FundingThis work was supported by funding from the British Heart Foundation [grant number PG/16/80/32411]Author ContributionsStudy Design: S.H.H., I.M., C.N.M., S.W.G.Data Collection and cleaning: S.H.H., M.H.Data analysis: S.H.H., M.H., I.M., C.N.M., S.W.G.First draft of manuscript: S.H.H.Revision of Manuscript: S.H.H., M.H., I.M., C.N.M., S.W.G.Table -1 The SOFA score ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>1996</Year><RecNum>1968</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>1968</rec-number><foreign-keys><key app="EN" db-id="zwxs0tfp6x550xervr1vazx10x2wx5x9ssdf">1968</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Moreno, R.</author><author>Takala, J.</author><author>Willatts, S.</author><author>De Mendonca, A.</author><author>Bruining, H.</author><author>Reinhart, C. K.</author><author>Suter, P. M.</author><author>Thijs, L. G.</author></authors></contributors><auth-address>Erasme University Hospital, Brussels, Belgium.</auth-address><titles><title>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</title><secondary-title>Intensive Care Med</secondary-title><alt-title>Intensive care medicine</alt-title></titles><alt-periodical><full-title>Intensive care medicine</full-title></alt-periodical><pages>707-10</pages><volume>22</volume><number>7</number><edition>1996/07/01</edition><keywords><keyword>Humans</keyword><keyword>Multiple Organ Failure/ classification/diagnosis/microbiology/mortality</keyword><keyword>Reproducibility of Results</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Sepsis/ complications</keyword><keyword>Severity of Illness Index</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0342-4642 (Print)
0342-4642 (Linking)</isbn><accession-num>8844239</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>2SOFA score12 34RespirationPaO2 / FiO2 (kPa)<53.3<40.0<26.7 and?mechanical ventilation<13.3 and?mechanical ventilationCoagulationPlatelets x103 ?l-1<?150<?100<?50<?20LiverBilirubin (μmol L-1)20-3233-101102-204>?204CardiovascularHypotensionMAP<70mmHgdopamine ≤?5?gkg-1min-1 or dobutamine (any dose)dopamine >?5?g kg-1min-1 or adrenaline ≤??0.1?g kg-1min-1 or noradrenaline ≤??0.1?g kg-1min-1dopamine >?15?g kg-1min-1 or adrenaline >?0.1?g kg-1min-1 or noradrenaline >?0.1?g kg-1min-1Central nervous system Glasgow Coma Score13-1410-126-9<6RenalCreatinine (μmol L-1) or urine output (mlday-1)106-177178-309310-442<?500?>?442<?200?PaO2, arterial partial pressure of oxygen; FiO2, fraction of inspired oxygen; MAP, mean arterial pressureTable 2 - Patient characteristicsVariableAll (n=2230)Unable to calculate SOFA rise (n=573)No SOFA rise (n=1334)SOFA rise > 2 but no infection (n=112)Sepsis SuspectedInfection (n=104)Sepsis Proven Infection (n=107)Age, Mean (range), years66.1 (18-93)63.2 (23-86)66.9 (19-93)69.6 (28-87)65.5 (29-89)68.6 (18-91)Female Gender, n (%) 615 (27.6)99(17.3)418 (31.3)36 (32.1)31 (29.8)31 (29.0)Height, mean (SD), cm 169.6 (9.2)171.5 (8.7)168.9 (9.3)169.1 (8.2)169.5 (8.8)168.0 (10.6)Weight, mean (SD), Kg 81.0 (15.9)81.7 (14.1)81.7 (16.6)81.6 (14.4)81.6 (15.2)80.1 (17.8)Type Surgery Isolated CABG, n (%)1214 (54.4)479(83.6)619 (46.4)46 (41.1)31 (29.8)39 (36.4) Isolated Valve, n (%)482 (21.6)37 (6.5)367(27.5)26 (23.2)26 (25.0)26 (24.3) Isolated Aortic, n (%)23 (1.0)2 (0.3)13 (1.0)2 (1.8)4 (3.8)2 (1.9) Combined cardiac procedures, n (%)404 (18.1)19 (3.3)296 (22.2)30 (26.7)32 (30.8) 27 (25.2) Other, n (%)107(4.8)36 (6.3)39 (2.9)8 (7.1)11 (10.6)13 (12.1)Urgency Elective/Scheduled, n (%)1324 (59.3)317 (55.3)823 (61.7)61 (54.5)62 (59.6)61 (57.0) Urgent, n (%)842 (37.8)244 (42.5)488 (36.5)45 (40.1)29 (27.9)36 (33.6) Emergency/Salvage, n (%)64 (2.9)12 (2.1)23 (1.7)6 (5.4)13 (12.5)10 (9.3)Duration of CPB, median (interquartile range), minutes100.0 (79.0-128.0)87.0 (69-105.0)104.0 (84.0-134.0)101.0 (84.0-135.5)118.0 (94.0-165.0)108.0 (84.0-147.0)Logistic euroSCORE, median (Interquartile range) 4.0 (2.1-7.7)2.3 (1.4-3.5)4.6 (2.4-8.4)5.1 (3.3-11.8)7.5 (3.1-19.7)7.8 (3.6-15.1)Requirement for Renal Replacement Therapy, n (%) 107 (4.8)7 (1.2)24 (1.8)10 (8.9)26 (25.0)40 (37.4)Mechanical Ventilation > 72 hours n (%)147 (6.6)-37 (2.8)7 (6.3)29 (27.9) 50 (46.7)CABG, coronary artery bypass graft; CPB, cardiopulmonary bypassTable 3 – Suspected or proven sources of infection in those diagnosed with sepsisSuspected sourceSuspected infection*Proven Infection*Not specified (antibiotics started)51NAUnknown10NARespiratory14896Abdominal/Gastrointestinal6-Wound68Genitourinary35Bacteraemia/catheters624Endocarditis/myocarditis9-Dental1-* Multiple sites were implicated in many patientsTable 4 – Patient outcomesSepsis StatusSubgroupn (%)30-day mortality, n (%)Median ICU stay, hours (interquartile range)2 year survival, n (%)No SepsisAll patients2019 (90.5)20 (1.0)47.0 (28.8-72.6)1904 (94.3)SOFA rise not calculable573 (25.7)4 (0.7)22.6 (20.0-25.3)553 (96.5)SOFA rise < 21334 (59.8)13 (1.0) 52.6 (45.4.-86.2) 1248 (93.6)SOFA rise ≥ 2 without infection112 (5.0)3 (2.7) 83.2 (48.5 -124.9) 102 (91.1)SepsisAll patients211 (9.5)14 (6.6)*176.0 (115.7-404.6)*170 (80.5)*Suspected infection 104 (4.7)6 (5.8)*145.2 (114.5-261.7)*91 (87.5)*Proven infection107 (4.8)8 (7.5)*211.5 (117.2-478.1)*79 (73.8)** indicates p value of <0.05 when compared with the frequency of the outcome in the No Sepsis group during univariate analysesFigure LegendFig. 1. Two-year survival according to sepsis statusReferences ADDIN EN.REFLIST 1 Singer M, Deutschman CS, Seymour C, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315: 801-102 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; 22: 707-103 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: 1644-554 Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive care medicine 2003; 29: 530-85 Michalopoulos A, Stavridis G, Geroulanos S. Severe sepsis in cardiac surgical patients. European Journal of Surgery 1998; 164: 217-226 Fowler VG, O’Brien SM, Muhlbaier LH, Corey GR, Ferguson TB, Peterson ED. Clinical Predictors of Major Infections After Cardiac Surgery. Circulation 2005; 112: I-358-I-657 Oliveira DC, Oliveira Filho JB, Silva RF, et al. Sepsis in the postoperative period of cardiac surgery: problem description. Arq Bras Cardiol 2010; 94: 332-6, 52-68 R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing 20159 Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996; 49: 1373-910 Roques F, Michel P, Goldstone AR, Nashef SA. The logistic EuroSCORE. Eur Heart J 2003; 24: 881-211 Hickey GL, Grant SW, Murphy GJ, et al. Dynamic trends in cardiac surgery: why the logistic EuroSCORE is no longer suitable for contemporary cardiac surgery and implications for future risk models. Eur J Cardiothorac Surg 2013; 43: 1146-5212 Chen LF, Arduino JM, Sheng S, et al. Epidemiology and outcome of major postoperative infections following cardiac surgery: risk factors and impact of pathogen type. American journal of infection control 2012; 40: 963-813 Sahu M, Siddharth B, Choudhury A, et al. Incidence, microbiological profile of nosocomial infections, and their antibiotic resistance patterns in a high volume Cardiac Surgical Intensive Care Unit. Annals of Cardiac Anaesthesia 2016; 19: 281-714 Michalopoulos A, Geroulanos S, Rosmarakis ES, Falagas ME. Frequency, characteristics, and predictors of microbiologically documented nosocomial infections after cardiac surgery. Eur J Cardiothorac Surg 2006; 29: 456-6015 Falagas ME, Rosmarakis ES, Rellos K, Michalopoulos A, Samonis G, Prapas SN. Microbiologically documented nosocomial infections after coronary artery bypass surgery without cardiopulmonary bypass. Journal of Thoracic and Cardiovascular Surgery 2006; 132: 481-9016 Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE. Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med 2010; 38: 1276-8317 Donnelly JP, Safford MM, Shapiro NI, Baddley JW, Wang HE. Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) Classification: a retrospective population-based cohort study. The Lancet Infectious diseases 2017; 17: 661-7018 Sterling SA, Puskarich MA, Glass AF, Guirgis F, Jones AE. The Impact of the Sepsis-3 Septic Shock Definition on Previously Defined Septic Shock Patients. Crit Care Med 2017; 45(9):1436-144219 Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006; 34: 344-53 ................
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