Despite advances in diagnosis and treatment of infective endocarditis (IE) the overall in-hospital mortality remains high (11%–26%) (1–5), approaching 30% at 1 year (6, 7). Main reasons for unfavorable outcomes are cardiac and extracardiac complications, one or more of which occur in the majority of patients. Although all patients with IE are treated with antibiotics, recent data suggests that approximately 50% of patients underwent early valve replacement or repair (8, 9).
IE presents mainly with clinical and laboratory characteristics of sepsis. Sepsis and septic shock are common presentations of IE and these patients usually require treatment in intensive care units (ICUs) (10–12). Intensivists often encounter difficult decisions regarding treatment in this subgroup of patients. Unfortunately, very few studies exist which focus on patients with severe IE leading to ICU admission (10–15). Moreover, clinical characteristics of severe septic patients with IE, use of surgical treatment, and their associations with patient's outcome are scarcely presented.
The main objectives of this study were (a) to describe the clinical, microbiological and echocardiographic characteristics of patients with IE and different stages of sepsis and (b) to determine the influence of sepsis severity on outcome in patients with IE (c) to estimate the efficacy of CS in patients with sepsis and septic shock during IE and its impact on patient's outcome.
MATERIALS AND METHODS
We performed a prospective, single-center observational study at 220-bed University Hospital for Infectious Diseases in Zagreb, Croatia. Patients were adults with definite native or prosthetic valve IE established by the modified Duke criteria (16) admitted between January 2000 and December 2011. Twenty-six patients were excluded because of possible or rejected IE by modified Duke criteria or missing data. The study was approved by the ethics committee of University of Zagreb, Medical School in Zagreb, Croatia. The ethics committee waived the need for informed consent.
From the medical records the following patient information was obtained: age, sex, comorbid conditions, echocardiographic and microbiological results, use of mechanical ventilation and vasopressors, complications, and treatment (medical with CS and only medical). Underlying conditions were evaluated by the Charlson Comorbidity Score (17). In addition, each patient's condition at ICU admission was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) score (18).
Sepsis and septic shock were defined according to The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (19). Sepsis was defined as life-threatening organ dysfunction as a consequence of host response to infection, clinically represented by an increase in the SOFA score of 2 points or more. Septic shock was defined as a subset of sepsis, clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level greater than 2 mmol/L in the absence of hypovolemia. Surgery was defined as replacement or repair of the affected valve during the initial hospitalization for IE. Survival duration was defined as the time since admission to hospital time of death or last contact. Definitions of IE complications, that is, neurological complications, congestive heart failure (CHF), as well as antibiotic regimens and indications for CS are described elsewhere (20, 21).
On the basis of the severity of sepsis, patients were assigned into three groups:
- (1) patients with IE and no sepsis
- (2) patients with IE and sepsis
- (3) patients with IE and septic shock.
Follow-up data were gathered predominantly by telephone contact with the patients or relatives and/or their referring physicians.
Descriptive analyses were performed to check and summarize the data. Categorical variables are reported as frequency and percentage. Continuous variables are reported as median and 25th and 75th percentiles. Simple comparisons were done for categorical variables using the χ2 test or Fisher exact test as appropriate. If the number of patients within the cell was <10 patients, we used the Freeman–Halton extension of the Fisher exact test as a more conservative approach. The Wilcoxon rank-sum test was used for continuous variables.
To estimate the impact of sepsis and septic shock on patients’ outcome, multivariate logistic regression was performed. Variables included in the model, which fitted the best beside clinical presentation (no sepsis, sepsis, septic shock) were neurological complications, CHF and, S. aureus IE. The model itself showed high explanatory value and fitted well (Hosmer–Lemeshow test). All variables that were statistically significant (α = 0.05) in the bivariable analyses were included in the initial (full) multivariable logistic regression model. The Cochran–Mantel–Haenszel statistics was performed to analyze the association between CS and outcome (in-hospital mortality and 1-year mortality) after adjusting for severity of sepsis.
To assess the impact of CS on long-term survival, the probability of survival was estimated the Kaplan–Meier method and the log-rank test for patients with IE regarding treatment (medical compared with surgery group). Multivariable Cox proportional hazard regression model was used to determine the impact of CS on long-term survival after adjustment for clinical covariates found to be associated with survival.
For all statistical tests, significance was determined at an α level of 0.05. All analyses were performed using SAS software (version 9.4, SAS Institute, Cary, NC).
Among 56,264 patients hospitalized at the University Hospital for Infectious Diseases, Zagreb during the 12-year period, 294 (0.5%) patients were treated for definite IE. The study schema is depicted in Figure 1. Demographic characteristics and baseline clinical data for overall cohort and each group of patients is presented in Table 1. Patients were characterized by a median age of 63 years (25th, 75th percentile = 48, 71) and substantial rate of medical comorbidities (arterial hypertension 40.5%, diabetes 23.1%, ischemic heart disease 10.9%, malignancy 8.2, alcoholic liver disease 7.8%). Native valve IE occurred in 241 patients (82.0%) and prosthetic valves were affected in 46 (15.6%) patients. Seven patients (2.4%) had an infection of an intracardial device (pacemaker or implantable cardioverter-defibrillator). Right-sided IE was present in 19 (6.5%) patients.
Admission to the ICU was considered necessary in 141 (48.0%) patients. Factors indicating ICU admission were predominantly neurological complications (94 patients, 32%), sepsis and septic shock (91 patients, 31%), CHF (74 patients, 25.2%) and cardiogenic shock (30 patients, 10.2%). Sixty-eight (23.1%) patients required mechanical ventilation.
Causative pathogens were identified in 274 (93.2%) patients. The most common pathogen was S. aureus in 103 patients (35%), followed by viridans streptococci in 20.1% patients and enterococci in 14.6%. Etiology was undetermined in 6.8% of patients.
Comparison of IE patients without sepsis and with sepsis or septic shock
Several differences were observed between the three groups. Although there was no significant difference in Charlson score between the three groups, patients in sepsis and septic shock group were more likely to have medical comorbidities such as diabetes and alcoholic liver disease. S. aureus was the predominant microorganism in patients with sepsis and septic shock (60.3% and 66.7%, respectively) while the leading pathogen in patients without sepsis was S. viridans. Patients with sepsis or septic shock and IE were more likely to be admitted earlier to the hospital (median 3 and 5 days, respectively) compared with patients with IE and sepsis (median 7 days). Complications such as CHF, neurological complications (including stroke) and respiratory failure were also associated with sepsis and septic shock. Consequently, patients in these two groups had higher APACHE II scores (median 14 and 23, respectively) and SOFA score (median 4 and 9.5, respectively).
Overall in-hospital mortality in our patients was 20.1%. Main prognostic factors associated with in-hospital mortality in patients with IE are presented in Table 2. Most common complications of IE (CHF, neurological complications—especially stroke, and S. aureus in blood cultures) were associated with higher mortality. The size of a vegetation on echocardiography was also a predictor of in-hospital mortality (P = 0.009) but the presence of paravalvular abscess did not have any influence on outcome.
To estimate the impact of sepsis and septic shock on patient's outcome, multivariate logistic regression was performed. Variables included in the model, which fitted the best beside clinical presentation (no sepsis, sepsis, shock) were neurological complications, CHF and S. aureus IE. Results showed that mortality in patents with IE was significantly associated with sepsis and septic shock after adjustment for other risk factors of poor outcome (odds ratio [OR] 8.915, P < 0.001 and OR 35.969, P < 0.001, respectively) (Table 3).
CS regarding severity of sepsis
CS was performed during hospitalization in 113 (38.4%) patients. Despite severity of sepsis, there was no significant difference in frequency of CS in the three groups of patients (38.8% for no sepsis group, 43% for sepsis group and 26.7% in septic shock group, P = 0.520).
We compared the outcome of sepsis in operated and nonoperated patients stratified by the severity of disease regarding new sepsis criteria. Positive correlation was observed in sepsis and septic shock group although the number of patients in the shock group was too small to draw any final conclusions. The Cochran-Mantel-Haenszel statistics performed with significant P value (<0.001) indicates that the association between CS and outcome (in-hospital mortality) remains strong after adjusting for severity of sepsis (Table 4). Patients who underwent CS with sepsis and septic shock were five times more likely to improve compared to medically treated patients (RR 5.157, CI 2.192–12.131). In addition, we performed Cochran–Mantel–Haenszel statistics for establishing associations between CS and 1-year mortality, and again, the probability of improvement after CS was three times higher compared with medical treatment alone (RR 3.25, CI 0.166–0.568, P < 0.001) (Table 5).
The Kaplan–Meier estimates of the probability of 1-year survival in operated and nonoperated patients regarding severity of sepsis are shown in Figures 2 and 3. Survival was significantly better in sepsis and septic shock group with IE who were operated (log-rank test, P < 0.001), but not in the no sepsis and IE group (log-rank test, P = 0.07). Cox regression analysis was performed to estimate factors associated with 1-year survival after adjustment for other risk factors of an unfavorable outcome. Independent variables included in the model were age, CHF, S. aureus IE, sepsis and shock with no sepsis as a referent value, and absence of CS. CS was treated as a time-dependent variable. After adjustment, absence of CS was significantly associated with 1-year mortality (hazard ratio 3.092 [CI 1.889–5.224], P < 0.001) (Table 6).
We here present the results of our single-center study on 294 consecutive adults admitted to hospital for IE. To our knowledge it represents the first systematic analysis of different stages of sepsis during IE and their influence on outcome by using new (Sepsis-3) criteria (19). This study highlights the influence of CS on outcome in IE patients with sepsis or septic shock. The strengths of our study are as follows: all patients met the modified Duke criteria to secure definite IE diagnosis, all patients had met new criteria for sepsis and finally, that all patients were included in the 12-year follow-up period in a single center to assure comparable therapeutic measures.
Although IE is an infection of the inner surface of the heart (mainly heart valves), it is also a blood stream infection that is clinically presented with signs and symptoms of sepsis. In our cohort, 29.9% of patients with IE had sepsis or septic shock and they were all treated in the ICU. Our results do not differ greatly from previous studies, where severe forms of sepsis were present in 25%–50% of patients with IE treated in ICU (10, 12, 14, 15, 22). Overall in-hospital mortality was 20.1%. This high mortality is attributed to the fact that our center is a referral center for treatment of severe forms of IE and that 75% of patients had at least one complication of IE. Furthermore, almost 50% of our patients were treated in ICU. S. aureus was the leading cause of IE in our cohort and it is well known that this agent can be associated with high mortality and complication rate (23). Nearly all complications of IE in our patients were associated with an unfavorable outcome. In contrast, paravalvular abscess that is previously mentioned by some authors to impact mortality (24, 25) showed no impact on mortality in our cohort. Interestingly, there was no difference in frequency of paravalvular abscess in the three groups. This may suggest that the local propagation of infection is not necessarily associated with severity of sepsis.
One-year mortality reached 34% and this is in line with previous studies on long-term outcome of patients with IE (14, 26, 27). Although septic shock is associated with very high mortality (up to 50%), it was not analyzed as a predictor of outcome in previous studies involving predictors of mortality (1, 3, 8). We found that by using new sepsis criteria, the severity of sepsis and septic shock after adjusting for other risk factors, independently increases in-hospital mortality in patients with IE. This finding does not differ from Gelsomino et al. (28) study, which showed that septic shock increased the risk of death in patients with mitral valve IE.
CS in patients with IE and sepsis or septic shock
Presence of complications and predictors of an unfavorable outcome often necessitates combined medical and surgical treatment. Over the last three decades, valve replacement (or repair) became standard treatment in selected groups of patients with IE. The impact of surgery on IE prognosis was the subject of numerous studies. Despite some conflicting results, CS appears to be most often associated with improved survival (3, 8, 11, 29, 30). Frequency of surgical procedures is constantly increasing (between 30% and 60%) (31) mostly because of the epidemiological profile change of patients IE and positive results of this type of treatment (1, 3, 30). In our cohort 38.4% were treated surgically and the positive effect of surgery regarding in-hospital mortality was observed in patients with sepsis and septic shock, but not in patients with IE without sepsis. In addition, 1-year survival analysis showed a higher chance for survival if surgery was performed in severe forms of sepsis (including septic shock). These results can be explained through the obvious positive effect of CS, but also with the fact that some patients treated only medically die because they are too ill to be operated. Better delineation of the impact of CS on IE patients with sepsis and septic shock can be clinically relevant since it may help clinicians better determine which patients are surgical candidates among the most severely ill.
Patients with IE and sepsis or septic shock are an important group of IE patients for several reasons. First, these patients are often complex and usually treated in ICU often with high mortality. Second, sepsis and septic shock during IE often accompanies S. aureus bacteriemia followed by neurological complications and embolic events, which are associated with unfavorable outcomes (11, 32, 33). Third, if these patients have indications for CS, presence of severe generalized infection makes the surgeon hesitate whether to operate because of fear of early relapse risk of infection. Although some studies point out safety risks of valve repairment during active phase of IE with low risk of relapse (even in staphylococcal endocarditis) (34), the presence of sepsis or septic shock during IE often defers CS until patients are hemodynamically stable.
CS had a positive influence on in-hospital mortality as well as on 1-year follow-up in our IE patients with sepsis and septic shock. In patients without sepsis and IE there was no difference between medical and surgical treatment. These results suggest that in patients with IE, severity of sepsis should be analyzed according to the sepsis definitions since this special subgroup of IE patients could benefit from CS.
This report has several limitations to be considered. Our study represents results from a single-center; hence, influences of local therapy strategies according to actual guidelines are possible. The study also addresses the effect of surgery in critical IE carried out during a relatively long period, thereby bias due to changes and advances in the field of CS, antimicrobial treatment and intensive care medicine can not be eliminated. Finally, relatively small number of patients with septic shock was analyzed and a much larger study will have to be undertaken regarding severity of septic shock per se.
Our results show that in all patients with sepsis during IE, after the diagnosis is definite, it is prudent to estimate the severity of disease and the need for performing surgery. Sepsis and septic shock, although having important influence on mortality in patients with IE, should not deter surgeons from performing surgery when there is an indication for operation. Other studies (multicenter and randomized) are needed to confirm our results since this could be a way to reduce mortality in critically ill patients with IE.
We thank Marija Santini, MD, Martina Vargovic, MD, and Marko Kutlesa, MD for contribution during data collection and direct observations.
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