In 2016, the Society of Critical Care Medicine updated the definition of sepsis to be a life-threatening organ dysfunction due to a dysregulated host response to infection. This new definition was recommended to facilitate earlier recognition and more timely management of patients with sepsis, or those at risk of developing sepsis, by placing an emphasis on the nonhomeostatic host response.[2,6] While the true incidence of sepsis is unknown, it is thought to be the leading cause of mortality and critical illness worldwide and is the primary cause of death from infection. In the United States, sepsis is the leading cause of death in hospitalized patients, claiming 220,000 lives in the United States, annually and has a mortality rate estimated to be between 25% and 50%. Additionally, sepsis is the single most expensive disease to treat in the hospital with an annual cost of approximately 20 billion dollars. This is a devastating disease and its presence should be considered in any patient presenting with infection. Conversely, unexplained organ damage should prompt the search for an underlying infection.
Due to the volatile nature of sepsis, several guidelines have been put in place in an attempt to standardize care and improve mortality rates. In 2015, the Centers of Medicare and Medicaid Services (CMS) implemented the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1). This required U.S. hospitals to report compliance rates with core sepsis measures. These requirements involved lactate measurements, fluid resuscitation, and antibiotic coverage. Critics argued that the guidelines were too rigid and did not allow physicians to individualize care and noted that the difference in mortality rate was not significant in patients that "failed" (ie, were not identified and treated in accordance with SEP-1 criteria) versus those who “passed.”
In 2018, the Society of Critical Care Medicine (SCCM), through the Surviving Sepsis Campaign (SSC), released an updated guideline for sepsis treatment known as the hour-1 bundle. This five-step protocol included (1) measuring a lactate level; (2) drawing blood cultures; (3) giving broad-spectrum antibiotics; (4) giving fluids; and (5) vasopressors when appropriate.
This approach is governed by a theoretical acknowledgment of septic shock as a form of hypovolemic shock with clinical signs of organ hypoperfusion. Early goaldirected therapy (EGDT) protocol(s) have been accepted as the standard of care for treating patients with sepsis and septic shock since the early 2000s. Recently, the 3-hour and 6-hour bundles were combined into a single "hour-1 bundle" with intention of resuscitation and management beginning immediately upon patient presentation. In response to this recommendation, there has been a growing body of scientific and clinical evidence in support of more conservative fluid management within EGDT. Furthermore, despite the SSC recommendations, these studies have revealed EGDT as responsible for increasing healthcare costs in patients with sepsis and have been implicated in worsening healthcare outcomes for both adult and pediatric patient populations.[8–12] Because of this, clinical acknowledgment is largely based on expert opinion with little-to-no clinical data supporting improved patient care or outcomes at lengths up to 12 months. Several recent large randomized prospective studies have provided mounting evidence that aggressive fluid resuscitation is demonstrating harm and poorer outcomes.[4,8–13] New research recommendations have suggested a more conservative fluid management than the SSC recommendation.
EGDT has been clinically proven to improve short-term mortality in sepsis management. However, with new data being released, it is also important to look at long-term management. One study found that positive fluid balance, defined as fluid input greater than output, was among the strongest prognostic factors for death. Another study found that patients receiving EGDT often have clinical evidence of fluid overload and an increased incidence of medical interventions including, thoracentesis and use of diuretics directly related to fluid overload. Following the release of these guidelines, several organizing bodies including the American College of Emergency Physicians (ACEP) and the American Academy of Emergency Medicine (AAEM), issued statements expressing concerns over the new guidelines. They cited a lack of research and worsening clinical outcomes as concerns, as well as debating the 1-hour time frame. Moreover, problems arise when individualized fluid resuscitation treatment plans are not adequately used. Recent studies have shown that there are in fact 5 distinct phenotypes of septic patients, and proper treatment is dependent on which class the patient falls in.
Because of the incidence and high mortality rate of sepsis, it is important for clinicians to understand the interplay in sepsis diagnosis and treatment with comorbid conditions in varying patient populations. Congestive heart failure (CHF) is one of the most prevalent chronic diseases in the United States. In the United States, 2% of the population has heart failure, totaling 4.8 million Americans. In patients aged 65 and over, CHF comprises 20% of all hospitalizations, making it the most common reason for hospital admission. Furthermore, 30% to 40% of patients with CHF have a history of hospitalization associated with worse outcomes.
Along with morbidity, there is a significant financial burden on these patients and the U.S. healthcare system. The annual median cost for care and hospitalizations of a single patient with CHF is estimated at $24,383. In 2012, the overall cost globally was estimated at $108 billion. Due to lack of access to comprehensive care, this burden is likely increased in rural areas. Fortunately, in a metaanalysis reviewing over 1.5 million cases, they found 1-and 5-year survival rates in patients with CHF are approximately 50%, which is improved compared to previous decades. This is in large part due to advances in pharmaceutical and transplant technology. However, along with this advancement in treatment, there has been an increase in noncardiovascular death in patients with CHF. Sepsis, in particular, is a key contributor to mortality in patients with CHF.
The indication for aggressive fluid management in a patient with CHF presents a complicated clinical course. The fluids must compensate for hypoperfusion without overwhelming the cardiovascular system, thus potentially leading to third-spacing and worsening pulmonary function. A previous study indicated that septic patients with a past medical history of CHF received 1 L less of IV fluids on admission compared to those without a history of CHF with no difference in mortality. Data on whether or not patients met the SSC hour-1 bundle criteria was collected. This study hopes to expand further on this topic by looking at patients with the diagnosis of “Hypertensive Heart Disease with Heart Failure”—International Classification of Diseases (ICD)10 code: I11.0 who were hospitalized with a diagnosis of sepsis. We will compare their mortality rate outcomes with patients who were hospitalized with sepsis only and see if there is any variability in sepsis outcomes given the presence of CHF as a comorbidity. We will present the following article in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist.
Research study design
A retrospective clinical study was designed to investigate outcomes of septic patients treated at Freeman Hospital in Joplin, MO. This hospital is one of two major centers in Southwest MO that serves the four-state area of Oklahoma, Arkansas, Kansas, and Missouri. By using patients from the same regional area, within the same hospital, we hoped to limit confounding outside factors. Data from January 1, 2019 to June 27, 2020 was collected via electronic medical records (EMR). Inclusive criteria included a diagnosis of sepsis for all patients selected using the ICD codes in Table 1. In addition, for the study group, a diagnosis of hypertensive heart disease with heart failure, specifically ICD code I11.0 was selected. This ICD code was chosen because it included the largest patient population from our data set, which amounted to 184 individuals. In order to isolate our study group, we excluded ICD codes: 150.31, 150.33, 150.43, 150.23, 150.21, 150.32, 150.42, 150.22, 127.81, I11.0, I13.0, I13.2, 126.09, 150.9, and 150.20 from the baseline group (Table 2). This allowed us to reduce the number of patient duplications, as many patients admitted with sepsis had multiple ICD codes pertaining to heart failure. There were no restrictions in terms of age, gender, ethnicity, or other health history.
Table 1 -
ICD-10 Inclusion Criteria for All Patients
||Sepsis due to streptococcus, group A
||Sepsis due to streptococcus, group B
||Sepsis due to Streptococcus pneumonia
||Other streptococcal sepsis
||Streptococcal sepsis, unspecified
||Sepsis due to Methicillin susceptible Staphylococcus aureus
||Sepsis due to Methicillin resistant Staphylococcus aureus
||Sepsis due to other specified staphylococcus
||Sepsis due to unspecified staphylococcus
||Sepsis due to Haemophilus influenza
||Sepsis due to anaerobes
||Gram-negative sepsis, unspecified
||Sepsis due to Escherichia coli [E. coli]
||Sepsis due to Pseudomonas
||Sepsis due to Serratia
||Other Gram-negative sepsis
||Sepsis due to Enterococcus
||Other specified sepsis
||Sepsis, unspecified organism
||Severe sepsis without septic shock
||Severe sepsis with septic shock
ICD, International Classification of Diseases.
Table 2 -
ICD-10 Codes Excluded in Baseline Group
|Acute Diastolic Heart Failure
|Acute on Chronic Diastolic Heart Failure
|Acute on Chronic Systolic and Diastolic Heart Failure
|Acute on Chronic Systolic Heart Failure
|Acute Systolic Heart Failure
|Chronic Diastolic Heart Failure
|Chronic Systolic and Diastolic Heart Failure
|Chronic Systolic Heart Failure
|HHD and CKD with Heart Failure and Stag1 Through
|4 CKD or NOS
|HHD with Heart Failure
|Pulmonary Embolism NEC with Acute Cor Pulmonale
|Right Heart Failure NOS
|Systolic Heart Failure NOS
CKD, chronic kidney disease; HHD, hypertensive heart disease; ICD, International Classification of Diseases; NEC, not elsewhere classifiable; NOS, not otherwise specified.
Our baseline group, or patients with sepsis but without the diagnoses listed in Table 2, consisted of 348 people. Within this group, there were 178 males (52%) and 170 females (48%). Additionally, 264 patients were over the age of 65 (79%), with a mortality rate of 30%. Within these groups, there were 94 mortalities (27%), 50 females (30%), and 44 males (25%) (Table 3).
Table 3 -
Total Mortality Difference between Sepsis
Only and Sepsis
with HTN/HF Comorbidity
||Baseline Patient Mortalities
||HTN HF Patients
||HTN HF Patient Mortalities
HF, heart failure; HTN, hypertension.
The baseline group was further broken down into those that met the sepsis bundle criteria and those that failed bundle criteria. Of the group, 65 patients met the bundle criteria; 29 were males (45%) and 36 were females (55%). Of this cohort, there were 12 mortalities; 7 were females (20%) and 5 were males (17%) (Table 4). There were 87 patients that failed the bundle criteria; 52 were males (60%) and 35 were females (40%). Of the group that failed to meet the bundle criteria, there were 25 mortalities; 11 were females (31%) and 14 were males (27%) (Table 4).
Table 4 -
Difference in Mortality Rate for Met vs Failed Bundle within the Baseline and HTN HF Groups
|Baseline patient total
|Baseline patients met bundle
|Baseline patients failed bundle
|HTN HF patient total
|HTN HF patients met bundle
|HTN HF patients failed bundle
HF, heart failure; HTN, hypertension.
We identified 184 patients with hypertensive heart disease and heart failure as a diagnosis for comparison. This group was further broken down into 88 male patients (48%) and 96 female patients (52%). Within this group, there were 37 mortalities (20%), 18 males (20%), and 19 females (20%). Additionally, this group contained 111 patients over the age of 65 (60%) with a specific mortality rate of 30% (Table 4).
We stratified the study group based on whether or not they met or failed sepsis bundle criteria. There were 35 patients that met the bundle criteria, 12 male patients (34%) and 23 female patients (66%), and a total of 4 mortalities—1 male patient (8%) and 3 female patients (13%). On the other hand, 50 patients in the study group failed to meet sepsis bundle criteria; 31 were men (62%) and 19 were women (38%). There were 14 mortalities; 9 were men (64%) and 5 were women (36%) (Table 4).
The purpose of this study was to determine whether heart failure is associated with worse mortality outcomes in patients with sepsis. This was further broken down into the differences in mortality between genders with and without heart failure, between patients that initially met sepsis bundle criteria and those that did not, and between patients that were over the age of 65 compared to those below the age of 65.
We did not find any statistically significant results between patients with and without the diagnosis of hypertensive heart disease with heart failure. Unfortunately, the patient sample size for the bundle criteria groups was not large enough to perform statistical analyses.
There were several limitations in this study. Given the retrospective nature, data may have been absent for some patients. Additionally, in order to effectively isolate a study group, several ICD codes were excluded from the final patient population that may have affected data outcomes. Because all data were collected on patients from a single-center, the outcomes may not be generalizable.
Given the delicate balance between maintaining proper tissue perfusion in sepsis and attempting to limit the positive fluid balance associated with worse mortality outcomes in patients with sepsis, further studies should look at CHF as a comorbidity. Specifically, the added difficulties with fluid balance encountered in this patient population.
Patients were not randomly selected from the population. Therefore, we are uncertain whether the samples are representative of their respective populations. This study is further limited due to the inability to completely isolate the effects of heart failure on sepsis. We also acknowledge that there are numerous billing codes for heart failure. By choosing to focus on "Hypertensive Heart Disease with Heart Failure" and eliminate patients coded under multiple heart failure diagnoses, some patients may have been excluded unintentionally Additionally, there are numerous other comorbid conditions that negatively contribute to a patient's prognosis and while we focused on heart failure, we recognize that other diagnoses can account for increased mortality. We did not have access to echocardiogram results and were thus unable to break down the stages of heart failure severity which may play a significant role in CHF's effect on sepsis mortality rates. Data on medications and fluid type or volume administered was also not collected and we acknowledge that these could have an impact on renal perfusion and sepsis recovery rates. Unfortunately, we were unable to run any statistical analysis between the groups when we sought to investigate whether the mortality in HTN/HF septic patients was impacted by SEP-1 Bundle compliance. Data on bundle compliance was only available for 85 of our 184 patients, and thus comparisons between the 2 groups were too small for any statistical analysis. Lastly, we chose to focus on mortality as the primary outcome. We deemed this to be the most valuable indication of treatment success, as it was not possible to directly correlate the length of stay with sepsis resolution.
There were no significant differences detected between the baseline group and the hypertensive heart disease with heart failure group. This does not mean there are no differences; rather, no significance was found within this population using the statistical tests we performed. While our hypothesis that CHF as a comorbidity in septic patients would worsen mortality outcomes was not proven statistically, further studies should investigate the association between the two diseases. A larger population, increased data stratification with heart failure severity and a more focused look on fluid resuscitation volumes may yield significant results and warrants further investigation.
Conflict of interest statement
The authors declare no conflict of interest.
All authors participated in conception and design, provision of study materials or patients, collection and assembly of data, data analysis and interpretation, and manuscript writing. Sloan SNB, Arnce R, Goade S, Stahl G, and Johnson K contributed to administrative support. All authors approved the final manuscript.
Ethical approval of studies and informed consent
The authors 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved and written informed consent was waived by the institutional ethics board of Freeman Health System under the Protocol Title: The Surviving Sepsis Campaign and Its Effect on Patient Populations with Sepsis and Preexisting Comorbidities (8/24/2020), owing to the anonymized retrospective nature of the analysis.
We would like to thank Shelly Sloan, Gregory Stahl, Dr Kerry Johnson, Dr Scott Goade, and Dr Robert Arnce for their assistance with this project.
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