Sepsis,Septic Shock,and Differences in Cardiovascular Event Occurrence

Abstract

Introduction: Mortality estimates from sepsis and septic shock ranged from 18% to 35% and 40% to 60%, respectively, prior to 2014. Sepsis patients who experience subsequent cardiovascular events have increased mortality; however, data are limited among septic shock patients. This study reports in-hospital mortality, incident cardiovascular events, and cardiovascular procedures among sepsis patients with and without subsequent septic shock. Methods: Patients with a primary diagnosis of sepsis with and without a secondary diagnosis of septic shock were identified from the 2016 and 2017 National Readmissions Database. These patients were then evaluated for the occurrence of cardiovascular events and procedures. Results: A total of 2,127,137 patients were included in the study, with a mean age of 66 years. Twenty percent of patients (n = 420,135) developed subsequent septic shock. In-hospital mortality among patients with a primary diagnosis of sepsis was 5.3%, and it was 31.2% for those with subsequent septic shock. Notable cardiovascular events occurring among sepsis patients with and without subsequent septic shock, respectively, included: acute kidney injury (65.1% vs. 32.8%, P < .0001), acute systolic heart failure (9.8% vs. 5.1%, P < .0001), NSTEMI (8.8% vs. 3.2%, P < .0001), and ischemic stroke (2.3% vs. 0.9%, P < .0001). Similarly, the most common cardiovascular procedures between the two groups were: percutaneous coronary intervention (0.37% vs. 0.20%, P < .0001), intra-aortic balloon pump (0.19% vs. 0.02%, P < .0001), and extracorporeal membrane oxygenation (0.18% vs. 0.01%, P < .0001). Conclusions: Sepsis with subsequent septic shock is associated with an increased frequency of in-hospital cardiovascular events and procedures.

Keywords

sepsis septic shock acute kidney injury myocardial infarction heart failure

Introduction

Acute myocardial infarction (AMI) and stroke account for more than 250,000 deaths annually in the United States,¹ with more than 800,000 cases of AMI² and more than 795,000 strokes.³ These cardiovascular events commonly occur in association with underlying disease states,⁴ including sepsis.⁵ Sepsis, with more than 1.5 million annual cases,⁶ and its progression to septic shock,⁷ have mortalities of 18% to 30% and 40% to 60%, respectively.⁸ Sepsis causes an excessive, systemic inflammatory response with tissue hypoperfusion, hypoxia, and organ dysfunction,^9–11 which can lead to various complications,¹² including AMI,^13–15 stroke,^13–16 acute heart failure,^13,17,18 cardiogenic shock,¹⁹ and acute kidney injury (AKI).^20,21 Together, heart diseases, stroke, and sepsis are 3 of the 10 leading causes of death among U.S. adults.²²

The significant mortality associated with sepsis and septic shock led to several treatment guideline updates, guideline implementation campaigns, and changes in diagnostic criteria of sepsis and septic shock between 2012 and 2015, associated with decreased sepsis and septic shock mortality.^23–29 However, no national research has investigated the frequency of cardiovascular events among sepsis patients since these recent treatment and diagnostic classification changes. Additionally, no previous national research has compared cardiovascular event frequency between sepsis and septic shock patients. Therefore, the purpose of this study was to investigate the frequency of acute cardiovascular events among patients hospitalized with sepsis and septic shock. Specifically, we investigated the frequency of in-hospital AKI, acute heart failure, AMI, cardiogenic shock, stroke, and transient ischemic attack (TIA) after a primary diagnosis of sepsis with and without subsequent septic shock.

Methods

Adult patients (18 years and older) were included in this study if they had a primary diagnosis of sepsis (identified by using ICD-10 codes) in the National Readmission Database (NRD; Appendix Table A) from 2016 and 2017.³⁰ Patients older than 90 years were considered to be 90 years. Pregnancy-related sepsis and pregnancy-related septic shock ICD-10 codes were excluded.

This study was conducted by using the Healthcare Cost and Utilization Project's NRD core files from 2016 and 2017.³¹ The NRD is the largest, all-payer readmission database in the U.S., including 58% of U.S. hospital stay data from 28 states.³² Using a large, stratified national database such as the NRD minimizes regional influences on disease states and outcomes.

Demographic variables (eg, age, sex) were abstracted using demographic codes in the NRD files (Appendix Table B). Primary outcome variables included in-hospital mortality, in-hospital cardiovascular events, and cardiac procedures. Mortality, length of stay, and form of insurance were abstracted from the NRD database (Appendix Table B). Cardiovascular events were abstracted from the NRD database based on ICD-10 codes. They included AKI, acute heart failure, AMI, cardiogenic shock, and stroke (Appendix Table C). Cardiac procedures (eg, percutaneous coronary intervention or PCI) were abstracted using procedure codes (Appendix Table D). Comorbidities were assessed using ICD-10 codes from the Elixhauser Comorbidity Index,³³ a scoring system containing 31 comorbidities associated with increased length of hospital stay, increased mortality, and increased hospital readmission.^33–35

This study was considered “not human subjects” research by the University of Kansas Medical Center's Human Research Protection Program. It was assumed that a primary diagnosis of sepsis (diagnosis 1) indicated that a patient was hospitalized for sepsis and not for a primary cardiovascular event. By selecting patients with a primary diagnosis of sepsis, the researchers excluded patients that presented to the hospital experiencing a primary cardiovascular event. Secondary diagnoses of acute cardiovascular events or cardiac procedures used during hospitalization indicated that a patient developed a cardiovascular event or underwent a cardiac procedure after hospitalization for sepsis. Additionally, the forms of cardiovascular support included in this analysis are only implemented in the setting of severe cardiac distress, indicating that the patients receiving these forms of mechanical support did not present to the hospital for these procedures, but rather were ill from other causes, such as sepsis or acute cardiovascular events, at the time of the procedure. It was also assumed that a secondary diagnosis of septic shock suggested that the patient developed septic shock after hospitalization for sepsis.

Pearson's chi-square, likelihood ratio chi-square, and Fisher's exact tests were used to test the association between categorical and nominal variables. The propensity score was run before analyses because there may have been systematic differences between the frequency of cardiovascular events in patients who experienced sepsis or septic shock using ICD codes. This score plays an essential role in balancing the study groups to make them comparable and reduce selection bias for the parameter estimates. Generalized logistic regression model with Firth-type penalization method to reduce the bias of maximum likelihood estimations was used to test for associations between the presence or absence of septic shock and mortality, cardiovascular event, or cardiovascular procedure occurrence. All statistical tests at P ≤ .05 were considered significant. Statistical Analysis System (SAS) version 9.4 (SAS/STAT, SAS Inst., Inc. Carry, NC) was used for all data analyses.

Results

In total, 2,127,137 patients met the inclusion criteria and 50.6% were female (n = 1,075,818). The mean age was 65 years for patients experiencing sepsis alone and 67 years for patients experiencing sepsis with subsequent septic shock. The mean length of hospitalization was 7 days for patients with sepsis without septic shock and 11 days for sepsis patients experiencing subsequent septic shock. The median length of hospitalization for sepsis patients without septic shock was 4 days and 7 days for sepsis patients with septic shock.

Comorbidities among the study population were reported using the Elixhauser comorbidity index (Table 1). The most common comorbidities included: hypertension, fluid and electrolyte disturbances, diabetes mellitus, deficiency anemias, and chronic pulmonary disorders.

Table 1.

Elixhauser Comorbidity Index.

Comorbidity	Patients with Sepsis with Subsequent Septic Shock (n = 420,135)	Patients with Sepsis Alone (n = 1,707,002)
Alcohol abuse	6.3% (26,317)	4.3% (73,496)
Blood loss anemia	1.3% (5,603)	0.9% (15,427)
Cardiac arrhythmias	38.1% (160,140)	25.4% (434,040)
Chronic peptic ulcer disease	2.4% (10,046)	1.2% (20,652)
Chronic pulmonary disorders	29.1% (122,447)	29.3% (499,787)
Coagulation disorders	26.8% (112,700)	10.8% (183,646)
Coagulopathy	0.1% (158)	0.1% (1,169)
Congestive heart failure	31.6% (132,851)	21.3% (363,228)
Deficiency anemias	36.0% (151,361)	29.0% (495,110)
Depression	12.2% (51,292)	13.9% (238,124)
Diabetes mellitus	36.7% (154,028)	36.6% (625,221)
Drug abuse	5.5% (23,254)	6.3% (108,264)
Fluid and electrolyte disturbances	76.5% (321,282)	54.9% (937,267)
HIV/AIDS	0.6% (2,542)	0.5% (9,224)
Hypertension	63.0% (264,594)	64.4% (1,099,844)
Hypothyroidism	15.4% (64,637)	14.7% (250,921)
Liver disease	17.8% (74,773)	7.4% (126,963)
Lymphoma	2.4% (9,908)	1.7% (28,240)
Metastatic cancer	6.8% (28,417)	4.4% (75,800)
Neurological disorders other than paralysis	39.5% (166,163)	25.1% (428,070)
Obesity	17.0% (71,396)	17.5% (298,028)
Paralysis	9.6% (40,466)	7.3% (124,141)
Peripheral vascular disorders	10.0% (42,166)	8.2% (139,301)
Pulmonary circulation disorders	8.3% (35,020)	5.2% (88,647)
Psychoses	4.8% (20,068)	4.7% (80,559)
Renal failure	29.7% (124,571)	23.0% (392,638)
Rheumatoid arthritis/collagen vascular disorders	4.2% (17,588)	4.2% (71,653)
Solid tumor without metastases	10.0% (41,951)	7.4% (125,982)
Valvular heart disease	9.1% (38,263)	7.0% (120,066)
Weight loss	25.1% (105,342)	14.3% (244,195)

One-fifth of patients with a primary diagnosis of sepsis (19.8%, n = 420,135) experienced subsequent septic shock during their hospital stay. The mortality among patients with a primary diagnosis of sepsis without septic shock was 5.3%, whereas those with a subsequent septic shock diagnosis were 31.2% (Table 2). Males were slightly more likely to die than females among patients experiencing sepsis alone (P = .027) and those experiencing sepsis with subsequent septic shock (P = .004).

Table 2.

Mortality, Cardiovascular Outcomes, and Cardiovascular Procedures.

Outcome	Patients with Sepsis with Subsequent Septic Shock (19.8%; n = 420,135)	Patients with Sepsis Alone (80.2%; n = 1,707,002)	P-value	95% Confidence Interval for Frequency Difference	Logistic Regression Odds Ratio (95% CI)
Mortality
Male mortality	31.4% (66,672)	5.3% (44,491)	<.0001	(0.259, 0.263)	0.142 (0.140, 0.144)
Female mortality	31.0% (64,520)	5.2% (45,352)	<.0001	(0.250, 0.256)	0.150 (0.149, 0.152)
Cardiovascular Events
AKI	65.1% (273,331)	32.8% (559,834)	<.0001	(0.321, 0.324)	0.262 (0.260, 0.264)
Cardiogenic Shock	2.8% (11,949)	0.3% (5,350)	<.0001	(0.025, 0.026)	0.107 (0.104, 0.111)
Acute heart failure
Acute diastolic heart failure	11.0% (46,269)	9.0% (153,736)	<.0001	(0.019, 0.021)	0.800 (0.791, 0.809)
Acute systolic heart failure	9.8% (41,273)	5.1% (87,454)	<.0001	(0.046, 0.048)	0.496 (0.490, 0.502)
Combined acute diastolic and systolic heart failure	3.5% (14,597)	1.9% (33,019)	<.0001	(0.015, 0.016)	0.548 (0.537, 0.559)
AMI
NSTEMI	8.8% (36,966)	3.2% (55,251)	<.0001	(0.055, 0.057)	0.347 (0.342, 0.351)
STEMI	0.9% (3,983)	0.2% (4,026)	<.0001	(0.0068, 0.0074)	0.247 (0.236, 0.258)
Stroke
Ischemic stroke	2.3% (9,620)	0.9% (16,127)	<.0001	(0.013, 0.014)	0.407 (0.397, 0.417)
Hemorrhagic stroke	0.7% (2,812)	0.3% (4,521)	<.0001	(0.0038, 0.0043)	0.394 (0.376, 0.413)
TIA	0.1% (568)	0.1% (2,511)	.069	(−0.00024, 0.0000060)	1.088 (0.993, 1.192)
Cardiovascular Procedures
PCI	0.37% (1,570)	0.20% (3,495)	<.0001	(0.0015, 0.0019)	0.547 (0.515, 0.581)
Intra-aortic balloon pump (IABP)	0.19% (805)	0.02% (406)	<.0001	(0.0015, 0.0018)	0.124 (0.110, 0.140)
Extra corporeal membrane oxygenation (ECMO)	0.18% (759)	0.01% (158)	<.0001	(0.0016, 0.0018)	0.051 (0.043, 0.061)
Impella	0.04% (167)	0.01% (110)	<.0001	(0.00027, 0.00039)	0.162 (0.127, 0.206)

Several cardiovascular events occurred more frequently among patients who experienced septic shock (Table 2 and Figure 1). Sepsis patients with subsequent septic shock experienced twice the frequency of AKI (65.1%, n = 273,331) and non-ST elevated AMI (NSTEMI, 8.8%, n = 36,966) compared to those with sepsis alone (32.8%, n = 559,834 for AKI and 3.2%, n = 55,251 for NSTEMI). Additional differences in cardiovascular event frequencies between patients with septic shock and those with sepsis alone included: acute heart failure (24.3%, n = 102,139 and 16.0%, n = 274,209), cardiogenic shock (2.8%, n = 11,949 and 0.3%, n = 5350), and ischemic stroke (2.3%, n = 9620 and 0.9%, n = 16,127). Although cardiovascular procedures were relatively uncommon among the study population, they generally occurred at a greater frequency for patients who experienced septic shock than sepsis alone.

Discussion

The mortality findings from this study are similar to those previously reported for 2016 and 2017.²⁹ Still, in the current analysis, mortality among patients experiencing septic shock was nearly six times greater than those with sepsis alone. This suggests worse outcomes and a potentially more challenging clinical course for patients experiencing septic shock. In addition to the increased mortality among patients who experience septic shock, this study also suggests that in-hospital cardiovascular events occur more frequently among sepsis patients with subsequent septic shock than among patients with sepsis alone, especially AMI (both NSTEMI and STEMI), AKI, acute heart failure, cardiogenic shock, and ischemic stroke. This study was the first to report cardiovascular event occurrences among sepsis patients experiencing subsequent septic shock (except AKI³⁶⁾ and compare cardiovascular event occurrences among sepsis patients with and without subsequent septic shock.

It is difficult to determine one single underlying factor that could account for the increased occurrence of cardiovascular events among sepsis patients with subsequent septic shock compared to patients with sepsis alone. Potential differences in disease severity and pathophysiology between sepsis and septic shock could have contributed to the findings in the current study, as septic shock is a more severe form of sepsis with significant hypotension and elevated blood lactate levels, ultimately leading to worse organ ischemia and dysfunction in septic shock patients.^8,23 Organ ischemia can cause several of the cardiovascular events evaluated in this study, including AKI and ischemic stroke.^37,38 Additionally, prolonged endothelial damage that occurs in both sepsis and septic shock is associated with end-organ damage; however, this endothelial damage appears to be most severe in septic shock.³⁹ Outside of organ damage, sepsis-induced coagulation, an increased likelihood of forming thrombi in sepsis and septic shock, is also associated with endothelial damage.³⁹ Thrombi can cause several cardiovascular events evaluated in the current study, such as AMI and ischemic stroke.^40,41 Lastly, sepsis-induced cardiomyopathy, a form of cardiac dysfunction occurring in sepsis and septic shock that is poorly defined, can lead to ventricular dysfunction and altered cardiac output. Septic cardiomyopathy occurs more frequently among patients with elevated lactate levels,^42,43 indicating that septic cardiomyopathy could occur more frequently among septic shock patients. Overall, many pathophysiological components of sepsis and septic shock appear to be more severe among septic shock patients than those with sepsis alone. This could contribute to the differences in cardiovascular event frequencies between sepsis patients with and without subsequent septic shock observed in the current analysis. With future research, an improved understanding of the pathophysiology contributing to differences in disease states between sepsis and septic shock could clarify underlying mechanisms contributing to the current study's findings.

Unlike septic shock, the occurrence of select cardiovascular events among patients diagnosed with sepsis were reported;^{13–17,19–21} however, these data were collected before 2016. From 2002 to 2011, national data found that 4.5% of sepsis patients experienced an in-hospital AMI, with the majority being NSTEMI,¹⁴ as in the current study. Additionally, AMI occurrence was 4.4% among sepsis patients in a 2011–2014 national study;¹⁵ however, neither of these studies differentiated AMI frequency among patients who experienced subsequent septic shock from patients with sepsis alone. When comparing the current analysis to previous research, a similar frequency of AMI occurrence (4.7%) among all patients with a primary diagnosis of sepsis was observed. This indicates that AMI occurrence among sepsis patients has remained relatively constant despite updates to sepsis and septic shock treatments.^23–29,44

Similar to AMI, AKI occurrence among sepsis patients has been evaluated in prior studies; however, national epidemiological data from the U.S. are lacking.⁴⁵ AKI occurrence among septic shock patients has been reported since the early 2000s, finding that among ICU patients experiencing an AKI, approximately 50% were associated with septic shock;³⁶ however, this multinational data was limited by only including ICU patients. There are many potential causes of AKI among these patient populations, some of which could include hypoperfusion from sepsis, cardiorenal syndrome, or nephrotoxic medications.⁴⁶ Therefore, it is difficult to accurately compare the prior estimates of AKI occurrence among sepsis and septic shock patients to the current analysis findings. It is also difficult to precisely determine why AKIs occurred more frequently among patients experiencing sepsis with subsequent septic shock.

Although acute heart failure frequencies among sepsis patients have been reported,^13,17 the data are from small studies that lack generalization. At the same time, this analysis used a national database and further investigated differences in the occurrence of these events based on whether patients experienced subsequent septic shock. Both cardiovascular event risk factors and sepsis survival have historically varied between different U.S. regions,^47,48 which could exacerbate differences between cardiovascular event occurrences reported in regional studies compared to the current national analysis. Therefore, it is difficult to compare the current analysis observations for acute heart failure occurrence among patients experiencing sepsis to previous regional studies. Still, some notable differences in disease frequencies of acute heart failure were observed in this study.

Acute systolic heart failure occurred nearly twice as often among patients with subsequent septic shock compared to patients with sepsis alone (9.8% vs. 5.1%, P < .0001), while the difference in the occurrence of acute diastolic heart failure between the two groups was 11.0% and 9.0% (P < .0001). The diagnosis of acute heart failure in the septic patient is admittedly difficult due to multiple changing hemodynamic parameters throughout sepsis and septic shock progressions. For example, cardiac output is thought to increase early in sepsis and septic shock; however, cardiac output decreases as septic shock progresses.⁴³ Additionally, changes in preload and mean arterial pressure throughout the progression of sepsis and septic shock complicate the diagnosis of acute diastolic heart failure in this patient population. Overall, a detailed discussion on the interactions between hemodynamic changes in sepsis and septic shock induced by a severe inflammatory response and the development of acute heart failure are beyond the scope of this study. However, given the morbidity associated with acute heart failure,⁴⁹ the topic warrants further research.

Cardiogenic shock, a disease characterized by acute, decreased cardiac output,⁵⁰ can occur following various cardiovascular stressors. The current analysis was the first to evaluate the occurrence of cardiogenic shock among patients diagnosed with sepsis and septic shock. In the current analysis, the frequency of cardiogenic shock was considerably higher among patients who experienced subsequent septic shock than those with sepsis alone (2.8% vs. 0.3%, P < .0001). These findings could be due to various pathologies associated with cardiogenic shock, such as septic cardiomyopathy or acute heart failure, or to some inherent differences between sepsis and septic shock.

Similar to acute heart failure, stroke frequency among sepsis patients has been previously explored in small studies^13,16 that cannot be generalized to the current analysis. In the current study, ischemic stroke was more common among sepsis patients with subsequent septic shock than sepsis alone (2.3% vs. 0.9%, P < .0001). Ischemic stroke is commonly caused by a thrombus or embolus within the brain vasculature;⁴¹ however, ischemic stroke can also be caused by hypotension and brain hypoperfusion.³⁸ Therefore, several of the potential underlying mechanistic differences between sepsis and septic shock could be contributing to the differences in ischemic stroke occurrence observed in the current study. Interestingly, unlike an ischemic stroke, there was no statistically significant difference in transient ischemic attack (TIA) occurrence between sepsis patients with and without subsequent septic shock (0.1% vs. 0.1%, P = .0935). This could mean that there is no increased risk of developing TIA between sepsis and septic shock patients, or it could reflect possible underdiagnoses of TIA.⁵¹

Like cardiovascular events among septic shock patients, little prior research has investigated the use of interventional cardiovascular procedures among sepsis and subsequent septic shock patients. This study also reported and compared the most common interventional cardiovascular procedures between sepsis patients with and without subsequent septic shock. In a prior national study from 2002–2011, 0.1% of patients hospitalized with sepsis underwent PCI,¹⁴ which is almost similar to the 0.2% of the current study population that experienced PCI; however, a more significant percentage of those experiencing AMI had a STEMI in the previous data compared to the current analysis (28.6%¹⁴ vs. 8.0%).

In addition to PCI, this study also reported the use of mechanical support forms of cardiovascular procedures among sepsis and septic shock patients, such as extracorporeal membrane oxygenation (ECMO). These forms of mechanical support are cumbersome procedures only performed during severe cardiac compromise. Additionally, these percutaneous endovascular procedures introduce a slight increase in patients’ risk of developing bacteremia and subsequent septic shock.⁵² While ECMO use to treat septic shock patients was relatively low in this study (0.19%), data published since 2017 suggest that ECMO may improve outcomes among select septic shock patients,^53,54 such as patients experiencing septic shock and subsequent cardiogenic shock.⁵⁵ However, any routine implementation of mechanical support devices among patients experiencing septic shock remains unlikely at this time due to a lack of substantial evidence to support widespread expansion.

Using an extensive, national database such as the NRD, which can only be searched via diagnosis codes, relies on correct coding for each patient by the hospital and during data abstraction. Any errors in coding can inadvertently introduce unwanted data or omit desired data. Additionally, because of the nature of the NRD, several assumptions were made about the order of events based on the numbering of diagnosis codes within the database, as noted in the methods section. If there were errors in the order that these diagnoses were coded, these assumptions could be invalid, thus potentially introducing error into this study. Even with these limitations, the large sample size of the data and the differences in outcomes between the two groups in this study lead the research team to believe that these assumptions did not contribute substantial error into the study findings.

Conclusions

This study suggests that sepsis patients who develop subsequent septic shock experience a greater frequency of in-hospital cardiovascular events and are more likely to undergo an interventional cardiovascular procedure than sepsis patients without subsequent septic shock.

Supplemental Material

sj-docx-1-jic-10.1177_08850666221083644 - Supplemental material for Sepsis, Septic Shock, and Differences in Cardiovascular Event Occurrence

Supplemental material, sj-docx-1-jic-10.1177_08850666221083644 for Sepsis, Septic Shock, and Differences in Cardiovascular Event Occurrence by Grace E. Falk, Jerad Rogers, Liuqiang Lu, Elizabeth Ablah, Hayrettin Okut and Mohinder R. Vindhyal in Journal of Intensive Care Medicine

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dean's Level One Grant from the University of Kansas School of Medicine-Wichita.

Ethical Approval

Not applicable, because this article does not contain any studies with human or animal subjects.

ORCID iDs

Grace E. Falk

Mohinder R. Vindhyal

Supplemental Material

Supplemental material for this article is available online.

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