Impact of Cirrhosis on Outcomes in Patients with Septic Shock

Keywords

Sepsis 1; Septic Shock 2; Cirrhosis 3.

Abstract

Background: Patients with cirrhosis are at increased risk of sepsis due to cirrhosis-associated immune dysfunction, bacterial translocation, and hemodynamic derangements. However, large-scale propensity matched data comparing outcomes between cirrhotic and non-cirrhotic patients with septic shock remain limited. This study aimed to evaluate the impact of cirrhosis on mortality, renal, hemorrhagic, thromboembolic, and respiratory outcomes in patients with septic shock.

Methods: We conducted a retrospective propensity score-matched cohort study using the US Collaborative Network from 43 healthcare organizations in the TriNetX research network. Patients with septic shock were identified using ICD-10 CM codes and stratified by the presence or absence of cirrhosis. Propensity score matching (1:1) was performed for age, sex, race, BMI, diabetes, and baseline laboratory values, yielding 96,986 patients per cohort. Outcomes included mortality, acute kidney injury (AKI), continuous renal replacement therapy (CRRT), disseminated intravascular coagulation (DIC), gastrointestinal bleeding (GIB), intracranial hemorrhage (ICH), pulmonary embolism (PE), hospital-acquired pneumonia (HAP), and mechanical ventilation. Cross-sectional risk analysis and Kaplan-Meier survival analysis with hazard ratios (HR) were performed.

Results: Patients with cirrhosis and septic shock had significantly higher mortality compared to non-cirrhotic patients (32.8% vs 27.3%; HR 1.23, 95% CI 1.21–1.25, p = 0.001). Cirrhosis was associated with significantly increased risks of AKI (39.0% vs 34.1%; HR 1.18, 95% CI 1.16–1.20, p = 0.001), CRRT (8.2% vs 6.0%; HR 1.39, 95% CI 1.34–1.44, p = 0.001), DIC (2.3% vs 1.4%; HR 1.68, 95% CI 1.57–1.80, p = 0.001), GIB (7.6% vs 4.6%; HR 1.67, 95% CI 1.61–1.73, p = 0.001), and mechanical ventilation (22.5% vs 19.3%; HR 1.18, 95% CI 1.16–1.21, p = 0.001). There was no significant difference in ICH (HR 1.01, p = 0.906) or HAP (HR 0.96, p = 0.371). PE risk was marginally lower in cirrhotic patients on cross-sectional analysis (RR 0.95, p = 0.025) but did not reach significance on survival analysis (HR 0.96, p = 0.054).

Conclusions: In this large propensity score-matched cohort, cirrhosis was independently associated with significantly higher rates of mortality, AKI, CRRT, DIC, GIB, and mechanical ventilation in patients with septic shock. These findings highlight the need for early aggressive management and close monitoring of hemorrhagic, renal, and coagulation complications in cirrhotic patients presenting with septic shock.

Citation

Grover P, Kaur G, Jain R, Singh K, Singh B, (2026) Ferritin as a Prognostic Marker for Mortality and Critical Inpatient Outcomes in the Alco hol Related Hepatitis Population . J Gen Med 6(1): 1025.

INTRODUCTION

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and septic shock represents its most severe form, characterized by circulatory and cellular/metabolic abnormalities that substantially increase mortality [1]. Patients with cirrhosis are disproportionately affected; approximately one-third of hospitalized cirrhotic patients develop bacterial infections, and the risk of sepsis is 2.6 times higher than in patients without underlying liver disease [1,2]. Approximately two-thirds of cirrhotic patients with extrahepatic organ failure have sepsis, and mortality associated with septic shock in this population approaches 65% [3]. One-third of patients hospitalized for cirrhosis develop sepsis, and 6% develop septic shock [4]. The most prevalent infections in patients with cirrhosis are spontaneous bacterial peritonitis and urinary tract infections, followed by pneumonia, spontaneous bacteremia, and skin and soft tissue infections [3-5]. Of increasing concern is the rising prevalence of multidrug resistant organisms, which account for approximately 35% of infections in cirrhotic patients and are associated with higher rates of treatment failure [1-5].

Cirrhosis-associated immune dysfunction (CAID) is a well characterized syndrome encompassing both systemic inflammation and immunodeficiency that predisposes patients to infection and its complications [1]. The liver plays a central role in systemic immunity through the synthesis of complement components, acute-phase proteins, and pattern recognition receptors; cirrhosis impairs this function, compromising the opsonization and bactericidal capacity of phagocytic cells [1-6]. Concurrently, in-creased gut permeability, reduced gut motility, and intestinal dysbiosis promote bacterial translocation from the gut lumen into the systemic circulation [7-8]. As cirrhosis progresses, the immune phenotype shifts from a predominantly pro-inflammatory state to one of immune paralysis, with functional defects in neutrophils, monocytes, and lymphocytes that critically impair pathogen clearance [1 9]. Com-pounding this vulnerability, relative adrenal insufficiency (RAI) is present in up to 49% of hospitalized patients with decompensated cirrhosis and is independently associated with higher risks of sepsis, septic shock, organ failure, and 90-day mortality [10,11]. The term “hepato-adrenal syndrome” has been proposed to describe this entity, which reflects impaired cortisol synthesis due to decreased high-density lipoprotein cholesterol substrates for steroidogenesis and cytokine mediated adrenal suppression [1-11].

Patients with cirrhosis are particularly susceptible to acute kidney injury (AKI), which occurs in up to 50% of hospitalized cirrhotic patients and up to 80% of those admitted to the intensive care unit [12]. The hemodynamic alterations of portal hypertension: splanchnic vasodilation, reduced effective arterial blood volume, and compensatory activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, result in renal vasoconstriction and decreased renal blood flow [1]. Bacterial infections further exacerbate this physiology through the release of vasodilatory cytokines and systemic inflammatory mediators, making infection one of the most common precipitants of AKI and hepatorenal syndrome in this population [1-12].

Coagulation disturbances in cirrhosis add another layer of complexity to the management of septic shock. Although cirrhotic patients exist in a “rebalanced” hemostatic state due to a parallel decline in both pro- and anticoagulant factors, this equilibrium is fragile and easily disrupted by acute illness [13]. Sepsis-induced endothelial damage, combined with impaired hepatic synthesis of both procoagulant factors (II, VII, IX, X) and anticoagulant proteins (protein C, protein S, antithrombin), can tip the balance toward disseminated intravascular coagulation (DIC) or hemorrhage [13,14]. Portal hypertension-related variceal disease, coagulopathy, and sepsis-induced stress gastropathy collectively place cirrhotic patients at elevated risk for gastrointestinal bleeding, which is recognized as a major risk factor for clinically important upper gastrointestinal hemorrhage in critically ill adults [15,16]. Conversely, the risk of venous thromboembolism, including pulmonary embolism, in cirrhotic patients remains debated; some studies suggest a 1.7-fold increased risk of VTE, while others report that severe liver dis-ease may attenuate thrombotic risk [17,18].

In this study, we aimed to evaluate the impact of cirrhosis on clinical outcomes in patients admitted with septic shock using a large, propensity score-matched retrospective cohort from the TriNetX re-search network. Specifically, we examined the risks of mortality, acute kidney injury, need for continuous renal replacement therapy, disseminated intravascular coagulation, gastrointestinal bleeding,intracranial hemorrhage,pulmonary embolism, hospital-acquired pneumonia, and mechanical ventilation in cirrhotic versus non-cirrhotic patients with septic shock. By controlling for key comorbidities and baseline laboratory values, this study seeks to isolate the independent contribution of cirrhosis to adverse outcomes in septic shock and to identify areas where targeted interventions may improve care for this high-risk population.

MATERIALS AND METHODS

We used the US Collaborative Network from 43 healthcare organizations (HCOs) in the TriNetX re-search network. The initial search yielded 704,595 patients across 2 cohorts, which were reduced to 96,986 per cohort after propensity matching. The HCOs were hospitals, primary care units, or specialists, providing data on uninsured or insured patients. The TriNetX database is a global health collaborative clinical research platform that collects real-time electronic medical data from a network of HCOs. Because the data were anonymous, informed consent was waived.

The available data included information on demographics, diagnoses (based on the International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes), and laboratory tests (coded using Logical Observation Identifiers Names and Codes [LOINC]). Inclusion and exclusion criteria are shown in Table 1.

Table 1: Inclusion and exclusion criteria

Propensity Matching

Propensity score matching was performed to minimize confounding, including variables such as age, sex, race, BMI, diabetes status, and baseline laboratory values. We used the TriNetX built-in function and matched the two groups at a 1:1 ratio. Characteristics of the cohorts before and after matching are summarized in Table 2.

Table 2: Propensity matching

Outcomes

Diagnoses, medications, procedures, or laboratory values that occur within the time window starting after the first occurrence of the index event, as mentioned in Table 3.

Table 3: Diagnoses, medications, procedures, or laboratory values that occur within the time window starting after the first occurrence of the index event

Statistical Analysis

Our study employed a two-step approach comparing outcomes between cirrhotic and non-cirrhotic patients: (1) cross-sectional risk analysis and (2) time-to-event survival analysis.

1. Cross-Sectional Risk Analysis - This approach assessed whether outcomes occurred, without considering timing. The following outcomes were obtained using the built-in TriNetX analysis:

- Risk (Incidence) - Proportion of patients experiencing each outcome in each group

- Risk Difference - Absolute difference between groups

- Risk Ratio (RR) - Relative risk comparing cirrhosis to non-cirrhosis

- Odds Ratio (OR) - Alternative measure; approximates RR when event rates are low (10%)

- p-value - Statistical significance (p < 0.05 considered significant)

2. Kaplan-Meier Survival Analysis - This approach assessed time-to event, accounting for when out-comes occurred. The following outcomes were obtained using the built-in TriNetX tools:

- Survival Probability - Proportion remaining event-free over follow up

- Hazard Ratio (HR) - Represents instantaneous risk at any given time

- Proportionality Test - Schoenfeld residuals test; p <0.05 indicates the HR is not constant over time (violation)

RESULTS

Disseminated Intravascular Coagulation (DIC)

Patients with cirrhosis had a 68% higher risk of developing DIC (HR 1.68, 95% CI 1.57–1.80, p = 0.001). Freedom from DIC was 97.49% in cirrhotic patients versus 98.51% in non-cirrhotic patients (p = 0.001). The absolute risk difference was +0.9% (2.3% vs 1.4%). The proportional hazards assumption was violated (p = 0.006), suggesting the effect may vary over time (Table 4 and Table 5).

Table 4: Comparison of risk amongst the 2 cohorts

Table 5: Kaplan Meier Survival Analysis amongst the 2 groups

Gastrointestinal Bleeding (GIB)

Patients with cirrhosis had a 67% higher risk of developing GIB (HR 1.67, 95% CI 1.61–1.73, p = 0.001). Freedom from GIB was 91.45% versus 94.76% in non-cirrhotic patients (p = 0.001). The absolute risk difference was +2.9% (7.6% vs 4.6%). The proportional hazards assumption was violated (p = 0.006), suggesting the effect may vary over time.

Intracranial Hemorrhage (ICH)

There was no significant difference in ICH risk between groups (RR 1.00, 95% CI 0.91–1.10, p = 0.981; HR 1.01, 95% CI 0.92–1.10, p = 0.906).

Pulmonary Embolism (PE)

Patients with cirrhosis had a marginally lower risk of PE (RR 0.95, 95% CI 0.91–0.99, p = 0.025), with an absolute risk difference of −0.2% (3.7% vs 3.9%). However, survival analysis did not reach statistical significance (HR 0.96, 95% CI 0.91–1.00, p = 0.054). The proportional hazards assumption was violated (p = 0.037).

Acute Kidney Injury (AKI)

Patients with cirrhosis had an 18% higher risk of developing AKI (HR 1.18, 95% CI 1.16–1.20, p = 0.001). Freedom from AKI was 58.02% versus 63.46% (p = 0.001). The absolute risk difference was +4.9% (39.0% vs 34.1%). The proportional hazards assumption was violated (p = 0.001), suggesting the effect may vary over time.

Continuous Renal Replacement Therapy (CRRT)

Patients with cirrhosis had a 39% higher risk of requiring CRRT (HR 1.39, 95% CI 1.34–1.44, p = 0.001). Freedom from CRRT was 90.97% versus 93.41% (p = 0.001). The absolute risk difference was +2.2% (8.2% vs 6.0%). The proportional hazards assumption was met (p = 0.651), suggesting the effect may not vary over time.

Hospital-Acquired Pneumonia (HAP)

There was no significant difference in HAP risk between cirrhotic and non-cirrhotic patients (RR 0.95, 95% CI 0.86–1.04, p = 0.265; HR 0.96, 95% CI 0.87–1.05, p = 0.371).

Mechanical Ventilation

Patients with cirrhosis had an 18% higher risk of requiring mechanical ventilation (HR 1.18, 95% CI 1.16–1.21, p = 0.001). Freedom from mechanical ventilation was 75.52% versus 78.95% (p = 0.001). The absolute risk difference was +3.1% (22.5% vs 19.3%). The proportional hazards assumption was met (p = 0.096), suggesting the effect may not vary over time.

Death

Patients with cirrhosis had a 23% higher risk of mortality (HR 1.23, 95% CI 1.21–1.25, p = 0.001). Survival probability was 65.55% versus 71.19% in non-cirrhotic patients (p = 0.001). The absolute risk difference was +5.5% (32.8% vs 27.3%). The proportional hazards assumption was violated (p = 0.001), indicating the mortality risk associated with cirrhosis changes over time.

DISCUSSION

This is a retrospective cohort study with propensity matching to study the effects of cirrhosis on patients admitted with septic shock. In the retrospective analysis, patients were matched for comorbidities, including diabetes, hypertension, obesity, chronic kidney disease, and chronic obstructive pulmonary disease, to reduce confounding. Furthermore, creatinine and bilirubin were matched for renal and hepatic function. Patients with cirrhosis and septic shock experience significantly worse clinical outcomes compared to non-cirrhotic patients. Bilirubin discrepancy post-matching demonstrates poor hepatic function in the cirrhotic population; however, contributing to matching bias.

Our findings of increased DIC (HR 1.68) reflect hemostatic changes seen in cirrhosis. In a retrospective analysis by Chebl et al., elevated INR was identified as one of the independent predictors of ICU mortality (OR 1.69; 95% CI 1.29–2.23); however, a direct association with DIC was not established [18]. Drolz et al., demonstrated that lower platelet counts (30×10⁹/L) and fibrinogen levels (60 mg/dL) were the strongest independent predictors for new onset of major bleeding events in critically ill patients with cirrhosis [14]. The liver is responsible for the synthesis of both anticoagulant factors (protein C and protein S) and procoagulant factors (Factors II, VII, IX, and X). An imbalance between these factors, exacerbated by sepsis-induced endothelial damage, accounts for the development of microthrombi or micro-hemorrhages characteristic of DIC [13,14].

Increased risk of gastrointestinal bleeding (HR 1.67) was also observed in cirrhotic patients. The combination of portal hypertension, coagulopathy, and sepsis-induced stress gastropathy likely contributes to the elevated GI bleeding risk. A systematic review and meta-analysis by Granholm et al. identified coagulopathy, shock, and chronic liver disease as the three leading risk factors for clinically important gastrointestinal bleeding in critically ill patients, with chronic liver disease carrying a relative effect of 7.64 (95% CI 3.32–17.58) [15]. The 2024 SCCM/ ASHP guideline similarly recommends that critically ill adults with coagulopathy, shock, or chronic liver disease be considered at risk for clinically important upper GI bleeding [16]. Enteral nutrition is protective in mechanically ventilated patients [19]. Stress ulcer prophylaxis with proton-pump inhibitors has been shown to reduce the incidence of clinically important bleeding (RR 0.52; 95% CI 0.30–0.81) in a network meta-analysis, and the 2026 Surviving Sepsis Campaign guidelines suggest stress ulcer prophylaxis with PPIs for adults with sepsis or septic shock who have risk factors for GI bleeding [16-20].

Compared to GIB, ICH outcomes were not significant in our study, sharply contrasting with previous findings from Parikh et al. (HR 1.9 for ICH in cirrhosis), which demonstrated a higher risk of intracranial hemorrhage in a nationally representative Medicare cohort [21]. A meta-analysis by Zheng et al. found that cirrhosis significantly increased the risk of subarachnoid hemorrhage (HR 2.36; 95% CI 1.80–3.09) and intracranial hemorrhage (HR 1.48; 95% CI 1.06–2.05) [22]. The discrepancy with our findings may reflect the propensity-matched design controlling for confounders that were unaccounted for in prior studies.

Patients with cirrhosis had a marginally lower risk of PE in our study. Barba et al., reported that hospitalized patients with moderate-severe liver disease had a lower incidence of VTE (0.9 per 100 dis-charges) compared to those without liver disease (2.7 per 100 discharges), although VTE in the setting of moderate-severe liver disease was associated with significantly increased mortality (OR 1.63; 95% CI 1.42 1.88) [18]. In contrast, Ambrosino et al., demonstrated a significantly increased VTE risk in cirrhotic patients (OR 1.703; 95% CI 1.333–2.175), including a higher risk of PE specifically (OR 1.655; 95% CI 1.042–2.630) [17]. A Danish nationwide cohort study by Jepsen et al., similarly found a 2-fold increased risk of VTE in cirrhosis (aHR 2.0; 95% CI 1.5–2.6) [23]. These varying results reflect the fragile balance between pro- and anti thrombotic effects of liver disease, and the AGA Technical Review on Coagulation in Cirrhosis acknowledges that patients with cirrhosis are at significantly increased risk of VTE despite traditional assumptions to the contrary [24-30].

There is a significantly elevated risk of AKI in our cirrhotic cohort (HR 1.18, 95% CI 1.16–1.20). The 2023 NEJM review by Nadim and Garcia Tsao explores the hemodynamic alterations from portal hypertension, splanchnic vasodilation, and renin-angiotensin activation that predispose cirrhotic patients to renal injury [1]. AKI is present in 30%–50% of hospitalized patients with cirrhosis, and infection is one of the most common precipitating factors, driving further deterioration through vasodilatory cytokines and systemic inflammatory mediators [1-12]. The increased requirement for CRRT in cirrhotic patients (HR 1.39, 95% CI 1.34–1.44) reflects both the higher incidence of AKI and the severity of renal dysfunction in the cirrhotic population. Chebl et al. further confirmed this association, demonstrating that hemodialysis was an independent predictor of mortality in septic cirrhosis patients (OR 3.09; 95% CI 1.76–5.42) [18].

The study showed an 18% higher risk for mechanical ventilation requirements but did not demonstrate increased rates of hospital acquired pneumonia. Bajaj et al., demonstrated pneumonia as the third most prevalent infection in cirrhosis (19% of infections), following spontaneous bacterial peritonitis and urinary tract infections [3]. In our study, the difference in HAP could not be established. The dissociation likely stems from ICD coding practices for hospital-acquired pneumonia; most pneumonias in the hospital are billed as community-acquired pneumonia, and hence, the association of a nosocomial infection could not be established. The rate of mechanical ventilation was higher, reflecting increased risk for respiratory indications including ARDS or aspiration, neurological indications with inability to maintain airways in late stages of hepatic encephalopathy, and intubations for gastrointestinal bleeding. While cirrhosis increases mechanical ventilation need, Chebl et al., showed that mechanical ventilation is an independent predictor of mortality in septic cirrhosis patients (OR 2.61; 95% CI 1.60–4.28), making this a critical outcome [18].

Our observed mortality difference (HR 1.23) aligns with previous studies demonstrating the profound impact of cirrhosis on sepsis mortality. Bajaj et al. reported that mortality associated with septic shock in cirrhosis approaches 65%, with in-hospital mortality upwards of 50% [3]. Chebl et al., found that 64.78% of cirrhotic patients with sepsis died during hospitalization compared to 31.54% of non-cirrhotic patients (OR 2.53; 95% CI 2.04–3.15) [18].

The study has some limitations warranting consideration. First, reliance on ICD-10 codes may result in misclassification of exposures and outcomes. Second, we could not differentiate between compensated and decompensated cirrhosis, which have markedly different prognoses. Third, despite propensity score matching, residual confounding may persist, as evidenced by the persistent imbalance in total bilirubin between cohorts. Fourth, we lacked data on cirrhosis severity scores (Child-Pugh, MELD) and specific etiologies of liver disease.

CONCLUSIONS

In this large propensity score-matched cohort study, patients with cirrhosis and septic shock demonstrated significantly higher rates of mortality, acute kidney injury, gastrointestinal bleeding, disseminated intravascular coagulation, and need for renal replacement therapy compared to non-cirrhotic patients. These findings underscore the need for close monitoring, early aggressive management, and involvement of palliative services in this high-risk population.

AUTHOR CONTRIBUTIONS

Conceptualization, B.S. and P.G.; methodology, P.G.; software, B.S.; validation, N.R..; formal analysis, B.S.; investigation, B.S.; data curation, P.G.; writing—original draft preparation, R.J.; writ-ing—review and editing, G.K.; supervision, P.G.. All authors have read and agreed to the published version of the manuscript.

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