The diagnosis of sepsis has evolved over time, the most recent one being the Sepsis-3 definition as measured by the Sequential Organ Failure Assessment score (SOFA) score and National Early Warning Score (NEWS), is presented in Table 1- which emphasizes the presence of organ dysfunction, particularly cardiovascular dysfunction, like decreased peripheral resistance and increased vascular permeability, leading to tissue hypoperfusion, oliguria, elevated lactate and creatinine levels, coagulopathies, and subsequent organ failure. While effective fluid resuscitation is a mainstay of sepsis management, aiming to restore hemodynamic stability and improve tissue perfusion, this also raises concern in heart failure patients [³].

Cardiovascular insufficiency in heart failure can arise from structural or functional heart disorders that impair the heart’s ability to fill with or eject blood. The pathophysiology of HF is complex, involving hemodynamic, neurohormonal, and cellular mechanisms. Hemodynamic changes include a reduced cardiac output and elevated ventricular filling pressures due to volume overload and impaired relaxation. Neurohormonal activation significantly impacts HF, with the renin-angiotensin-aldosterone system (RAAS) causing vasoconstriction, sodium retention, and fluid overload [⁴]. The sympathetic nervous system (SNS) increases catecholamine levels, thereby raising heart rate and contractility, but also contributes to myocardial damage over time [⁵]. On a cellular level, myocytes undergo hypertrophy to handle the increased workload, fibrosis stiffens the myocardium due to excess collagen, and apoptosis, or the programmed cell death of myocytes, further impairs cardiac function [⁶].

Sepsis is a life-threatening condition resulting from a dysregulated immune response to infection, leading to widespread inflammation, tissue damage, and organ dysfunction. The immune response in sepsis involves both pro-inflammatory and anti-inflammatory processes. Pro-inflammatory responses include the release of cytokines such as TNF-\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\alpha$\end{document}α, IL-1, and IL-6 [⁷]. Anti-inflammatory responses involve the production of IL-10 and other mediators to counteract inflammation [⁷]. Endothelial dysfunction is a key feature of sepsis, with increased permeability leading to fluid leakage, edema, and hypotension [⁷], and microvascular thrombosis occurring due to coagulation activation and impaired fibrinolysis [⁷]. Metabolic changes in sepsis include mitochondrial dysfunction, which reduces ATP production and contributes to cellular energy failure [⁷], and hyperglycemia resulting from stress-induced insulin resistance and increased gluconeogenesis [⁷]. These processes contribute to multiple organ dysfunction syndrome (MODS), characterized by impaired perfusion and oxygen delivery to tissues [⁷].

Sepsis exerts profound effects on cardiac function, leading to septic cardiomyopathy, a reversible dysfunction of the heart. Hemodynamically, the combined effects of heart failure and sepsis lead to decreased preload and mean arterial pressure (MAP), increased heart rate, neutral effect on systemic vascular resistance, and varying effect on contractility [⁴]. The mechanisms of cardiac dysfunction in sepsis are summarized in Table 2: The pathophysiological processes in a patient with heart failure complicated by sepsis are multifaceted and interlinked. The systemic inflammatory response of sepsis exacerbates cardiac dysfunction, precipitates coagulopathy, and leads to multi-organ failure. Understanding these mechanisms is crucial for managing such critically ill patients and highlights the need for integrated therapeutic approaches to mitigate the impact of these concurrent conditions. The challenge lies in finding the delicate balance between providing sufficient fluid to support circulation without exacerbating heart failure; careful monitoring is essential, as fluid overload in the above condition has been associated with exacerbation of heart failure with vasodilation, pulmonary edema, peripheral edema, elevated jugular venous pressure, increased intra-abdominal pressure leading to liver and kidney injury-hyponatremia in critically ill patients, and increased mortality [⁸]. Heart failure can manifest as either a reduced ejection fraction or a preserved ejection fraction. Both types are further complicated by sepsis, because the inflammatory response can worsen cardiac function and lead to fluid overload.

However, evidence suggests that guideline-based fluid resuscitation (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\geq$\end{document}≥30 mL/kg within 3 hours) is associated with lower in-hospital mortality compared to restrictive approaches in sepsis patients with HF [⁹,¹⁰]. The use of careful management of chronic HF medications and consideration of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\beta$\end{document}β-blockers after hemodynamic stabilization with balanced crystalloids and albumin may be beneficial [¹⁰]. Additional research is needed to determine optimal fluid resuscitation strategies in this population, as clinicians must balance the need for volume expansion against the risk of fluid overload and worsening of cardiac dysfunction.

The Surviving Sepsis campaign recommends giving at least 30ml/kg fluid bolus, preferably with IV Crystalloids, in septic shock patients within 3 hours as a best practice measure to correct hypotension, but this recommendation is criticized as based on poor quality evidence, as it doesn’t take other patient comorbidities into consideration [¹¹]. Additionally, the Centers for Medicare and Medicaid Services also mandated this recommendation as part of its SEP-1 sepsis management bundle. Despite these guidelines, many physicians are often hesitant to administer fluid resuscitation to sepsis patients with heart failure due to concerns about potential fluid overload [¹²]. In line with this, several retrospective cohort studies have indicated that patients with heart failure often experience delays in fluid administration [¹³] those who are more likely to fail to comply with guidelines for fluid resuscitation [¹⁴,¹⁵,¹⁶] and generally receive less aggressive resuscitation compared to sepsis patients without heart failure [¹⁷,¹⁸].

In a study of 552 patients, Wardi et al. in a retrospective cohort study found that individuals with sepsis and heart failure with reduced ejection fraction (HFrEF) received an average of 9.8 mL/kg less fluid compared to those without HFrEF (31.7 mL/kg versus 41.5 mL/kg, respectively; p = 0.03). Moreover, among the heart failure patients, those who did not survive received 21 mL/kg of fluid, whereas survivors with HFrEF received 35 mL/kg (p = 0.16). These findings suggest that administering a fluid bolus of at least 30 mL/kg could be beneficial for this subgroup of patients. However, the study’s findings may be constrained by the relatively small number of heart failure patients included [¹⁹].

Among a retrospective cohort of 505 patients, Singh et al. found that sepsis patients with HFrEF who received more than 3 liters of fluid had a higher in-hospital mortality and longer hospital stays. While Singh et al.’s findings suggest an association between higher fluid volumes and increased mortality in septic patients with HFrEF, the retrospective design and limited adjustment for clinical variables, such as sepsis severity or vasopressor use, introduce potential confounding elements. The absence of a detailed methodology and a small sample size further limits the generalizability of these results. Therefore, these observations should be viewed as hypothesis-generating. Future prospective studies with proper control of confounders are needed to clarify the causal relationship between fluid resuscitation strategies and outcomes in this high-risk population [²⁰].

Additionally, current guidelines may allow for the administration of more than 3 liters of fluid in patients with a body weight of 100 kg, which means that many individuals may not reach the threshold for excessive fluid according to these guidelines. But most importantly, the study did not report the period over which the fluid was administered, making it challenging to apply these findings in clinical practice [²⁰]. Additionally, in a more comprehensive retrospective study, Tam et al. found that patients with sepsis who had a known history of heart failure (HF) received less fluid than those without HF at 6, 12, 24, and 48 hours post-injury. Despite this reduced fluid volume, patients with HF still received over 40 mL/kg of fluids within the first 6 hours of sepsis onset. Nevertheless, there were no significant differences between the HF and non-HF groups in terms of net fluid balance at 6 and 48 hours, hospital length of stay (LOS), ICU LOS, rates of persistent hypotension at 48 hours, intubation, CPAP/BIPAP use, cardiovascular complications, acute kidney injury (AKI), or mortality [²¹]. In this context, administering at least the recommended 30 mL/kg of fluid resuscitation within the first six hours of sepsis might be safe for patients with septic shock or severe sepsis and a known history of HF. A recent case-control study of 671 patients revealed that compliance with \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\geq$\end{document}≥30ml/kg fluid resuscitation was lower in sepsis patients, with even lower compliance among heart failure patients with sepsis. However, the study also found that the use of a fluid bolus (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\geq$\end{document}≥30 mL/kg) in heart failure patients presenting with severe sepsis or septic shock appeared to reduce the risk of in-hospital mortality (OR 0.95, 95% CI 0.90–0.99, p<0.05). Additionally, there was no increased risk of mechanical ventilation associated with the fluid bolus (OR 1.01, 95% CI 0.96–1.06, p = 0.70) [¹⁰].

In a retrospective chart review, Boccio et al. found that the only significant difference between sepsis fluid bolus-compliant and non-compliant patients with congestive heart failure (CHF) was a shorter stay in the intensive care unit (ICU) for the compliant group. Additionally, there were no statistically significant differences in mortality rates, the probability of intubation within 72 hours or during hospitalization, or inpatient length of stay among CHF patients who were compliant versus those who were noncompliant. However, the sample size may have been insufficient to detect a meaningful difference in mortality.[¹⁴]. In their retrospective chart review, Akhter et al. categorized sepsis patients with a history of CHF and/or ESRD into two groups based on their fluid intake: those who received at least 30 ml/kg and those who received a fluid-restrictive regimen of < 30 ml/kg. They found that the compliance group did not have a higher likelihood of intubation compared to the other group. There was also no significant difference in hospital length of stay or mortality. However, the study has limitations, including potential baseline differences- unadjusted confounders between the two patient groups, like sepsis severity or vasopressor use, and insufficient sample size(for calculating mortality), which may have influenced the results [²²]. However, in a separate study with a larger sample size and similar patient grouping in a prospective observational design, Akhter et al. utilized a multivariate logistic regression model to account for confounding factors and showed that sepsis fluid bolus administration does not elevate the risk of mortality or intubation [²³]. Similarly, in a retrospective cohort study, Duttuluri et al demonstrated that in heart failure patients with severe sepsis or septic shock presenting with hypotension, an adequate fluid bolus (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\geq$\end{document}≥30 mL/kg) decreased the risk of in-hospital mortality and intubation [²⁴]. In a smaller prospective observational study by Ehrman et al., patients with reduced left ventricular ejection fraction (rLVEF) and those without rLVEF received similar volume fluid boluses. Interestingly, despite this similarity in fluid administration, both groups had comparable hospital days, ICU days, and ventilator days [²⁵].

Khan et al., in a retrospective study, found that administering more than 30 mL/kg of fluid resuscitation was not independently linked to intubation (aOR 0.75, 95% CI 0.41-1.36, p = 0.34) after adjusting for confounders using multivariable generalized estimating equations. The number of ICU-free days at 28 days was similar between the restricted and standard fluid groups (17±10 days vs. 17±11 days, p=0.64). Additionally, there was no significant difference in the number of days on mechanical ventilation between the groups (11±16 days vs. 10±12 days, p=0.96), and hospital mortality rates were comparable (45 [21%] vs. 19 [18%], p=0.21), but an insufficient sample size may limit the study [²⁶]. Ouellette and Shah, in their case-control study, used total intravenous fluid volume administered during the first 24 hours of patient admission as exposure and found no correlation between intravenous fluid volume and the PO2/FiO2 (oxygenation) at 24 hours in either cohort (r2 = 0.019 for cases, r2 = 0.001 for controls). In-hospital mortality rates (P = 0.117) and intubation rates at 24 hours (P = 0.687) were not significantly different between cases and controls either. However, the study may have been underpowered to detect differences in mortality [²⁷].

In a retrospective cohort study Kuttab et al. found that, after accounting for various confounders, patients who did not receive the 30-by-3 fluid resuscitation protocol had higher odds of in-hospital mortality (OR=1.52, 95% CI 1.03–2.24), delayed onset hypotension (OR=1.42, 95% CI 1.02–1.99), and a longer ICU stay among those admitted to the ICU (mean increase of about 2 days, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\beta$\end{document}β=2.0, 95% CI 0.5–3.6). The study also showed that patients with severe sepsis and septic shock who were elderly, male, obese, with documented volume “overload” from bedside examination, and had a history of heart failure or end-stage renal disease were less likely to receive the 30-by-3 protocol [¹²]. An older retrospective study by Shah and Ouellette found that adherence to early goal-directed therapy improved in-hospital mortality in patients with a reduced LVEF and sepsis [²⁸]. In a retrospective study using claims data from elderly patients with a history of congestive heart failure (<35% EF) who presented with severe sepsis or septic shock, adherence to the initial fluid resuscitation guidelines outlined in the 3-hour sepsis bundle was associated with better in-hospital and [²⁹] one-year mortality outcomes [²⁹]. These results are also validated by a massive multisite observational study of nearly 15,000 severe sepsis/septic shock patients across three independent, prospective cohorts. Strict adherence to a 3-hour sepsis bundle, emphasizing rapid intervention that is not reliant on physiological endpoints, demonstrated lower in-hospital mortality, even after adjusting for confounding factors. This compliance also yielded significant cost savings in cohorts 2 and 3, which included over 7,500 patients. Furthermore, these results were validated within the CHF subpopulation of the study [³⁰].

Liu et al. assessed the effects of implementing a treatment bundle for sepsis patients with intermediate lactate levels across multiple centers. This retrospective study found that the bundle implementation significantly improved compliance and brought down hospital mortality rates. Crucially, this drop in mortality did not result in longer hospital stays or more ICU transfers. When patients were stratified based on pre-existing heart failure or kidney disease, those with these conditions experienced significant reductions in both hospital and 30-day mortality post-implementation. Compliance with antibiotic timing and lactate reassessment was similar in these patient groups before and after implementation, highlighting that the improved outcomes were largely due to increased fluid administration for patients with heart failure and/or chronic kidney disease [³¹].

A recent large retrospective cohort study revealed that patients with septic shock and HFrEF were less likely to receive guideline-recommended intravenous fluids compared to those with septic shock but without HFrEF. Even after adjusting for confounding factors, HFrEF was linked to a reduced likelihood of receiving 30 mL/kg of intravenous fluid within the first 6 hours of sepsis onset (aOR-0.63; 95% confidence interval [CI], 0.47-0.85; P = 0.002). However, the adjusted risk of mortality did not significantly differ between patients with HFrEF (aOR-0.92; 95% CI, 0.69-1.24; P = 0.59) and those without it, and there was no interaction with the volume of intravenous fluid administered (aOR-1.00; 95% CI, 0.98-1.03; P = 0.72) [¹⁵].

In a retrospective study by Herndon et al., involving a cohort primarily consisting of patients with various types of heart failure and sepsis-induced hypoperfusion, no difference in mortality was found between those who received the recommended 30 mL/kg fluid bolus and those who did not. The study observed shorter hospital and ICU lengths of stay, as well as a higher incidence of new invasive or noninvasive mechanical ventilation. But multivariate analysis indicated that these outcomes were influenced by factors unrelated to the initial fluid bolus. This suggests that administering a 30 mL/kg fluid bolus did not significantly impact outcomes in patients with mixed types of heart failure and sepsis-induced hypoperfusion [³²].

In contrast to the above studies, Wiczorek et al., in a retrospective study of sepsis patients with CHF/CKD, found a significant correlation between receiving more than 30 mL/kg of intravenous fluids at 3 and 6 hours from emergency department arrival and the need for BiPAP (p-value 0.006, p 0.02, respectively). Surprisingly, there was no statistically significant difference in in-hospital mortality between the sepsis patients with CHF/CKD and those without CHF/CKD, with regard to receiving more than 30 mL/kg of IVF at either 3 or 6 hours from ED (p-value 0.614, p-value 0.115, respectively) [³³].

Multiple studies have found that higher fluid balance is associated with negative outcomes. A recent retrospective cohort study by Dong et al. sought to investigate the link between fluid management and in-hospital mortality in sepsis patients with heart failure. The study aimed to identify a superior indicator for fluid management among fluid balance (FB), fluid intake (FI), and the fluid intake ratio (FB/FI), termed the fluid accumulation index (FAI). The findings revealed that a high FAI (FB/FI ratio) correlated with an increase in in-hospital mortality in these patients [³⁴]. To understand the link between fluid balance (FB) and in-hospital mortality, a retrospective study by Zhang et al. categorized sepsis patients with heart failure into two groups based on FB levels: high (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\geq$\end{document}≥ 55.85 ml/kg) and low (< 55.85 ml/kg). Their research uncovered that a high FB was an independent predictor of both in-hospital and 30-day mortality and was also linked to extended ICU and hospital stays. These conclusions remained solid and consistent even after adjusting for potential confounders, making them a dependable measure for evaluating the impact of FB on patient outcomes in clinical practice [³⁵]. In a study of 633 patients, Dhondup et al. revealed that each 1-liter increase in daily negative fluid balance during the de-escalation phase significantly lowered mortality rates across several time points: ICU, hospital, 90-day, and 1-year [³⁶].

Overall, research on the safety, complications, and outcomes of fluid resuscitation in heart failure patients with sepsis is still limited. Septic shock treatment is structured into four phases: Resuscitation, Optimization, Stabilization, and Evacuation. Based on existing literature, following SCC fluid resuscitation guidelines is advisable, as they are likely to produce favorable or neutral outcomes with minimal adverse effects. Nonetheless, the risk of volume overload persists, as highlighted by recent studies [³⁶,³⁴,³⁵]. Thus, fluid management should be optimized in heart failure patients with septic shock, and it is advisable to adopt a conservative approach during the other phases of septic shock treatment. New prospective studies are essential to conclusively determine the safety and effectiveness of fluid management in this subgroup.