Sepsis and septic shock are common complications experienced by patients in the cardiac intensive care unit (CICU) [1]. The intricate pathophysiologic features and interactions between cardiogenic shock (CS) and septic shock crucially inform theour current, multi-faceted diagnostic and therapeutic approach.

2. Pathophysiology of Cardiogenic and Septic Shock

Cardiogenic shock most commonly occurs in the setting of acute myocardial infarction (AMI), but can also occur due to decompensated HF, massive pulmonary embolism (PE), myocarditis, severe valvular dysfunction, and other causes ^[2][10]. In AMI-CS, the infarct results in reduced contractility and cardiac output (CO), which leads to increases in LV end-diastolic pressure (LVEDP). As left-side coronary perfusion depends on the difference between diastolic blood pressure and LVEDP, stiffer LV walls (and thus higher LVEDP) decrease coronary perfusion pressure (CPP), thus reducing aerobic respiration capabilities to initiate a vicious downward spiral towards systemic hemodynamic instability ^[3][11]. Unlike the LV, the RV can be perfused during both diastole and systole, though its CPP is still decided by the difference between MAP and RV pressure. The initial response of peripheral vasculature in the setting of cardiac dysfunction is to vasoconstrict to preserve perfusion pressure ^[4][12], and cells throughout the body maximize oxygen extraction from their respective capillary beds to compensate for reduced flow ^[5][13]. Sepsis results in peripheral circulatory vasodilatation through the action of nitric oxide (NO). Proinflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1) are upregulated as a result of the acute infection and inflammation, ramping up the production of NO, which diffuses through the circulation to activate guanylate cyclase ^[6][14]. The final product of this cascade, cyclic GMP, then relaxes vascular smooth muscle and inhibits vascular tone ^[7][15]. Dilated vessels thus can no longer maintain the perfusion pressure needed for optimal physiologic functioning, leading to widespread organ failure. Cardiac dysfunction can exist in up to 44% of patients presenting with septic shock ^[8][16]. Sepsis can worsen circulatory function by affecting either peripheral vasculature ^[6][14] or myocardial function ^[9][17]. Sepsis adversely impacts myocardial function directly via several distinct mechanisms. First, the aforementioned vasodilatory factor, NO, exerts inhibitory effects on beta-adrenergic (β₁) receptors, which are normally responsible for increasing heart rate and contractility ^[9][17]. Decreased β₁-receptor activity causes the heart to lose its compensatory reserve to combat shock. Second, sepsis-related mitochondrial dysregulation and subsequent reactive oxygen species (ROS) formation may also directly suppress cardiac function ^[10][18]. Myocardial cells are often saturated with mitochondria due to their high aerobic energy production needs. Thus, inflammatory cytokines that lead to mitochondrial dysfunction can lead to excessive ROS build-up and direct cytotoxic damage to the cardiomyocytes. Additionally, sepsis can induce complement system dysfunction, whereby complement factor C5a, a potent chemotaxis agent for mast cells and neutrophils, can directly suppress myocardial cell function ^[11][19]. Targeting these less-understood mechanisms of direct myocardial suppression can be a worthy pursuit in future biomedical or pharmaceutical research.

3. Hemodynamic Assessment and Diagnosis of Comorbid Sepsis and Cardiogenic Shock

Recognition and timely diagnosis of comorbid septic and cardiogenic shock in the CICU can be challenging. A comprehensive hemodynamic assessment is warranted to further understand (Table 1) the etiology of shock, whether cardiogenic, distributive, obstructive, or some combination. Comorbid septic and cardiogenic shock exhibit unique alterations in hemodynamic parameters (e.g., cardiac index, ventricular filling pressures, mixed venous oxygen saturation) that may exist in “paradoxical” combinations (e.g., coexisting preserved cardiac index with high filling pressures). Thus, in these complicated mixed shock scenarios, frequent and careful assessments of patients’ clinical status and hemodynamic parameters become even more necessary to inform proper diagnostics and ultimately guide management. Cardiac biomarkers have been commonly obtained as part of the initial investigation for suspected acute cardiac dysfunction, including troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ^[12][6]. Specifically, troponin I, is often trended as a marker for myocardial injury in the setting of acute coronary syndrome, one of the most common etiologies for cardiogenic shock. Meta-analysis data also suggest the potential use of troponin I as a prognostic marker in septic shock, and there have been ongoing efforts to investigate this in large-scale, prospective trials ^[13][14][20,21]. NT-proBNP, on the other hand, is often used as a surrogate for estimating fluid status and cardiac congestion in the setting of heart failure. Similarly, in retrospective analysis, NT-proBNP has also been found to have prognostic value in septic shock ^[15][22]. However, a significant limitation of the utility of both troponin I and NT-proBNP in comorbid septic and cardiogenic shock lies in their specificity. Both markers are often found to be elevated in patients with chronic inflammatory conditions, as well as renal dysfunction, resulting in challenges with interpretation. Additionally, plasma renin has also been investigated as a biomarker for prognosis and treatment guidance in shock, with a comparison of its prognostic value against that of serum lactate. For example, a positive rate of change in plasma renin, but not lactate, for over 72 hours has been associated with increased in-hospital mortality ^[16][23]. In a similar context, newer biomarkers, such as ST2 (a member of the interleukin receptor family) ^[17][24], copeptin (a molecule co-release with arginine vasopressin) ^[18][25], and growth differentiation factor 15 (GDF-15, a member of the transforming growth factor β superfamily) ^[19][26] are undergoing both retrospective and prospective investigations for their prognostic value in both cardiogenic and septic shock. However, their current clinical utility is greatly hindered by their limited availability and accessibility, which is heavily concentrated at large, academic clinical sites. Two decades ago, a landmark trial showed mortality benefit from early goal-directed therapy (EGDT) involving hemodynamic monitoring of preload, afterload, and oxygen saturations with a central venous catheter in patients with septic shock ^[20][27]. Despite subsequent studies and meta-analyses not validating the benefits of deploying the specific EGDT protocol ^[20][27], close hemodynamic monitoring and the resultant timely appropriate resuscitative interventions have nevertheless been widely popularized in the intensive care setting. A wide variety of invasive and noninvasive tools and markers (e.g., end-tidal CO₂, [ETCO₂], inferior vena cava [IVC] collapsibility index as seen on point-of-care ultrasound [POCUS]) have been evaluated for their usefulness in hemodynamic monitoring in sepsis and CS ^[21][28]. Specifically, POCUS provides rapid and convenient global assessments of both LV and RV function, and it can be performed using remote guidance even in the most austere settings ^[22][29]. POCUS studies have explored the utility of venous doppler waveform analyses of the IVC alone, as well as composite analyses of the hepatic, portal, and renal veins to create the venous excess ultrasound score (VExUS), to help predict the severity of venous congestion ^[23][24][30,31]. Additionally, the rise of artificial intelligence-guided POCUS has the potential to reduce overall barrier-to-entry and increase inter-operator reliability for more skill-dependent measures such as the LV outflow tract velocity-time integral (VTI) ^[25][32]. However, the limitations of POCUS are equally important to recognize as it alone cannot replace a comprehensive cardiovascular assessment. Thus, POCUS findings must always be considered in the context of a physical exam and other clinical parameters to inform a more comprehensive picture of hemodynamic status. Additionally, perhaps the most straightforward method to assess fluid responsiveness can be achieved using a “passive leg raise”, which effectively delivers approximately 300 mL of preload to the heart ^[26][33]. This maneuver is safe due to its rapid reversibility and can be used as part of the initial hemodynamic assessment, even before test fluid boluses are given. New advances in critical care technology have introduced tools to approach hemodynamic monitoring, such as pulse contour analysis, which gathers data from an arterial line to calculate cardiac output ^[27][28][34,35]. This technology has been validated against pulmonary arterial catheterization in stable patients undergoing surgery, yet its performance may be less reliable in clinical scenarios involving extremely low vascular resistance, such as sepsis and cirrhosis ^[28][35]. While these devices may account for the effects of fluid administration, their reliability should be balanced with a comprehensive clinical picture. The current gold standard in hemodynamic assessment of cardiogenic shock remains the pulmonary artery catheter (PAC) ^[29][36]. Though invasive, the PAC can provide crucial, real-time guidance regarding left- and right-sided filling pressures and cardiac output to guide resuscitation decisions. Despite its ability to provide these hemodynamic data, many questions remain about its ability to translate those data into improved CS mortality, as suggested by a landmark meta-analysis conducted by Shah et al. in 2005 ^[30][37]. The authors concluded that perhaps the lack of benefit of PAC use resulted from a lack of “effective evidence-based treatments” used in conjunction with PAC ^[30][37]. However, in the past decade, advancements and tools in cardiac critical care have popularized the use of PACs for real-time monitoring of the therapeutic effect. Recent retrospective analyses suggest that the PAC is associated with lower propensity-matched 30-day mortality ^[31][38]. For example, PAC can characterize mixed shock profiles and can aid MCS-related clinical decision-making. Continually worsening hemodynamics may warrant escalating from an IABP to an Impella, adding left-ventricular assist device (LVAD) support to patients with only an RVAD, or initiating and up-titrating extracorporeal membrane oxygenation (ECMO) parameters ^[32][39]. While prospective, randomized control trials (RCTs) are needed, the PAC remains an invaluable tool to assist intensivists’ hemodynamic status assessment of complex CS patients.