The Third International Consensus Definitions for Sepsis and Septic Shock1 defines sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is defined by a vasopressor requirement to maintain a mean arterial pressure (MAP) ≥65 mmHg and serum lactate level ≥2 mmol/L (≥18 mg/dL), after adequate fluid resuscitation. Mortality lies between 30% and 50% in developed countries.1–3

Sepsis-induced myocardial dysfunction (SIMD) or septic cardiomyopathy is a reversible myocardial dysfunction that occurs as part of multi-organ failure caused by sepsis.4 Forty to fifty percent of septic shock patients have SIMD, depending on the definition used, and this seems to be one of the major predictors of unfavorable prognosis.5–7 According to Flynn et al., patients with SIMD have 70–90% mortality, compared to a 20% in septic patients without SIMD.5 In septic patients, cardiac dysfunction manifests itself with hemodynamic instability or end-organ hypoperfusion, associated with raised cardiac biomarkers and myocardial dysfunction documented on multiple imaging techniques.8 The complexity of the cardiovascular system, the myriad methods of assessment, and variations in the pre-septic state of the heart makes elucidating a cause-and-effect relationship difficult.9

Septic cardiomyopathy was first described by McLean et al.10 in 1967, where the diagnostic criteria to identify heart failure (HF) was a low cardiac index (CI). Subsequently, in 1984, Parker et al.,11 using radionuclide cineangiography, characterized SIMD as reversible myocardial depression due to sepsis and septic shock, defined by decreased initial LV ejection fraction (LVEF) <40% with increased mean end-diastolic and end-systolic volumes (EDV, ESV), that usually occur within two to three days of the onset of sepsis and resolves in seven to 10 days.3,11–13

The current definition characterizes SIMD as:14

• I.

  Ventricular dilatation with an increase in ventricular compliance and normal to low filling pressure, unlike the pattern of cardiogenic shock where ventricular pressures are elevated.15

• II.

  Decreased EF, without a decrease in stroke volume (SV).

• III.

  Diminished response to fluid resuscitation and catecholamines.16

• IV.

  Reversibility in seven to 10 days. Cardiac magnetic resonance imaging (CMRI) detects changes suggestive of myocardial edema or an altered metabolic state, a pattern distinct from that seen in ischemia and necrosis consistent with irreversibility. Some theorize that SIMD may represent a protective “hibernating” state of the heart.9

• V.

  Exclusion of acute coronary syndrome as etiology.

In 1947, Wiggers17 described the presence of a circulating myocardial depressant factor responsible for myocardial dysfunction for the first time. The host immune system identifies infection through recognition of pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid of bacteria, which bind to pattern-recognition receptors, such as toll-like receptors (TLRs), expressed on the surface of host cells.3,15,18 This binding activates intracellular pathways that culminate in the expression of the nuclear translocation of nuclear factor-κB and the increased transcription of inflammatory mediators,19 such as TNFα and IL-1β. These cytokines induce myocyte apoptosis, with consequent ventricular dilatation, and act directly in the peripheral vasculature. This affects myocardial performance via alterations in systemic vascular resistance and venous return.9,20–22 TNFα can also block β-adrenergic effects on contractility.18 Early infection control with adequate antibiotic care is important during septic shock to decrease PAMPs arising from invasive microorganisms. TLRs are also activated after binding to endogenous danger-associated molecular patterns (DAMPs). Through TLRs, PAMPs and DAMPs have a direct cardiodepressant effect by downregulating β-receptors, and therefore impairing the adrenergic response of the cardiomyocytes. They also trigger cardiomyocyte apoptosis and impair myofibril function due to the disruption of calcium liberation.18 On the other hand, they also have an indirect cardiodepressant effect by causing endothelial dysfunction, microcirculatory dysfunction and fluid maldistribution.18 LPS activates TLRs in cardiomyocytes, activating intracellular pro-apoptotic patterns and increasing caspase-3 activity, which may be associated with decreased sensitivity of the myofilaments to calcium, or even structural breakdown of the sarcomere itself.18,23 Clinically, there is depressed myocardial contraction.23

High mobility group box 1 (HMGB1), a circulating histone, is a DAMP released during tissue damage. It acts by amplifying oxidative stress through HMGB1–TLR4 interactions, reducing mitochondrial membrane potential and adenosine triphosphate levels and by impairing cardiac excitation-contraction coupling.18,19 Mitochondrial dysfunction, one of the major pathways of sepsis-induced cardiomyopathy, is a result of an unbalanced production of reactive oxygen species (ROS) and reactive nitrogen species, which impairs oxidative phosphorylation and culminates in mitochondrial apoptosis.14,18

The production of excess antimicrobial products and inflammatory mediators elicits the generation of ROS and nitric oxide (NO), causing adjacent tissue damage and an amplified inflammatory reaction.19 Cytokines increase the activity of inducible nitric oxide synthase, enhancing NO production, and decreasing myofibril response to calcium, which contributes to focal rupture of actin-myosin interactions, resulting in ventricular dilatation.7,12,14,20–22 As in the case of cytokines, NO and ROS cause down-regulation of β-adrenergic receptors and depression of post-receptor signaling pathways, further depressing myocardial function.18

Finally, despite the usual increase of coronary blood flow characteristic of sepsis,13 there is an imbalance between oxygen delivery and consumption.12,15,21 Cardiac microcirculation undergoes major changes during sepsis with endothelial disruption and blood flow maldistribution, which can worsen cardiac function, contributing to the multi-organ failure of sepsis.24

However, therapies aimed at targeting a single mechanism or pathway have not been effective in improving outcomes in these patients.7Figure 1 summarizes the pathophysiology of SIMD.

Figure 1.

Pathophysiology of sepsis cardiomyopathy. FFA: free fatty acids; NO: nitric oxide.

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Clinical features suggestive of a diagnosis of SIMD include: a prior history of HF, a “septic cool extremities phenotype” on clinical exam, hemodynamic instability despite vasopressor therapy, failure to respond to a preload challenge, an abnormal cardiac function and elevated cardiac biomarkers. For the diagnosis of SIMD, it is essential to use imaging techniques and cardiac biomarkers.

The mainstream of sepsis management is fluids, non-specific organ support (vasopressors, inotropes, renal replacement techniques, artificial ventilation) with optimization of hemodynamic parameters and antibiotic therapy according to the infection origin. No specific treatment exists for SIMD.20

Fluid therapy with crystalloids is the cornerstone of early sepsis management, as recommended by Surviving Sepsis Campaign (SSC)50 and it should be initiated with an intravenous fluid challenge of 20 mL/kg to increase preload and thereby CO.19,51 Recent research suggests that hypodynamic shock is a mere manifestation of inadequate volume resuscitation and may be prevented by appropriate early volume loading.23 However, it is being increasingly recognized that over fluid resuscitation, in the days following initial sepsis resuscitation, can have detrimental effects. The risk of pulmonary edema is particularly elevated due to increased permeability of the pulmonary microcirculation and vasodilation, causing prolonged artificial ventilation.19,51 Positive fluid balance is a poor prognostic factor, and this effect is likely to be more dramatic in patients with septic cardiomyopathy because of the abnormal Frank–Starling relationships.17

Current SSC Guidelines recommend continuous hemodynamic monitoring and the use of dynamic variables predictive of “fluid responsiveness” to guide fluid resuscitation.50,51

The role of echocardiography in this scenario is crucial. First, it can evaluate or exclude the presence of SIMD, for which it is mandatory to have a prior (pre-sepsis) evaluation. Second, fluid responsiveness can be predicted by echo variables, such as the collapsibility index of the superior vena cava, by transesophageal echocardiography,36 or the collapsibility or distensibility index of the inferior vena cava, by transthoracic echocardiography. Third, after initial resuscitation, echocardiography identifies patients with persistent hypovolemia or fluid responsiveness, and so, it can help to optimize volume status and to avoid fluid overload,36 including the monitoring of LV filling pressure with E/e′.

The loss of vascular tone secondary to arterial vasodilation is among the main factors behind hemodynamic instability in septic patients and contributes to fluid resuscitation resistance. Norepinephrine (NE), an α and β-agonist, is the first-choice vasopressor in patients suffering from hypotension, despite adequate volume resuscitation, to restore adequate organ perfusion.19,50

Norepinephrine has a stronger α-adrenergic profile compared with β-1 which results in increased afterload more than increased myocardial function.17 While this is essential for the treatment of distributive shock, increasing afterload in SIMD causes CO to drop and could result in the “unmasking” of cardiac dysfunction. Repeated echocardiography could unmask LV systolic failure caused by sepsis after correction of LV afterload with norepinephrine.35 Epinephrine and dopamine have more favorable α to β-1 adrenergic activity profiles, consequently associated with more arrhythmias and increased afterload. The risk of arrhythmias and potential increased mortality has led to the recommendation against the use of dopamine in septic shock.50 The risk of isolated α-vasoconstriction without any β-1 of both vasopressors could cause increased afterload and decreased CO potentially worsening hemodynamics.17 Although catecholamines are the recommended first-line therapy for septic shock, high doses of administered catecholamines are associated with poor outcomes and severe side effects, including myocardial injury and peripheral ischemia.

In patients diagnosed with SIMD, with low CI and EF and persistent signs of hypoperfusion, despite the optimization of volume status, an inotropic agent is recommended to augment CO.50 Dobutamine is the first-line inotropic for SIMD.

Dobutamine is a synthetic catecholamine that acts on α-1, β-1, and β-2 adrenergic receptors.52 The SSC Guidelines support the use of dobutamine in the presence of myocardial dysfunction, indicated by elevated cardiac filling pressures and low CO or ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and MAP.50 Although dobutamine leads to an increase in CI, myocardial oxygen demand also increases, thus increasing the risk of myocardial ischemia and tachyarrhythmias.52

The use of dobutamine in septic patients may also not be effective in patients with severe HF since myocardial adrenergic responsiveness is depressed among septic patients.52

Vieillard-Baron et al.53 found, in a cohort of 67 septic patients, that echocardiography could be used to guide inotropic treatment. Global hypokinesia was present in 60% of patients, and the administration of dobutamine plus a reduced dose of NE partially corrected LV hypokinesia. Hemodynamic improvement were observed within 24 hours. In contrast, the administration of NE (alone) in the absence of hypokinetic state in septic shock caused global LV hypokinesia within 24 or 48 hours of continuous NE infusion.53 This can be explained by the fact that, by increasing afterload, NE unmasks potential myocardial failure.53 Increasing norepinephrine dosage in a patient exhibiting global LV hypokinesia associated with a drop in arterial pressure is logically expected to worsen hypokinesia. For this reason, the authors considered that, when global hypokinesia is found, hemodynamic support should be modified, reducing norepinephrine dosage and adding an inotropic agent.53

Levosimendan, a calcium-sensitizing drug with both inotropic and vasodilatory properties,50,54 was also proposed in sepsis. Currently there are no studies about the use of levosimendan in patients with SIMD. The LeoPARDS54 study assessed the efficacy of levosimendan to reduce acute organ dysfunction, including the heart, in patients with septic shock (regardless of EF) versus standard of care (e.g., fluids, NE and dobutamine). The study showed no differences between both arms and there was no difference in terms of 28-day mortality. In a meta-analysis of seven RCTs, Bhattacharjee et al. found that levosimendan had no benefit in terms of mortality at the longest follow-up and length of ICU stay in comparison to dobutamine in patients with sepsis and septic shock with myocardial dysfunction. Norepinephrine requirements were similar in both groups.

However, due to the higher cost of levosimendan, dobutamine remains the inotropic treatment of choice.50

In conclusion, judicious fluid resuscitation and a balanced infusion of inotropic and vasopressor agents can reverse tissue hypoperfusion and attenuate sympathoadrenergic stress. Potential therapies to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs and supplementary hydrocortisone and/or vasopressin infusion.55,56

Finally, extracorporeal life support, commonly referred to as extracorporeal membrane oxygenation (ECMO), provides cardiopulmonary support to patients with refractory cardiovascular failure of various etiologies and should be considered for septic cardiomyopathy with intractable circulatory failure.57

Sepsis-induced cardiogenic shock, presumed due to SIMD, is considered a potential indication for venous-arterial (VA) ECMO, as a bridge to recovery, because SIMD can be reversed in seven to 10 days; and appears to be associated with better prognosis.57 VA- ECMO increases afterload and decreases SV but provides systemic perfusion in the place of an injured heart.57

In a cohort of 14 refractory septic shock patients, VA-ECMO was indicated in case of acute refractory cardiovascular failure defined as the presence of tissue hypoxia (such as extensive skin mottling or elevated blood lactate), despite adequate intravascular volume, severely altered LV EF (<25%), low CI (<2.2 L/min/m2) and sustained hypotension despite infusion of very high-dose catecholamines.58 Results showed that the median time on ECMO was short (5.5 days (2–12) days), and median LV EF was 60% (40–70%) when VA-ECMO was removed, compatible with the reversibility of SIMD.58 Based on this assumption, the authors hypothesized that VA-ECMO could help salvage septic shock patients by restoring adequate perfusion to vital organs to reverse multiple organ failures buying time to achieve infection control by antibiotics.58

Veno-arterio-venous extracorporeal membrane oxygenation (VAV-ECMO) is another feasible rescue strategy for a small proportion of adult patients with combined respiratory and cardiac failure secondary to septic shock with septic cardiomyopathy.59 In a small cohort of patients supported with VAV-ECMO59 with 12 septic patients, all had cardiac dysfunction with median LV EF of 16% at time of cannulation. It was shown that, compared with ischemic cardiomyopathy, the rate of improvement was quicker and the need for additional support was lower in patients with SIMD,59 with better survival (reported as 75%). Currently, there are no studies comparing the use of VA-ECMO and VAV-ECMO in patients with SIMD. However, it is known that VAV-ECMO has a higher rate of thrombotic events, therefore VA-ECMO should be used as first-line in SIMD until further studies arrive.

Finally, in a very recent retrospective, multicenter, international, controlled trial60 that included 82 patients with sepsis-induced cardiogenic shock refractory to conventional treatment, it was shown a large and significant improvement in survival at 90 days in septic patients using VA-ECMO compared with controls not receiving VA-ECMO (mortality 60% vs. 25%, RR for mortality was 0.54, p=0.0029). All patients had severe myocardial dysfunction (EF<35%) and had severe hemodynamic compromise (severe lactic acidemia despite receiving high doses of catecholamines and aggressive fluid therapy). VA-ECMO permitted a rapid decrease in vasopressor dose and restored adequate perfusion of vital organs, as indicated by relatively rapid decreases in serum lactate. Improvement of cardiac function was also relatively quick and permitted weaning from ECMO support after six days in survivors; a shorter time than reported in patients who receive ECMO for primary cardiogenic shock.60 Therefore, early identification of this specific group of patients, which might represent up to 10% of all patients with septic shock, and the early application of VA-ECMO support, could be crucial to improving their outcomes.60 However, this study was not randomized, and thus is open to potential biases. Prospective, randomized, controlled trials in this field are needed.

Prognosis in SIMD is not clear, probably because of the multiple variabilities involved, such as age, patient history, type of microorganisms and time to resuscitation.15,61

Over the years, since Parker's studies, different parameters, from imaging techniques to laboratory biomarkers have been investigated as potential SIMD prognostic markers; however their results have been inconsistent and their prognostic value remains debatable. Table 1 summarizes the principal studies and their results on prognosis.

Since the early 19802, septic cardiomyopathy has been an increasingly recognized clinical entity. Myocardial dysfunction is only one of the organ dysfunctions that can be present in a patient with sepsis and its presence is associated with worse prognosis. Currently, diagnosis of SIMD is based on echocardiographic variables and the presence of high serum cardiac biomarkers, in a sepsis patient in a state of HF. With the advent of new echocardiographic techniques such as STE and TDI, it is possible to identify cardiomyopathy at an early stage in the natural course of SIMD. As there are no specific treatments for septic cardiomyopathy, the current sepsis guidelines represent the cornerstone of therapy. Physicians are encouraged to use VA-ECMO for patients refractory to conservative therapy, given the reversible nature of this condition. Prognosis associated with this condition is not consistent across all studies, therefore further evidence is needed.

None declared.