Management of Myocardial Dysfunction in Severe Sepsis

Mathieu Jozwiak, M.D.; Romain Persichini, M.D.; Xavier Monnet, M.D., Ph.D.; Jean-Louis Teboul, M.D., Ph.D.

Disclosures

Semin Respir Crit Care Med. 2011;32(2):206-214. 

In This Article

Treatment of Sepsis-induced Cardiac Dysfunction

Which Patients Need to be Treated?

Treating sepsis-induced cardiac dysfunction is a matter of debate. It must be remembered that therapeutic strategies aimed at systematically targeting supranormal cardiac output values using fluid and inotropes failed to improve outcome and could even be deleterious.[46] The most recent guidelines of the Surviving Sepsis Campaign recommend giving inotropic drugs if a value of central venous oxygen saturation (ScvO2) ≥70% is not achieved after adequate fluid resuscitation (guided with central venous pressure), vasopressive drug infusion, and correction of anemia.[1]

However, one may be cautious about these recommendations. First, ensuring that volume status is adequate before starting inotrope therapy is a difficult challenge when the central venous pressure alone is taken for guiding fluid resucitation.[47] More reliable tests (dynamic volume responsiveness indices) would indisputably be preferred.[48] Second, the threshold ScvO2 (70%) has been arbitrarily fixed, probably in relation to the protocol proposed by Rivers et al.[49] Finally, it is regrettable that the presence of a proven cardiac dysfunction (using echocardiography) was not mentioned as a prerequisite for the decision of inotropic therapy in these guidelines.

Because inotropic agents are not devoid of serious side effects (to be discussed), it seems to us more reasonable to carefully assess the patient's cardiac function—at best by echocardiography—before deciding to treat sepsis-induced myocardial depression.

When systolic cardiac dysfunction is diagnosed with certainty (eg, LVEF <45% in the presence of restored mean arterial pressure) while the patient is no longer fluid responsive and anemic, the decision to give inotropic therapy should take into account the SvO2/ScvO2 value (Fig. 1):

- In case of low SvO2/ScvO2 value (eg, <70%), it seems reasonable to give inotropes.

- In case of high SvO2/ScvO2 value (eg, > 80%), it seems preferable not to give inotropes.

- In case of intermediate SvO2/ScvO2 values (eg, between 70% and 80%), the decision is not straightforward. One should pay attention to other indicators such as veno-arterial PCO2 difference.[50] In difficult cases, efficacy and tolerance of the inotropic drug can be tested during a brief period before making a definitive therapeutic decision (see later discussion).

In any case, the value of arterial oxygen saturation must be taken into consideration when the SvO2/ScvO2 is interpreted. It is estimated that only 10 to 20% of patients who have sepsis-induced cardiac dysfunction really need to receive inotropic drugs.[13]

Treatment Options

The ideal inotrope is the drug that would improve myocardial contractility without (1) provoking tachycardia and/or arrhythmias, (2) producing arterial hypotension, and (3) impairing microcirculation.

Dobutamine remains the first-line therapy of sepsis-induced cardiac dysfunction.[1] It activates the β1-adrenergic pathway after its binding to the β1-receptor (Fig. 2). However, β1-agonist agents can be less effective in case of septic shock.[25] In this regard, Kumar et al showed that dobutamine infusion increased the LVEF by more than 10% in only 35% of patients with septic shock.[51] When dobutamine therapy is considered, it is important to test its short-term effects in terms of efficacy and in terms of tolerance before any prolonged administration.

Figure 2.

Different classes of inotropes with different mechanisms of action. β1R, β1-receptor; PDE, phosphodiesterase; PKA, protein kinase A; SR, sarcoplasmic reticulum; ATP, adenosine triphosphate; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; PDE-I, phosphodiesterase inhibitor; A, actin filament; m, myosin filament.

Criteria of efficacy should be predefined and generally include increases in stroke volume and myocardial function indices [echocardiography, PiCCO (Pulsion)], increase in SvO2/ScvO2, and reduction of blood lactate level (Fig. 1). Note that in case of profound tissue hypoxia, an increase in oxygen consumption should follow the increase in cardiac output such that SvO2/ScvO2 does not increase significantly until a critical level of cardiac output is achieved. In other words, the absence of a large increase of SvO2/ScvO2 during the initial period of resuscitation with dobutamine is not an indicator of inefficacy of the drug and should not discourage the clinician to continue this therapeutic strategy.

Regarding tolerance of dobutamine therapy, monitoring echocardiography is mandatory because this drug is able to induce tachycardia or arrhythmias. Blood pressure monitoring is also important to perform given that dobutamine can induce additional hypotension due to a specific vasodilation (through β2-adrenergic receptors activation).

Levosimendan is a calcium sensitizer, which acts directly on myofilaments by improving their calcium sensitivity. Its mode of action is thus completely independent of the β1-adrenergic pathway (Fig. 2), and it might represent an alternative to dobutamine. In septic animals, levosimendan improves both systolic and diastolic cardiac function.[52] In a prospective, randomized study, Morelli et al showed in 28 patients with refractory septic shock (ie, persisting LV dysfunction after 48 hours of conventional treatment including dobutamine 5 μg/kg/min), that levosimendan (0.2 μg/kg/min) but not dobutamine, increased cardiac index and LVEF while decreasing PAOP.[53] Moreover, levosimendan increased gastric mucosal flow and creatinine clearance while it decreased blood lactate level.[53] Finally, levosimendan can improve RV performance by decreasing RV afterload through pulmonary vasodilatator effect.[54] Owing to its vasodilatory effects, levosimendan should not be used in absence of a concomitant administration of vasoconstrictor agents in the setting of septic shock. More studies are required to conclude definitively about the utility of levosimendan in septic shock with myocardial depression. Nevertheless, because the place of levosimendan is unclear in cases of acute heart failure, the commercialization of this drug has been impeded in many countries over the World.

Norepinephrine is used as a first-line vasopressor in septic shock owing to its α-agonist properties. As a β1-agonist, it can also increase cardiac contractility and cardiac output.[55] Because these effects are moderate, norepinephrine is not considered as the drug of choice in case of patent sepsis-induced cardiac dysfunction.

Epinephrine is a potent inotropic agent owing to its β1-agonist properties. Although, it was shown to be as effective as the combination of norepinephrine plus dobutamine,[56] it is not recommended as a first-line therapy to treat sepsis-induced cardiac dysfunction.[1] Indeed, epinephrine can induce lactic acidosis[57,58] and impair splanchnic microcirculation and gastric mucosal perfusion.[57,59]

Milrinone, as well as all other phosphodiesterase inhibitors, exerts an inotropic effect by increasing the cAMP concentration in the cardiomyocyte cytosol (Fig. 2). Because of their vasodilatory effects and the lack of strong positive data, these drugs are not recommended for the management of sepsis-induced cardiac dysfunction.

Antiinflammatory therapies, such as transforming growth factor β1 and inflammation pathway inhibitors, could block the development of sepsis-induced cardiac dysfunction, although these agents have no inotropic effect.[20,60] They represent a potential new therapeutic approach of sepsis-induced cardiac dysfunction.

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