Sepsis and beta-blockade: a look into diastolic function

Abstract

There is growing interest on the modulation of the overwhelming sympathetic response of septic patients. Beta-blockers appear promising in this respect and, although we are at early stage, one large trial and a smaller one have demonstrated major beneficial effects. The modulation of diastolic function and the optimization of myocardial efficiency by beta-blockade is among the possible reason for the improvement in patients with severe sepsis or septic shock. It should be also considered that septic patients are at higher risk of cardiac arrhythmias and beta-blocker may have a protective effect in this regard. We are still at a preliminary stage and more research is needed it seems reasonable that beta-blockade will become an option for the treatment of septic patients over the next few years.

Keywords: :

• Beta blockade
• Myocardial dysfunction
• Septic shock
• Severe sepsis

In the present issue of CMRO, Sanfilippo et al.1 discuss the results of a systematic review on the use of beta blockade in patients with severe sepsis or septic shock. The authors found only two randomized controlled trials (RCTs) including a total of 195 patients, a few small prospective and retrospective studies and several experimental studies. Therefore it seems reasonable to wait for more data before attempting a meta-analysis. Nonetheless, this promising new approach to the care of septic patients has generated enthusiasm in the intensive care community and more research is ongoing.

Sepsis is still burdened by high mortality2^,3 and one of its main hallmarks is the profound cardiovascular derangement characterized by a high cardiac output state, profound vasodilatation and tachycardia4^,5. In this context, reducing heart rate (HR) may optimize myocardial efficiency while reducing myocardial oxygen consumption. Indeed, saving the heart almost 20 beats/min on average was safe in the RCT by Morelli et al.6. In this study a control of HR to a target range of 80–95 beats/min did not worsen any systemic or pulmonary hemodynamic parameters investigated and, on the contrary, showed a potential improvement in hemodynamics. Indeed, while maintaining the same mean arterial pressure target (>65 mmHg), esmolol infusion improved the stroke volume index and the LV stroke work index. More importantly, in the esmolol group the dosages of norepinephrine decreased significantly (median reduction of 0.11 mcg/kg/min) despite a less positive fluid balance (median fluid administration lower by roughly 500 ml per 24 hour period); this was also associated with improvements in markers of perfusion such as arterial lactate levels and glomerular filtration rate.

These results point towards a beneficial cardiovascular effect of beta blockade by blunting the septic hyper-adrenergic drive. Interestingly, in the VASST trial7 a reduction in HR in the subgroup with less severe septic shock was found in the treatment group (vasopressin) and was associated with a reduction in mortality, supporting the idea that avoidance of tachycardia and blunting catecholamine over-stimulation could be beneficial in septic patients.

Sepsis is associated with myocardial dysfunction both at systolic and diastolic level8^,9. Nonetheless, a recent meta-analysis did not find a correlation between left or right ventricle (LV or RV) systolic dysfunction and survival in patients with severe sepsis or septic shock10. On the other hand, another recent meta-analysis found a strong correlation between LV diastolic dysfunction and mortality in septic patients11^,12. With this background it is worth commenting about the potential beneficial action of beta blockade on the LV diastolic function. For instance, carvedilol – an alpha₁/beta-blocker – has significantly improved LV diastolic function in patients with diastolic heart failure and normal LV systolic function13. In patients with severe sepsis or septic shock, there are at least a couple of reasons why beta blockade may improve LV diastolic function. First of all, a reduction in tachycardia should ameliorate the LV filling by increasing the diastolic time. Although reasonable, it remains speculative that this reduction in HR improved the LV diastolic filling pattern in the trial by Morelli et al.6 since this study did not include a structured echocardiographic assessment. In this regard, the ongoing ESMOSEPSIS trial may appropriately answer this question because it includes a formal echocardiographic assessment of LV function. A second potentially beneficial action of beta blockade on LV diastolic function could come from its anti-arrhythmic effects. For instance, sepsis is a recognized independent risk factor for developing atrial fibrillation14 which itself causes the loss of late (atrial) contribution to LV filling during diastole. In patients with impaired LV diastolic function this loss is not always well compensated and can severely affect cardiovascular dynamics. This hypothesis remains speculative in explaining the benefits of beta blockade since the incidence of atrial fibrillation and arrhythmias has not been reported by the studies on beta blockade in sepsis.

On the other hand, the study by Morelli et al.6 has been criticized because almost half of the patients in the esmolol arm received infusion of the calcium sensitizer levosimendan15 in order to improve systemic oxygen delivery. Levosimendan increases inothropism without alteration in myocardial oxygen demand and improves LV relaxation pattern by shortening the iso-volumetric relaxation time16. Therefore it may have contributed to the possible improvement in LV filling pattern in a significant proportion of the population. It is also worth noting that levosimendan is under investigation in septic patients as a strategy to prevent acute organ dysfunction (the ongoing LeoPARDS trial)17.

In summary, we are still at a preliminary stage and more research is needed but there are reasonable chances that beta blockade will become an option for the treatment of septic patients over the next few years.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

M.A. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article.