Hemodynamic and anti-inflammatory effects of early esmolol use in hyperkinetic septic shock: a pilot study

Abstract

Background Several studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns. Methods Nine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1–H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases. Results Esmolol was infused 9 (6.4–11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34–0.83) to 0.78 (0.3–1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110–125) to 100 (92–103) beats/min and a decrease in cardiac index from 4.2 (3.1–4.4) to 2.9 (2.5–3.7) l/min/m−2. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients. Conclusion In the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287).

The autonomic nervous system in septic shock and its role as a future therapeutic target: a narrative review

“…Esmolol was associated with reduced HR and an unexpected faster vasopressor weaning together with an improvement in the 28-day mortality. This result still needs confirmation in a larger, multicenter clinical trial, however, because a recent attempt to replicate these observations was disappointing, mostly from a safety standpoint because of insufficient stroke volume compensation [ 91 ]. This risk related to the negative inotropic effect of esmolol was previously illustrated in another septic shock animal experiment, in which esmolol also had a global hypotensive effect [ 92 ].…”

Ultrashort-Acting β-Blockers

“…In the analyzed studies, administration of beta-blockers was avoided in the very early phase of septic shock to decrease the risk of blunting a chronotropic response, which at this stage represents the main mechanism for compensating the decrease in SV. In this regard, Levy et al 6 chestjournal.org the very early phase of septic shock, HR reduction with esmolol was associated with an increased risk of hypotension and decreased cardiac index. Although lactate and microcirculatory parameters were not affected, most pro-inflammatory proteins decreased in all patients, 6 supporting a possible immunomodulatory effect by beta-blockade.…”

“…In this regard, Levy et al 6 chestjournal.org the very early phase of septic shock, HR reduction with esmolol was associated with an increased risk of hypotension and decreased cardiac index. Although lactate and microcirculatory parameters were not affected, most pro-inflammatory proteins decreased in all patients, 6 supporting a possible immunomodulatory effect by beta-blockade.…”

“…5 Such findings support the assumption of beneficial pleiotropic (nonhemodynamic) effects of beta-blockers. 4,6 However, the bedside hallmark of sympathetic overstimulation in sepsis is tachycardia, which is also a well-known prognosticator of poor outcomes. 7 Whether tachycardia in septic shock is simply a prognostic biomarker or, more likely, a direct contributor to poor outcomes through a reduced myocardial performance is still a matter of debate.…”

“…Such "hidden" myocardial dysfunction may become evident only after HR reduction. 6,10,11 Another two important aspects are related to the the chosen HR range and the velocity of titration. The optimal HR threshold that should be reached with betablockade is one of the most difficult hemodynamic parameters to individualize, because it depends on myocardial performance, which may differ in sepsis.…”