Esmolol to Treat the Hemodynamic Effects of Septic Shock

The main purpose of this study is to determine the effects of controlling the heart rate of patients with septic shock using an intravenous medication called esmolol.

Septic shock is a leading cause of death around the world, with a mortality that often ranges 30-50% but in some locations may be even higher. Despite advances in critical care medicine over the last several decades, few therapeutic interventions have demonstrated mortality benefit in this population besides antimicrobial medications, intravenous fluids, and controlling the source of the infection; multiple agents which at one time showed promise have ultimately failed to deliver meaningful clinical benefit. As such, there is an ongoing need to identify therapeutic interventions which can modify the course of disease for these patients.

Septic shock is traditionally characterized by a hyperdynamic hemodynamic profile with a high cardiac output (CO) and low systemic vascular resistance (SVR) in association with excessive catecholamine stimulation. Tachycardia is a common finding in septic shock as an early compensatory mechanism to increase cardiac output in the setting of low SVR. Often tachycardia persists beyond the initial stages of septic shock, and has been associated with restricted diastolic ventricular filling, increased oxygen requirements, and tachycardia-induced cardiomyopathy, as well as myocardial depression, immunosuppression, and direct myocyte toxicity via calcium overload. Generally, clinical practice has been to avoid trying to control the tachycardic response for fear of worsening cardiac output and causing cardiovascular collapse. However, a recent single center randomized trial of the intravenous beta-1 adrenoreceptor antagonist esmolol demonstrated that control of heart rate to a more 'normal' range was safe, well-tolerated, and appeared beneficial, with a 30% reduction in mortality found in this trial.

While an intriguing concept with results that appear promising, further investigation among an ICU cohort in the United States is necessary before the administration of beta-blockade therapy to a patient in septic shock should be implemented in routine clinical practice. We hypothesize that the provision of esmolol to patients in vasopressor-dependent septic shock with tachycardia will lower the heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in need for vasopressor support. To test our hypothesis, we are conducting a Phase II randomized trial to determine if esmolol decreases vasopressor requirements (primary endpoint) and alters the inflammatory cascade as well as oxygen consumption in patients with septic shock (secondary endpoints).

Eligibility Criteria:
Inclusion Criteria:

* Adult (≥ 18 years)
* Sepsis defined as suspected or confirmed infection with at least two systemic inflammatory response syndrome (SIRS) criteria
* Norepinephrine (minimum 0.1 mcg/kg/min) support to maintain a mean arterial pressure ≥ 65 mmHg despite appropriate volume resuscitation (as defined by the clinical team, however at least 30mL/kg intravenous fluid
* Heart rate ≥ 95 per minute for at least 2 hours prior to enrollment
* 6-24 hours since ICU admission

Exclusion Criteria:

* Intravenous β-blocker therapy prior to randomization
* Pronounced cardiac dysfunction (i.e. cardiac index \[CI\] ≤ 2.2 L/min/m2)
* Known significant valvular heart disease
* Research-protected populations (pregnant women, prisoners, intellectually disabled)
* Known "Do-not-resuscitate" or "do-not-intubate" order at the time of enrollment
* Infusion of epinephrine, dopamine, dobutamine or milrinone at time of enrollment
* Known allergy/sensitivity to esmolol or history of asthma/COPD