Esmolol to Treat the Hemodynamic Effects of Septic Shock

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).

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