Esmolol to Control Adrenergic Storm in Septic Shock- ROLL-IN 2

This is a prospective, single arm, feasibility study of esmolol infusion in septic shock. The
objective is to evaluate the feasibility, adequacy, and efficiency of study protocols for a
subsequent ECASSS study. This study (ECASSS-R2) extends observations made in an initial
pilot, ECASSS-R.

Inclusion Criteria:

1. Age ≥ 18 years

2. Within 72 hours of admission to the ICU and septic shock (sepsis present at time of
admission)

a. Septic shock defined by SEPSIS-3 consensus criteria as i. Suspected or documented
infection ii. Sequential Organ Failure Assessment (SOFA) score increased by at least 2
points over baseline iii. Lactate > 2mmol/L iv. Receiving vasopressors to treat
hypotension after at least 20 ml/kg intravenous crystalloid volume expansion

3. Receiving vasopressors through a central venous catheter for more than 60 minutes.

4. Arterial catheter in place or expected to be placed imminently.

5. Heart rate > 90/min while receiving vasopressors for more than 60 minutes.

6. Adequately volume expanded, as manifest by any of the following, performed as part of
routine clinical care (i.e., no study procedures will be performed before signed
consent). If none of these measures are clinically available, the clinical attending
must confirm that volume expansion is adequate. (After enrollment, a final safety
check will confirm the adequacy of volume expansion.)

1. Central venous pressure (CVP) > 15 mm Hg.

2. Negative Passive-Leg Raise (PLR) maneuver (<10% increase in cardiac output after
PLR).

3. No cardiac output response (<10% increase) after rapid infusion (<5 min) of 250
ml of IV crystalloid (i.e., a graded volume expansion challenge [GVEC]).

4. Inferior vena cava (IVC) plethora

5. For patients who happen to be breathing passively (i.e., paralyzed or deeply
sedated) on a positive pressure mechanical ventilator delivering at least 8 ml/kg
tidal volumes and in normal sinus rhythm, stroke volume variability <13% (such
patients are acknowledged to be uncommon; the protocol does not recommend or
require the induction of passive breathing).

Exclusion Criteria:

1. Lack of informed consent.

2. Currently receiving ExtraCorporeal Membrane Oxygenation (ECMO).

3. Known pregnancy or nursing.

4. Patient is a prisoner.

5. Patient on hospice (or equivalent comfort care approach) at or before the time of
enrollment.

6. Known or current atrial fibrillation.

7. Previously enrolled in the trial.

8. Known allergy to esmolol or vehicle (see Appendix 2 for BREVIBLOC vehicle
ingredients).

9. Receipt of nodal blocking agents (see Appendix 3 for list of such agents) within three
half lives

10. Hemoglobin < 7 gm/dl.

11. Cardiac arrest within 24 hours.

12. Pulmonary hypertension (moderate or severe), from documented history of prior right
heart catheterization or current evidence on transthoracic echocardiogram (TTE) of any
of the following

- Mean Pulmonary Arterial Pressure (mPAP) ≥ 35mmHg (millimeters of mercury)

- Systolic Pulmonary Arterial Pressure (SPAP) ≥ 60mmHg (millimeters of mercury)

13. Cardiovascular collapse, as manifested by inability to achieve a mean arterial
pressure (MAP) of 65 mmHg with vasopressor therapy.

14. Cardiogenic shock, as defined by any of the following

- Cardiac index ≤ 2.3 L/min/m2

- Ejection fraction ≤ 30%

- ScvO2 ≤ 60%

- Current infusion of any dose of dobutamine, milrinone, or dopamine (if dopamine
is being used for clinically diagnosed bradycardia or cardiogenic shock)

- Current infusion of epinephrine for clinically diagnosed cardiogenic shock

15. Significant atrioventricular dysfunction

- Sick sinus syndrome

- PR interval > 200 msec

- Current evidence or prior history of Grade 2 or Grade 3 heart block

- Pacemaker or plans to place a pacemaker

16. Pheochromocytoma or status asthmaticus

17. Receiving clonidine, guanfacine, or moxonidine

18. Worse than moderate aortic stenosis

- Known aortic stenosis, with any of (1) mean gradient ≥ 40 mmHg OR (2) maximum
gradient ≥ 60mmHg OR (3) aortic valve area ≤ 1.0cm2 OR (4) aortic valve area
index ≤ 0.85cm2/m2 body surface area.

19. Worse than mild mitral stenosis

- Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5
mmHg.