This is a prospective, single arm, "roll-in" study of esmolol infusion for patients with septic shock with persistent tachycardia after adequate intravenous volume expansion. The study will evaluate the adequacy and efficiency of study protocols for the anticipated, main ECASSS study, which will have a separate entry in clinicaltrials.gov.

PRIMARY OBJECTIVE:

To evaluate the adequacy and efficiency of study protocols for the anticipated, randomized, controlled ECASSS study. The primary clinical outcome is organ-failure free days at 28 days, with multiple secondary outcomes, including those relevant to function of and compliance with the study protocols.

Inclusion Criteria:

1. Age ≥ 18 years

2. Within 48 hours of admission to the ICU and septic shock (sepsis present at time of admission)

   a. Septic shock defined by consensus criteria as i. At least two systemic inflammatory response syndrome (SIRS) criteria ii. Suspected or documented infection iii. 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. For patients who happen to be breathing passively on a positive pressure mechanical ventilator delivering at least 8 ml/kg tidal volumes and in normal sinus rhythm, stroke volume variability <10% (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 ECMO (extracorporeal membrane oxygenation).

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

9. Receipt of nodal blocking 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 TTE (transthoracic echocardiography) of any of the following

    • mPAP (mean pulmonary artery pressure) ≥ 35 mmHg
    • SPAP (systolic pulmonary artery pressure)≥ 60 mmHg

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

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

    • Cardiac index ≤ 2 L/min/m2
    • Ejection fraction ≤ 25%
    • ScvO2 ≤ 60%
    • Current infusion of any dose of dobutamine, milrinone, or dopamine
    • Current infusion of epinephrine for clinically diagnosed cardiogenic shock

15. Significant atrioventricular dysfunction

    • Sick sinus syndrome
    • PR interval (time from onset of P wave to start of QRS complex) > 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. Hemoglobin < 7 gm/dl

19. Cardiovascular collapse (failure to achieve MAP of 65mmHg)

20. Cardiac arrest within 24 hours

21. 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.

22. Worse than mild mitral stenosis • Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean gradient ≥ 5 mmHg.

Duration of esmolol infusion (approximately 2 days)