Esmolol Infusion for Patients With Septic Shock and Persistent Tachycardia
Condition: Septic Shock
MeSH terms: Shock, Septic; Shock
Intervention: Esmolol
Intervention description: Esmolol infusion
Intervention MeSH terms: Esmolol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: esmolol; adrenergic storm; septic shock

Summary:

      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.
    

Eligibility criteria:

        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.