Esmolol infusion in patients with septic shock and tachycardia: a prospective, single-arm, feasibility study

Samuel M Brown, Sarah J Beesley, Michael J Lanspa, Colin K Grissom, Emily L Wilson, Samir M Parikh, Todd Sarge, Daniel Talmor, Valerie Banner-Goodspeed, Victor Novack, B Taylor Thompson, Sajid Shahul, Esmolol to Control Adrenergic Storm in Septic Shock-ROLL-IN (ECASSS-R) study, Naresh Kumar, Brent Armbruster, Valerie Aston, Anne Haroldsen, Samuel M Brown, Sarah J Beesley, Michael J Lanspa, Colin K Grissom, Emily L Wilson, Samir M Parikh, Todd Sarge, Daniel Talmor, Valerie Banner-Goodspeed, Victor Novack, B Taylor Thompson, Sajid Shahul, Esmolol to Control Adrenergic Storm in Septic Shock-ROLL-IN (ECASSS-R) study, Naresh Kumar, Brent Armbruster, Valerie Aston, Anne Haroldsen

Abstract

Background: High adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. In preparation for a randomized trial, we conducted a prospective, single-arm pilot study of esmolol infusion for patients with septic shock and tachycardia that persists after adequate volume expansion.

Methods: From April 2016 to March 2017, we enrolled patients admitted to an intensive care unit with sepsis who were receiving vasopressor infusion and were tachycardic despite adequate volume expansion. All patients received a continuous intravenous infusion of esmolol, targeted to heart rate 80-90/min, while receiving vasopressors. The feasibility outcomes were proportion of eligible patients consented, compliance with pre-infusion safety check, and compliance with the titration protocol. The primary clinical outcome was organ-failure-free days (OFFD) at 28 days.

Results: We enrolled 7 of 10 eligible patients. Mean age was 46 (± 19) years, and mean admission APACHE II was 28 (± 8). Median norepinephrine infusion rate at the initiation of esmolol infusion was 0.20 (0.14-0.23) μg/kg/min. Compliance with the safety check was 100%; compliance with components of the titration protocol was 98-100%. OFFD were 26 (24.5-26); all patients survived to day 90. Median peak esmolol infusion was 50 (25-50) μg/kg/min. Median peak norepinephrine infusion rate during esmolol infusion was 0.46 (0.13-0.50) μg/kg/min. Four patients achieved target heart rate. Protocol-defined stop events, suggesting possible intolerance to a given infusion rate, occurred in three patients, all of whom were receiving at least 50 μg/kg/min of esmolol.

Conclusions: In a pilot, single-arm study, we report the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States. These findings support a phase 2 trial of esmolol infusion for septic shock. Lower infusion rates of esmolol infusion may be better tolerated and more feasible than higher infusion rates for such a trial.

Trial registration: This study was retrospectively registered at ClinicalTrials.gov (NCT02841241) on 19 July 2016.

Keywords: Adrenergic antagonism; Beta blockade; Clinical trial; Heart rate variability; Multiple organ dysfunction; Organ-failure-free days; Sepsis.

Conflict of interest statement

This study was approved by the Intermountain Medical Center Institutional Review Board (1050147). Written informed consent was obtained from all patients or their legally authorized representatives. NA. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow of patients screened and enrolled in the present study

References

    1. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, Kadri SS, Angus DC, Danner RL, Fiore AE, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. Jama. 2017;318(13):1241–1249. doi: 10.1001/jama.2017.13836.
    1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–1310. doi: 10.1097/00003246-200107000-00002.
    1. Zimmerman JE, Kramer AA, Knaus WA. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit Care. 2013;17(2):R81. doi: 10.1186/cc12695.
    1. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Jama. 2016;315(8):775–787. doi: 10.1001/jama.2016.0289.
    1. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308–1316. doi: 10.1001/jama.2014.2637.
    1. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007;35(6):1599–1608. doi: 10.1097/01.CCM.0000266683.64081.02.
    1. Rudiger A, Singer M. The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol. 2013;11(2):187–195.
    1. Blanco J, Muriel-Bombin A, Sagredo V, Taboada F, Gandia F, Tamayo L, Collado J, Garcia-Labattut A, Carriedo D, Valledor M, et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care. 2008;12(6):R158. doi: 10.1186/cc7157.
    1. Vincent JL, Nelson DR, Williams MD. Is worsening multiple organ failure the cause of death in patients with severe sepsis? Crit Care Med. 2011;39(5):1050–1055. doi: 10.1097/CCM.0b013e31820eda29.
    1. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996;97(3):713–719. doi: 10.1172/JCI118469.
    1. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis*. Crit Care Med. 2014;42(3):625–631. doi: 10.1097/CCM.0000000000000026.
    1. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54(19):1747–1762. doi: 10.1016/j.jacc.2009.05.015.
    1. Barger AC, Herd JA, Liebowitz MR. Chronic catheterization of coronary artery: induction of ECG pattern of myocardial ischemia by intracoronary epinephrine. Proc Soc Exp Biol Med. 1961;107:474–477. doi: 10.3181/00379727-107-26661.
    1. Cebelin MS, Hirsch CS. Human stress cardiomyopathy. Myocardial lesions in victims of homicidal assaults without internal injuries. Hum Pathol. 1980;11(2):123–132. doi: 10.1016/S0046-8177(80)80129-8.
    1. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330(24):1717–1722. doi: 10.1056/NEJM199406163302404.
    1. Wilkman E, Kaukonen KM, Pettila V, Kuitunen A, Varpula M. Association between inotrope treatment and 90-day mortality in patients with septic shock. Acta Anaesthesiol Scand. 2013;57(4):431–442. doi: 10.1111/aas.12056.
    1. Beesley SJ, Wilson EL, Lanspa MJ, Grissom CK, Shahul S, Talmor D, Brown SM. Relative bradycardia in patients with septic shock requiring vasopressor therapy. Crit Care Med. 2017;45(2):225–233. doi: 10.1097/CCM.0000000000002065.
    1. Barnes SJ, Ackland GL. Beta-adrenoreceptor modulation of metabolic, endocrine and immunologic function during critical illness. Endocr Metab Immune Disord Drug Targets. 2010;10(3):292–300. doi: 10.2174/187153010791936883.
    1. Novotny NM, Lahm T, Markel TA, Crisostomo PR, Wang M, Wang Y, Ray R, Tan J, Al-Azzawi D, Meldrum DR. beta-Blockers in sepsis: reexamining the evidence. Shock. 2009;31(2):113–119. doi: 10.1097/SHK.0b013e318180ffb6.
    1. de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: beta-adrenergic modulation in sepsis. Crit Care. 2009;13(5):230. doi: 10.1186/cc8026.
    1. Oberbeck R, Kobbe P. Beta-adrenergic antagonists: indications and potential immunomodulatory side effects in the critically ill. Curr Med Chem. 2009;16(9):1082–1090. doi: 10.2174/092986709787581770.
    1. Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, D'Egidio A, Cecchini V, Landoni G, Pietropaoli P, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study. Crit Care Med. 2013;41(9):2162–2168. doi: 10.1097/CCM.0b013e31828a678d.
    1. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310(16):1683–1691. doi: 10.1001/jama.2013.278477.
    1. Beesley SJ, Wilson EL, Lanspa M, Grissom CK, Shahul S, Talmor D, Brown SM. Persistent tachycardia and mortality in septic shock patients. American Journal of Respiratory and Critical Care Medicine. 2017; [Abstract]
    1. Aronson D, Burger AJ. Effect of beta-blockade on autonomic modulation of heart rate and neurohormonal profile in decompensated heart failure. Ann Noninvasive Electrocardiol. 2001;6(2):98–106. doi: 10.1111/j.1542-474X.2001.tb00093.x.
    1. Fiuzat M, Wojdyla D, Pina I, Adams K, Whellan D, O'Connor CM. Heart rate or beta-blocker dose? Association with outcomes in ambulatory heart failure patients with systolic dysfunction: results from the HF-ACTION trial. JACC Heart Fail. 2016;4(2):109–115. doi: 10.1016/j.jchf.2015.09.002.
    1. Bristow MR. Treatment of chronic heart failure with beta-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology. Circ Res. 2011;109(10):1176–1194. doi: 10.1161/CIRCRESAHA.111.245092.
    1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655. doi: 10.1378/chest.101.6.1644.
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287.
    1. Miller RR, 3rd, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, Allen TL, Clemmer TP, Intermountain Healthcare Intensive Medicine Clinical P: Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 2013, 188(1):77–82.
    1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377. doi: 10.1007/s00134-017-4683-6.
    1. Critical Care Minimum Data Set [].
    1. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–843. doi: 10.1016/S0140-6736(07)60411-5.
    1. Gates S, Perkins GD, Lamb SE, Kelly C, Thickett DR, Young JD, McAuley DF, Snaith C, McCabe C, Hulme CT, et al. Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. Health technology assessment (Winchester, England) 2013;17(38):1–87.
    1. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–1311. doi: 10.1056/NEJMoa1500896.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–829. doi: 10.1097/00003246-198510000-00009.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710. doi: 10.1007/BF01709751.
    1. Brown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, Miller RR, Hirshberg EL, Grissom CK, Morris AH. Survival after shock requiring high-dose vasopressor therapy. Chest. 2013;143(3):664–671. doi: 10.1378/chest.12-1106.
    1. Squara P, Rotcajg D, Denjean D, Estagnasie P, Brusset A. Comparison of monitoring performance of bioreactance vs. pulse contour during lung recruitment maneuvers. Crit Care. 2009;13(4):R125. doi: 10.1186/cc7981.
    1. Marque S, Cariou A, Chiche JD, Squara P. Comparison between Flotrac-Vigileo and bioreactance, a totally noninvasive method for cardiac output monitoring. Crit Care. 2009;13(3):R73. doi: 10.1186/cc7884.
    1. Squara P, Denjean D, Estagnasie P, Brusset A, Dib JC, Dubois C. Noninvasive cardiac output monitoring (NICOM): a clinical validation. Intensive Care Med. 2007;33(7):1191–1194. doi: 10.1007/s00134-007-0640-0.
    1. Bagger T, Sloth E, Jakobsen CJ. Left ventricular longitudinal function assessed by speckle tracking ultrasound from a single apical imaging plane. Critical care research and practice. 2012;2012:361824. doi: 10.1155/2012/361824.
    1. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, Kass DA. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86(2):513–521. doi: 10.1161/01.CIR.86.2.513.
    1. Morelli A, Singer M, Ranieri VM, D'Egidio A, Mascia L, Orecchioni A, Piscioneri F, Guarracino F, Greco E, Peruzzi M, et al. Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock: a prospective observational study. Intensive Care Med. 2016;42(10):1528–1534. doi: 10.1007/s00134-016-4351-2.
    1. R Development Core team . R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2015.
    1. Lanspa MJ, Shahul S, Hersh A, Wilson EL, Olsen TD, Hirshberg EL, Grissom CK, Brown SM. Associations among left ventricular systolic function, tachycardia, and cardiac preload in septic patients. Ann Intensive Care. 2017;7(1):17. doi: 10.1186/s13613-017-0240-2.
    1. Lanspa MJ, Gutsche AR, Wilson EL, Olsen TD, Hirshberg EL, Knox DB, Brown SM, Grissom CK. Application of a simplified definition of diastolic function in severe sepsis and septic shock. Crit Care. 2016;20(1):243. doi: 10.1186/s13054-016-1421-3.
    1. Lanspa MJ, Pittman JE, Hirshberg EL, Wilson EL, Olsen T, Brown SM, Grissom CK. Association of left ventricular longitudinal strain with central venous oxygen saturation and serum lactate in patients with early severe sepsis and septic shock. Crit Care. 2015;19:304. doi: 10.1186/s13054-015-1014-6.
    1. Balik M, Rulisek J, Leden P, Zakharchenko M, Otahal M, Bartakova H, Korinek J. Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Wien Klin Wochenschr. 2012;124(15–16):552–556. doi: 10.1007/s00508-012-0209-y.
    1. Schmittinger CA, Dunser MW, Haller M, Ulmer H, Luckner G, Torgersen C, Jochberger S, Hasibeder WR. Combined milrinone and enteral metoprolol therapy in patients with septic myocardial depression. Crit Care. 2008;12(4):R99. doi: 10.1186/cc6976.
    1. Berk JL, Hagen JF, Maly G, Koo R. The treatment of shock with beta adrenergic blockade. Arch Surg. 1972;104(1):46–51. doi: 10.1001/archsurg.1972.04180010040011.
    1. Gore DC, Wolfe RR. Hemodynamic and metabolic effects of selective beta1 adrenergic blockade during sepsis. Surgery. 2006;139(5):686–694. doi: 10.1016/j.surg.2005.10.010.
    1. Wang Z, Wu Q, Nie X, Guo J, Yang C. Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial. Clinical drug investigation. 2015;35(11):707–716. doi: 10.1007/s40261-015-0325-3.
    1. Du W, Wang XT, Long Y, Liu DW. Efficacy and safety of esmolol in treatment of patients with septic shock. Chin Med J. 2016;129(14):1658–1665. doi: 10.4103/0366-6999.185856.
    1. Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RM, Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-Lane J, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016;
    1. De Santis V, Frati G, Greco E, Tritapepe L. Ivabradine: a preliminary observation for a new terapeutic role in patients with multiple organ dysfunction syndrome. Clinical research in cardiology : official journal of the German Cardiac Society. 2014;103:831–834. doi: 10.1007/s00392-014-0722-2.
    1. Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Laderchi A, Bachetoni A, D'Alessandro M, Van Aken H, Pietropaoli P, et al. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care. 2008;12(6):R143. doi: 10.1186/cc7121.
    1. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887. doi: 10.1056/NEJMoa067373.
    1. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430. doi: 10.1056/NEJMoa1704154.
    1. Russell JA, Vincent JL, Kjolbye AL, Olsson H, Blemings A, Spapen H, Carl P, Laterre PF, Grundemar L. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017;21(1):213. doi: 10.1186/s13054-017-1798-7.
    1. Lewis RJ, Angus DC, Laterre PF, Kjolbye AL, van der Meulen E, Blemings A, Graves T, Russell JA, Carlsen JE, Jacobsen K, et al. Rationale and design of an adaptive phase 2b/3 clinical trial of selepressin for adults in septic shock. Selepressin evaluation programme for sepsis-induced shock-adaptive clinical trial. Annals of the American Thoracic Society. 2018;15(2):250–257. doi: 10.1513/AnnalsATS.201708-669SD.

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