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

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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.

Electronic supplementary material

The online version of this article (10.1186/s40814-018-0321-5) contains supplementary material, which is available to authorized users.

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Most cited references 34

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The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.

Filippos Triposkiadis, George Karayannis, Grigorios Giamouzis … (2009)

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta(1)-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta(2)-ARs and alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.

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To review mechanisms underlying sepsis-induced cardiac dysfunction in general and intrinsic myocardial depression in particular. MEDLINE database. Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis. Due to the lack of a generally accepted definition and the absence of large epidemiologic studies, its frequency is uncertain. Echocardiographic studies suggest that 40% to 50% of patients with prolonged septic shock develop myocardial depression, as defined by a reduced ejection fraction. Sepsis-related changes in circulating volume and vessel tone inevitably affect cardiac performance. Although the coronary circulation during sepsis is maintained or even increased, alterations in the microcirculation are likely. Mitochondrial dysfunction, another feature of sepsis-induced organ dysfunction, will also place the cardiomyocytes at risk of adenosine triphosphate depletion. However, clinical studies have demonstrated that myocardial cell death is rare and that cardiac function is fully reversible in survivors. Hence, functional rather than structural changes seem to be responsible for intrinsic myocardial depression during sepsis. The underlying mechanisms include down-regulation of beta-adrenergic receptors, depressed postreceptor signaling pathways, impaired calcium liberation from the sarcoplasmic reticulum, and impaired electromechanical coupling at the myofibrillar level. Most, if not all, of these changes are regulated by cytokines and nitric oxide. Integrative studies are needed to distinguish the hierarchy of the various mechanisms underlying septic cardiac dysfunction. As many of these changes are related to severe inflammation and not to infection per se, a better understanding of septic myocardial dysfunction may be usefully extended to other systemic inflammatory conditions encountered in the critically ill. Myocardial depression may be arguably viewed as an adaptive event by reducing energy expenditure in a situation when energy generation is limited, thereby preventing activation of cell death pathways and allowing the potential for full functional recovery.

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Effective arterial elastance as index of arterial vascular load in humans.

Jeffrey C. Liu, M. Yang, R. D. Kass … (1992)

This study tested whether the simple ratio of ventricular end-systolic pressure to stroke volume, known as the effective arterial elastance (Ea), provides a valid measure of arterial load in humans with normal and aged hypertensive vasculatures. Ventricular pressure-volume and invasive aortic pressure and flow were simultaneously determined in 10 subjects (four young normotensive and six older hypertensive). Measurements were obtained at rest, during mechanically reduced preload, and after pharmacological interventions. Two measures of arterial load were compared: One was derived from aortic input impedance and arterial compliance data using an algebraic expression based on a three-element Windkessel model of the arterial system [Ea(Z)], and the other was more simply measured as the ratio of ventricular end-systolic pressure to stroke volume [Ea(PV)]. Although derived from completely different data sources and despite the simplifying assumptions of Ea(PV), both Ea(Z) and Ea(PV) were virtually identical over a broad range of altered conditions: Ea(PV) = 0.97.Ea(Z) + 0.17; n = 33, r2 = 0.98, SEE = 0.09, p less than 0.0001. Whereas Ea(PV) also correlated with mean arterial resistance, it exceeded resistance by as much as 25% in older hypertensive subjects (because of reduced compliance and wave reflections), which better indexed the arterial load effects on the ventricle. Simple methods to estimate Ea (PV) from routine arterial pressures were tested and validated. Ea(PV) provides a convenient, useful method to assess arterial load and its impact on the human ventricle. These results highlight effects of increased pulsatile load caused by aging or hypertension on the pressure-volume loop and indicate that this load and its effects on cardiac performance are often underestimated by mean arterial resistance but are better accounted for by Ea.

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Author and article information

Contributors

Samuel M. Brown:

ORCID: http://orcid.org/0000-0003-1206-6261

801-507-6556 , samuel.brown@imail.org

Sarah J. Beesley: sarah.beesley@imail.org

Michael J. Lanspa: michael.lanspa@imail.org

Colin K. Grissom: colin.grissom@imail.org

Emily L. Wilson: emily.wilson@imail.org

Samir M. Parikh: sparikh@bidmc.harvard.edu

Todd Sarge: tsarge@bidmc.harvard.edu

Daniel Talmor: dtalmor@bidmc.harvard.edu

Valerie Banner-Goodspeed: vgoodspe@bidmc.harvard.edu

Victor Novack: VictorNo@clalit.org.il

B. Taylor Thompson: tthompson1@mgh.harvard.edu

Sajid Shahul: sshahul1@dacc.uchicago.edu

Journal

Journal ID (nlm-ta): Pilot Feasibility Stud

Journal ID (iso-abbrev): Pilot Feasibility Stud

Title: Pilot and Feasibility Studies

Publisher: BioMed Central (London )

ISSN (Electronic): 2055-5784

Publication date (Electronic): 3 August 2018

Publication date PMC-release: 3 August 2018

Publication date Collection: 2018

Volume: 4

Electronic Location Identifier: 132

Affiliations

[1 ]ISNI 0000 0004 0609 0182, GRID grid.414785.b, Pulmonary and Critical Care Medicine, , Intermountain Medical Center, ; Murray, UT USA

[2 ]ISNI 0000 0001 2193 0096, GRID grid.223827.e, Pulmonary and Critical Care Medicine, , University of Utah, ; Salt Lake City, UT USA

[3 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Nephrology and Vascular Biology, , Beth Israel Deaconess Medical Center, ; Boston, MA USA

[4 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Anesthesia and Critical Care Medicine, , Beth Israel Deaconess Medical Center, ; Boston, MA USA

[5 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Pulmonary and Critical Care Medicine, , Massachusetts General Hospital, ; Boston, MA USA

[6 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Department of Anesthesia, , University of Chicago, ; Chicago, IL USA

[7 ]ISNI 0000 0004 0609 0182, GRID grid.414785.b, Shock Trauma Intensive Care Unit, , Intermountain Medical Center, ; 5121 South Cottonwood Street, Murray, UT 84107 USA

Author information

Samuel M. Brown http://orcid.org/0000-0003-1206-6261

Article

Publisher ID: 321

DOI: 10.1186/s40814-018-0321-5

PMC ID: 6091011

PubMed ID: 30123523

SO-VID: 0a60cf7a-e786-491d-ae47-d2b2c455b083

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 August 2017

Date accepted : 17 July 2018

Custom metadata

Keywords: sepsis,beta blockade,adrenergic antagonism,clinical trial,heart rate variability,organ-failure-free days,multiple organ dysfunction

Data availability:

Keywords: sepsis, beta blockade, adrenergic antagonism, clinical trial, heart rate variability, organ-failure-free days, multiple organ dysfunction

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

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Abstract

Background

Methods

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Drug Repurposing

Most cited references 34

The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.

Mechanisms of sepsis-induced cardiac dysfunction.

Effective arterial elastance as index of arterial vascular load in humans.

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