Esmolol for Heart Rate Control in Septic Shock

Septic shock is associated with the excessive sympathetic stress associated with a number of adverse physiological effects, ranging from myocardial depression to immunosuppression. Morelli and colleagues from the Sapienza University of Rome conducted a study to determine whether administration of a short-acting beta-adrenoreceptor blocker, esmolol, could reduce heart rate to a target range of 80 to 94 beats per minute (bpm) in patients with septic shock. The physiologic consequences of heart rate reduction were also examined, as well as secondary clinical outcomes.

In this single-center, open-label (non-blinded), randomized two-group trial, patients with septic shock requiring norepinephrine to maintain a mean arterial pressure above 65 mm Hg, and a heart rate greater than 95 bpm were  monitored with a pulmonary artery catheter using continuous thermodilution. Esmolol was titrated, starting at a dose of 25 mg/h, to achieve the primary outcome: reduction of heart rate to between 80 and 94 bpm. Secondary outcomes included the effect of esmolol on norepinephrine requirements, cardiorespiratory and oxygenation indices, safety endpoints, and 28-day overall survival. The intention-to-treat principle was used in all analyses. Nonparametric and parametric statistics were used together with a multivariable Cox regression model to adjust for multiple covariates such as age, presence of multidrug-resistant infections, and severity of illness (Simplified Acute Physiology Score version II).

After 336 patients were screened, 77 were included in the experimental arm and 77 in the control arm. Baseline data were similar in the groups. Patients treated with esmolol had significantly lower heart rates throughout the study period. Mean arterial pressure was maintained despite a reduction in norepinephrine requirements in the esmolol group. Stroke volume, stroke volume ratio, and left ventricular stroke work index were increased in the esmolol group. Patients in the esmolol group had higher glomerular filtration rates, a trend maintained when patients requiring dialysis were excluded. Both unadjusted and adjusted mortality at 28 days was significantly lower  in the esmolol group compared to the control group (49.4% vs. 80.5%; hazard ratio, 0.392; 95% confidence interval, 0.261 to 0.59; P<0.001).

These results represent a single-center experience, and several additional factors may have played a role in the observed physiological changes, such as a high incidence of multidrug-resistant causative organisms, use of hydrocortisone in all patients, and use of the calcium channel sensitizer levosimendan in some patients. As pointed out in the accompanying editorial by Pinsky, beta-blockers may exert beneficial effects. Additional multicenter randomized trials are warranted to replicate the results of Morelli et al and to further elucidate mechanisms responsible for physiological and clinical outcomes in septic shock patients receiving esmolol.

Samuel M. Galvagno Jr., DO, PhD, is editor of Concise Critical Care Appraisal. An assistant professor at the University of Maryland, R Adams Cowley Shock Trauma Center, he is board certified in anesthesiology, critical care medicine, and public health.

eNewsletter Issue:

8 thoughts on “Esmolol for Heart Rate Control in Septic Shock

  1. Rajesh MISHRA

    This concept is already being practiced in CCF patient. Only concern to be watched for in hemodynamic . If is under control then we are heading for a breakthrough trail in critical care .

  2. Addison May

    As noted in one comment, mortality was reduced in the esmolol group. The concise review mistakenly stated that survival was lower in the the esmolol group, rather than mortality. This study demonstrates that heart rate can be successfully reduced in the face of vasopressor requirements. The improved measures and the reduction in mortality are very intriguing and clearly deserve further investigation. The single center, small numbers, and unblinded nature of this study precludes the generalization of these findings.

  3. Chet Morrison

    The author of this review did mean ‘Mortality’ not survival. It is an intriguing study to be sure with some points to recommend it, most notably the ability to individually titrate beta blockade therapy to a predetermined endpoint, rather than giving everyone the same dose, also ensuring patients were properly resuscitated before commencing beta blockade therapy. As some constructive criticism in terms of writing this eConnections abstract, it is helpful if the patient population is defined and most notably that the inclusion and exclusion criteria are explicitly stated. In this study, non-tachycardic patients were excluded, as well as patients who had prior beta blockade therapy, which is a bit surprising to me, and pts with preexisting cardiac dysfunction, which isn’t. But anyway this is a study that should be on the radar of critical care physicians so I appreciate the abstract.

  4. Alaa Mohamed

    The study had two end point , the primary which is the heart rate control and secondary which included the reduction in norepi requirement / 28 days mortality , but the study power which is 80% was mainly for the primary end point , so the secondary end point should be look at and interpret with caution , the NNT for 28 days with esmolol was 3 and total hospital mortality was 4 ….. its a remarkable results …. but as been said in the above comments its a single center study with small group size .

  5. Giuseppe Gristina

    Dear Colleague
    I read your comments in regard to the paper by Morelli and coworkers published in JAMA –
    Some aspects of this paper are unclear needing a careful consideration.

    1. the mortality of pts in control group was 80.5% vs 49.4% in esmolol group –
    In the year 2012 data from 147 Italian ICUs participating in GiViTI national database [1, 2] showed mortality related to Septic Shock (SeSh) was:
    a) for SeSh ICU admission : n=2574: ICU-mortality 48.7% ; H-discharge-mortality 56.7%
    b) for SeSh during ICU stay: n=451: ICU-mortality 55.5% ; H-discharge-mortality 61.3%
    c) for SeSh during ICU stay in pts admitted as infected : n=571 : ICU-mortality 47.9% ; H-discharge-mortality 55.9%

    2. 154 pts were included in the study from 1 November 2010 to 31 July 2012 (= 630 days), that is 630/154 = 1 SeSh pt enrolled/4 days.
    The GiViTI 2012 [1] database shows that 45.176 pts were admitted in 147 Italian ICUs. 5.6% of these pts (n=2574) received a SeSh diagnosis on admission. On the average this stands for 18 pts/ICU. Taking into account the same period of Morelli’s study (630 days) we expect 1 SeSh pt/35 days.

    3. Primary study endpoint was: 80/’ < HR < 95/’ ___ Secondary end-points were: norepinephrine requirement — cardiorespiratory and oxygenation indices — markers of organ function & injury — rescue therapy with other drugs — 28-day overall survival.

    The authors do not included mortality among end points. Mortality per se needs a different number of patients to be explored probably greater than 154 (to each end point his own power of study)

    4. In the methods section the authors declare:” After approval by the local institutional ethics committee, we performed the study in the 18-bed multidisciplinary intensive care unit (ICU) of the University of Rome “La Sapienza” Hospital, after written informed consent from the patients’next of kin.”

    In Italy the statute law do not consider the next of kin consent as a valid juridical tool for starting a research clinical trial involving non competent human beings that is the case of SeSh pts.

    1. http://www.giviti.marionegri.it/Download/ReportPetaloInfezioni_2012_IT_ITALIA.pdf
    2. Malacarne P, Langer M, Nascimben E, Moro ML, Giudici D, Lampati L, Bertolini G, GiViTI
    Building a continuous multicenter infection surveillance system in the intensive care unit: findings from the initial data set of 9,493 patients from 71 Italian intensive care units. Crit Care Med 2008; 36(4): 1105-13

    Best regards — Giuseppe R. Gristina, MD

  6. Sam Galvagno

    Dear Chett and Leo,

    Thanks for catching this error–I will make sure this gets reposted correctly.
    I am amazed by how many of our readers read these brief synopses with such detail! Regarding inclusion and exclusion criteria, we will try to add this information when possible, but as I am sure you understand, sometimes this information can spill over to two or more paragraphs. The goal of these CCAs is to simply introduce readers to the article with a succinct summary.

    Thank you for the excellent feedback!

    Very respectfully,
    Sam G.

  7. Dr Cate Fourie

    An unfortunate miss print; but excepting that the article suggests survival benefit from Esmolol in septic shock:
    Now the question remains whether it is a specific effect of Esmolol (beta blockers) or an effect due to heart rate control in general. Or may be our vasopressors induce a harmful tachycardia.
    I shall be watching future data with keen interest.

Comments are closed.