Beta blockade in sepsis

tachy-iconWhat do septic patients need if they remain shocked after fluid resuscitation? Catecholamines right? Let’s stimulate some adrenoceptors and support that circulation!
Sydney’s Prof Myburgh has told us why adrenaline (epinephrine) and noradrenaline (norepinephrine) are the go-to vasoactive choices, and Prof Singer from London likes to remind us about the detrimental effects of these drugs – the pros and cons are listed here. Tachycardia is associated with worse outcomes in sepsis, and the balance of oxygen supply and demand can be difficult to achieve. Beta blocking drugs could reduce tachycardia, but there does seem to be something counter-intuitive about giving both beta-blockers and catecholamines in the same patient. You might expect that beta blockers would cause fall in cardiac output and worsen tissue perfusion.
A small study previously showed possible helpful effects of beta blockers in children with burns. The potential benefits may extend beyond control of heart rate to anti-inflammatory / anti-catabolic effects. A recent publication evaluated beta blockers in adult patients with septic shock, which appears to be a pilot study for an ongoing randomised controlled trial.
They included patients who had been fluid resuscitated and who required noradrenaline, and treated them with a titrated esmolol infusion commenced at 25 mg/hr, with an upper dose limit of 2,000 mg/hr, to maintain a predefined HR range between 80 and 94 beats per minute. Esmolol was chosen because of its half-life of approximately 2 min, so any adverse effects could be rapidly reversed. They examined the macrocirculation using pulmonary artery catheterisation and the microcirculation using sublingual microvascular blood flow imaging.
Most of the patients had pneumonia, and interestingly, all patients received intravenous hydrocortisone (200mg/d) as a continuous infusion.
In this small cohort of patients, they found that titrating the heart rate to less than 95 bpm was associated with maintenance of stroke volume and preservation of microvascular blood flow. Although cardiac output fell because of the lower HR, stroke volume, MAP, and lactate levels were unchanged while noradrenaline requirements were reduced.

Increased vascular reactivity to norepinephrine following nonselective β-blockade is supported by volunteer and animal studies, and postulated mechanisms include:

  • blockade of a peripheral β2-mediated vasodilatory effect of noradrenaline
  • decreased clearance of infused noradrenaline
  • a centrally mediated effect on reflex activity
  • inhibition of vascular endothelial nitric oxide synthase activity

Microvascular Effects of Heart Rate Control With Esmolol in Patients With Septic Shock: A Pilot Study
Crit Care Med. 2013 Sep;41(9):2162-2168
[EXPAND Abstract]


OBJECTIVE: β-blocker therapy may control heart rate and attenuate the deleterious effects of β-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the β-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation.

DESIGN: Prospective, observational clinical study.

SETTING: Multidisciplinary ICU at a university hospital.

MEASUREMENTS AND MAIN RESULTS: After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart rate greater than or equal to 95 beats per minute and requiring norepinephrine to maintain mean arterial pressure greater than or equal to 65 mm Hg received a titrated esmolol infusion to maintain heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 24 hours after esmolol administration. Heart rates targeted between 80 and 94 beats per minute were achieved in all patients. Whereas cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m; p < 0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m; p = 0.32). Microcirculatory blood flow in small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p = 0.002), while the heterogeneity index decreased (median 0.06 [interquartile range 0; 0.21] vs 0 [0; 0]; p = 0.002). PaO2 and pH increased while PaCO2 decreased (all p < 0.05). Of note, norepinephrine requirements were significantly reduced by selective β-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03).

CONCLUSIONS: This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.


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