Beta-blockers in sepsis
Authors: Singer Mervyn 
Published: December 2019

Catecholamines are an integral component of the host stress response and usually increase appropriately at times of need. Unfortunately, in severe and prolonged critical illness, they can contribute to significant harm with unwanted biological effects on cardiac function, inflammatory, immune, metabolic, and coagulation pathways. A good example is Takotsubo (‘stress’) cardiomyopathy where heart failure ensues after an emotional stress resulting in extremely high levels of circulating catecholamines, considerably above that seen in a significant myocardial infarction.

Unwittingly, we are likely contributing to catecholamine toxicity in our management of the critically ill septic patient through use of exogenous catecholamine therapies which carry the same detrimental effects as endogenous catecholamines. Catecholamines are currently recommended first-line agents for septic shock, and are used in an attempt to overcome the vascular hyporeactivity and myocardial depression associated with sepsis. Use of higher doses of catecholamines is however associated with worse outcomes. This is usually ascribed to the patient's underlying illness severity and an iatrogenic contribution is not considered – but perhaps should be.

Beta-blockers have multiple actions, on cardiac function and beyond. They reduce cardiac work through negative inotropic and chronotropic effects. Importantly, through slowing an excessive heart rate, both systolic and diastolic ventricular function are improved. They also act on adrenergic receptor responsiveness, enhancing the activity of catecholamines and allowing reductions in dose to achieve the same haemodynamic effect. Outside the heart, they improve vascular tone, enhance metabolic efficiency, and have anti-inflammatory effects and anti-thrombotic activity.

The first use of beta-blockade in sepsis goes back nearly 50 years with successful use in some patients in refractory shock. In the last decade an increasing number of observational studies and a few single-centre randomised controlled trials have shown both safety and improved outcomes. These reflect findings in animal models of sepsis where various mechanisms were demonstrated including protective effects on the heart, anti-inflammatory actions and preservation of the gut barrier.

Clearly, the patient needs to be adequately fluid-resuscitated and stabilised before commencing beta-blockers. Ideally, the use of a short-acting agent such as esmolol or landiolol allows easy titration, or cessation, of the infusion should hypotension or excess bradycardia occur with the unwanted effects wearing off within minutes. The largest study to date by Morelli et al., randomised 154 septic shock patients to receive either placebo or esmolol to reduce heart rate to 80-95 bpm. This was successfully achieved with no increase in complication rates compared to placebo. Importantly, there were also benefits in terms of earlier recovery of renal function, cessation of norepinephrine infusion, lower troponin levels (indicative of less cardiac damage), and improved survival rates. These encouraging findings need to be repeated in multicentre settings and two studies (one UK-based “STRESS-L”, one in 4 European countries) are currently ongoing.