A large UK trial is testing whether a drug that slows the heart can save people dying from septic shock—a condition where the body’s own immune response becomes dangerously overactive. Sepsis kills over 40% of patients who develop septic shock, and current treatments—mainly the vasopressor noradrenaline—have not improved survival in decades. Beta-blockers have long been considered dangerous in sepsis because they counteract the adrenaline-like drugs used to maintain blood pressure. But a small Italian study found that giving the short-acting beta-blocker esmolol to patients with dangerously fast heart rates more than halved the risk of death. The STRESS-L trial will test whether a similar drug, landiolol, can replicate that result in 340 UK patients. If the approach works, it would represent a fundamental shift in how intensive care doctors manage septic shock—moving from simply propping up blood pressure to actively calming the runaway sympathetic nervous system. The researchers will also measure whether the drug reduces inflammation and heart muscle injury. A positive result could change treatment guidelines worldwide and save thousands of lives each year, with no new technology required—just a different use of an existing drug.
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Sepsis is a major cause of mortality and morbidity worldwide, and its incidence is increasing. The mortality rate from its most severe manifestation, septic shock, remains very high (>40% in 4 randomised controlled trials recently reported in the New England Journal and >60% with high noradrenaline doses and tachycardia). Until recently, specific therapeutic strategies have failed to reduce mortality but a recent randomised single centre study of 154 patients from Rome (Morelli 2013) found that beta-adrenergic blockade using the short-acting agent, esmolol could be safely administered to tachycardic septic patients who required high-dose vasopressor therapy for >24 hours. The dosing endpoint was reduction in heart rate to 80-94 beats/min (bpm). The study was not powered for mortality but marked improvements were seen in survival (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; p <0.001) as well as time on vasopressors, and biochemical and functional markers of renal, pulmonary and cardiac function. If replicable in larger studies, this represents an unexplored mechanism in sepsis and has important implications for the treatment and outcomes of this high-risk population. A recent review (Chacko 2015) concluded that there was currently insufficient evidence to justify the routine use of beta-blockade in septic shock and further adequately powered multi-centred randomized controlled clinical trials were required. The use of beta-blockade in septic shock has been traditionally regarded as contra-indicated, as the mainstay of therapy for the patient with septic shock is noradrenaline – an agonist at the alpha and beta adrenergic receptors. Beta blockade represents a paradigm shift in patient management which arises from observations in animal models and patients of harm induced by excessive sympathetic activation and benefit from beta-adrenergic blockade. Animal models suggest benefit from beta agonism at the time of septic insult but beta1 antagonism improves sepsis-induced immune, cardiovascular and coagulation dysfunction in established (>24 hr) sepsis (de Montmollin 2009). Cardiac and non-cardiac (e.g. metabolic, inflammatory) mechanisms are suggested as being responsible for the putative benefit of beta-blockade, we will study the impact of beta-blockade on myocardial injury and dysfunction, metabolism and systemic inflammation. We will test the hypothesis that beta-blockade with landiolol in established sepsis in tachycardic patients improves outcome measured by mean SOFA score through reduction in inflammation and cardiac dysfunction by conducting a multi-centre study of 340 patients. Secondary outcomes will include ICU stay, and biochemical and functional markers of organ function. Assessment of safety and feasibility will be key components of our study with the first interim analysis proposed after 60 patients examining known side effects of beta-blockade including the number of patients with symptomatic bradycardia and increased pressor use. Determinants of feasibility will be recruitment rate and proportion of time the patients treated with beta blocker are maintained in the target heart rate range. If we can demonstrate a strong indication of benefit, we would seek to apply for funding for a Phase III outcome study with survival as the primary outcome and cost-effectiveness as a secondary outcome.
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