Title: STRESS-L: STudy into the REversal of Septic Shock with Beta Blockade (Landiolol)
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Septic shock (blood poisoning) is a life-threatening condition caused by severe infection. For reasons still poorly understood, in some patients, their inflammation system remains excessively activated. So instead of simply fighting the infection, an ongoing inflammatory state results in widespread injury and failure of normal functioning of the body’s vital organs, such as the lungs, heart, brain and kidneys. A hallmark of septic shock is a very low blood pressure that does not improve with an intravenous fluid drip. According to the UK Sepsis Trust (http://www.sepsistrust.org), septic shock kills 37,000 patients per year on wards and ICUs in the UK (more than bowel cancer, breast cancer and prostate cancer put together). Yet despite huge research efforts over the last 20-30 years, the death rate from this most severe manifestation of sepsis has remained stubbornly unchanged. Outcomes have improved for sepsis in general through earlier recognition and intervention with antibiotics, however once the patient is in established shock, the risk of dying remains very high. For many years, we have routinely used in clinical practice a group of drugs known as ‘catecholamines’ to increase the patient’s blood pressure back to normal. The objective is that this will help their vital organs to function properly and to recover. The most commonly used catecholamine is noradrenaline, a synthetic form of a hormone produced by the body to deal with stressful situations. Noradrenaline does however carry side-effects when given at high doses and for extended periods of time, including adverse effects on the heart, the immune system and the patient’s metabolism. Thus, the drug treatment itself, augmenting the body’s own production of these hormones, may achieve the short-term goal of increasing blood pressure though at the possible expense of a worsened outcome. The role of catecholamines is therefore being questioned. A group in Italy recently performed an important study in their hospital in Rome. They selected patients with septic shock and fast heart rates; they were receiving high doses of noradrenaline. This subset of patients carries a particularly high mortality (over 60%). Half their patients were randomly allocated to receive a ‘beta-blocking’ drug infusion intravenously. These beta-blockers are already widely used in medicine for counteracting the stressful long-term actions of catecholamines, for example high blood pressure, chronic heart failure, abnormally fast heart rates and cardiac rhythms, and tremor. The Italian group gave enough drug to reduce, and then maintain, the patients’ heart rate at between 80-94 beats per minute. They found this strategy was not only safe but was associated with big improvements in survival and time in intensive care. However, their study was relatively small and from a single site so did not provide enough information to make the use of beta blockers a mainstream recommendation. We propose to repeat their study in multiple (approx. 30-35) intensive care units throughout the UK to see if we can confirm the safety and benefits found in Rome but also to extend it by taking blood samples to measure effects of the drug on the patient’s immune system, metabolism and heart function so that we may better understand its mechanisms of action.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM