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Trial overview

Sepsis is the leading cause of admission to an intensive care unit in the UK, accounting for about 30% of all admissions.

Background and study aims

Septic shock (blood poisoning) is a life-threatening condition caused by severe infection that causes atients to be admitted to the ICU.

For reasons still poorly understood, in some patients, their immune system remains excessively activated. Instead of fighting the infection, ongoing inflammation 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.

Despite huge research efforts over the last 20-30 years the survival rate has remained stubbornly unchanged. Outcomes have improved for sepsis in general through earlier recognition and intervention with antibiotics, however once septic shock takes hold, the risk of dying remains very high. This research project wants to see if infusing a very short-acting beta-blocker in addition to standard treatment improves organ failure in patients with septic shock. Beta-blockers are widely used to counteract the stressful long-term actions of the hormones adrenaline and noradrenaline, for example in high blood pressure, chronic heart failure, abnormally fast heart rates and cardiac rhythms, and tremor. Recently, an Italian group gave a beta-blocker to reduce, and then maintain, heart rates of patients with septic shock at between 80-95 beats per minute. They found this treatment strategy to be safe and associated with improvements in survival and reduced time in intensive care. However, their study was relatively small and recruitment occurred at a single centre so did not provide enough information to make the use of beta-blockers a mainstream recommendation. This trial aims to repeat the Rome study in approximately 35 ICUs in the UK to see if the safety and benefits that were seen can be confirmed and will also investigate the way in which beta blockers act in septic shock patients.

Who can participate?

The trial is no longer recruiting participants. Adults in ICU aged 18 and older who have septic shock, a fast heart rate and high dose noradrenaline treatment.

What happens to the patients taking part in the study?

In the study half of the patients received usual care with the addition of landiolol and the other half received usual care alone. Patients had a 50:50 random chance (like tossing a coin) of receiving usual care plus landiolol or usual care alone. Whichever treatment participants were given, their care was based on meeting their individual needs.

For participants in the landiolol group, the rate of the drug was adjusted until their heart rate was controlled at 80-95 beats per minute and the infusion stopped when they were able to control their heart rate themselves. Landiolol is given intravenously (IV) as an infusion whilst a participant’s heart rate is too high. This drug may be used for up to 2 weeks within the ICU where the treating team are able to monitor the participant closely. After discharge from ICU, or if the heart rate remains high after 14 days, ongoing treatment will be the decision of the treating doctor.

One of the aims of this study was to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood are taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples were taken at study entry, on days 0, 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). These samples are sent to University of Birmingham and will be used in laboratory research to help define the mechanisms involved in treating sepsis with beta blockade. These samples will be destroyed once analysis has been completed.

Routinely collected clinical data is recorded for the trial. However the progress of participants was followed at day 28 and day 90 after trial entry, at these time points the local research team contacted the participant and their GP to find out how they were. The trial did not follow participants beyond 90 days.

What's the treatment being investigated?

Landiolol is an ultra-short acting Beta blocker that targets the heart rate in a very specific way. It has been used safely in Japan for many years but has only recently become available in Europe. Landiolol has been used safely in some very sick patients who have unstable heart rhythms. It has not been systematically studied in Septic Shock; STRESS-L will be the first of several European evaluations of how Beta Blockers work when patients have that condition.

Which patients will be chosen to take part in STRESS-L?

We will be asking patients (or their relatives/carers if the patients can't communicate with us) who have been diagnosed with septic shock, still have a fast heart rates (95 beats per minute or more), and are on a high dose of noradrenaline.

What does the study involve?

We propose to run our study in multiple (approx. 35-42) intensive care units throughout the UK. We will allocate patients radomly either to continue with the standard care for Septic Shock or to also receive a landiolol infusion in addition to the standard care. The team on the ICU will adjust the dose of landiolol (if used) to bring the heatt rate down to less than 95 beats per minute. We will then compare the two groups to see whether one or other of the grops improve quicker. We will also be 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 beta blocker mechanisms of action in septic shock. We also propose to store blood samples for analysis of the genes and proteins that may predispose patients to become so severely septic and to identify those who respond to beta blocker therapy.

What are the possible disadvantages and risks of taking part?

Beta blockers are not confirmed to be useful in septic shock and it is possible that landiolol has the potential for toxicity. Full information on the possible side effects are available on request from local treating teams. The main risks are the heart could go too slowly or blood pressure could lower if a participant is sensitive to the drug. Trial participants will be closely monitored within the ICU and should they experience any side effects from the study drug, the hospital staff will take measures to stop the infusion as with any other inpatient treatment. As landiolol is an exceptionally short-acting drug, switching off the infusion is expected to reverse any possible side effects.

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Warwick Clinical Trials Unit
Warwick Medical School
University of Warwick
Gibbet Hill Road