Information for Patients

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

What is the background to the Study?

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Septic shock (sometimes called blood poisoning) is a life-threatening condition caused by severe infection. For reasons still poorly understood, in some patients, the inflammation in their system doesn’t reduce after an infection. Instead of fighting the infection, an ongoing inflammatory state results in widespread injury to the body and failure of normal functioning of the body’s vital organs, such as the lungs, heart, brain and kidneys.

Despite huge research efforts over the last 20-30 years, patients with septic shock are still just as likely to become seriously ill as in the past. The recovery of patients has improved for sepsis in general through earlier recognition and intervention with antibiotics, however once septic shock takes hold, there is still a high risk for patients to become seriously ill.

 

What are the study aims?

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This research project wants to see if using a very short-acting beta-blocker in addition to standard treatment helps some of the body’s organs to heal 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 of doctors gave a beta-blocker to patients with septic shock to reduce, and then maintain patients' heart rates at between 80-95 beats per minute (the healthy range). They found this treatment strategy to be safe and associated with more patients recovering and less 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 treatment. This trial aims to repeat the Rome study in approximately 40 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.

 

How does a beta blocker work?

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Septic shock causes the heart to beat very fast, which can overwork the heart, as it tries to compensate for the low blood pressure. This increases the chances of major cardiac problems and decreases the likelihood of recovery. Increases in heart rate are caused by hormones, such as adrenaline. Beta blockers work by blocking the action of these hormones, and therefore slowing the heart rate down.

Who can participate?

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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?

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In this study half of the patients will receive usual care with the addition of landiolol and the other half will receive usual care alone. Patients have a 50:50 random chance (like tossing a coin) to receive usual care plus landiolol or usual care alone. Whichever treatment participants are given, their care will be based on meeting their individual needs.

For participants in the landiolol group, the rate of the drug will be adjusted until their heart rate is controlled at 80-94 beats per minute and the infusion will be stopped when they are 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 is to better understand the biological mechanisms that are changed by using a beta-blocker in septic shock. As part of normal care, blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 0, 1, 2, 4 and 6 and at the end of noradrenaline treatment (if a trial blood sample hasn’t already been taken on that day). These samples will be sent to University of Birmingham and will be used in laboratory research to help understand the mechanisms involved in treating sepsis with beta blockers. These samples will be destroyed once analysis has been completed.

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

What's the treatment being investigated?

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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?

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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?

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We propose to run our study in multiple (approx. 45) intensive care units throughout the UK. We will allocate patients randomly either to continue with the normal care for Septic Shock or to also receive a landiolol infusion in addition to normal care. The team on the ICU will adjust the dose of landiolol (if used) to bring the heart rate down to less than 95 beats per minute. We will then compare the two groups to see whether one or other of the groups 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?

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As there hasn’t been a lot of research done on beta blockers in septic shock, there is a possibility that landiolol has the potential for toxicity – ie. to cause some unintended side-effects. 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.

Why is research into Septic Shock important?

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For patients with septic shock, the damaging effects of being on noradrenaline at high doses for a sustained length of time may be reduced by using a beta blocker like Landiolol. As there have only been a few studies looking into this, it is important that further research is conducted, to check not only that giving Beta blockers in septic shock is safe and beneficial, but also to further understand exactly how these drugs might work in septic shock specifically.

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

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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.