Sepsis: signs, symptoms and new treatments

At least 250,000 people get sepsis (also called blood poisoning or septicaemia) every year in the UK. More than one in five of those will die. That’s 52,000 people each year, or 140 people every day.

Sepsis is a life-threatening reaction to an infection. It can affect people of any age, and is responsible for one in 10 deaths in pregnancy and childbirth worldwide. And it’s all to do with blood vessels – the common thread that connects so many heart and circulatory diseases. That’s why BHF-funded researchers are searching for new treatments for this serious issue.

One of these projects is taking place at the BHF Glasgow Cardiovascular Research Centre, where Professor James Leiper is working to tackle this problem. “So many people die of sepsis and they needn’t,” he says. “If we can just control their blood pressure, we will be able to help more people survive.”

Professor James Leiper is working on research at the BHF Glasgow Cardiovascular Research Centre

So, what causes blood pressure to fall? Professor Leiper explains that your arteries and veins are like tubes that are constantly getting narrower or wider in order to regulate blood pressure. 

If you need to increase blood flow because you’re running, for example, your blood vessels dilate and they get bigger, and you get more blood going to the muscles.

Professor James Leiper

But if they dilate too much, there isn’t enough pressure to keep blood flowing through your arteries and veins, which means your organs are starved of blood, and you can die. This is what happens during sepsis.

Sepsis begins when a bacterial infection gets into your blood. The bacteria produce toxins, which prompt your immune system to release substances called cytokines. Cytokines are sometimes described as ‘half angel, half devil’. That’s because they help the body fight infection, but they can also have harmful effects, such as causing the blood vessels to widen so that blood pressure drops, as Professor Leiper explains: “Your blood pressure falls dramatically. It goes very low, and at that level you’re not getting enough blood to your organs to keep them alive.”

Erin Higgins is a BHF-funded PhD student

How to spot sepsis in adults

Sepsis can have different symptoms, but these are some warning signs:

• slurred speech or confusion
• extreme shivering or muscle pain
• passing no urine (in a day)
• severe breathlessness
• an overwhelming feeling of anxiety
• skin is mottled or discoloured. 

John McAbney is a research technician in the BHF Glasgow Centre of Research Excellence

How is the BHF tackling sepsis?

Currently, the treatment for sepsis is to give emergency antibiotics through a drip or injection to treat the underlying infection, and adrenaline to make the blood vessels contract. However, adrenaline can cause side effects such as irregular heart rhythms and reduced blood flow to some organs. There’s no treatment that directly tackles the life-threatening drop in blood pressure without significant harmful side effects.

“What we need is a new drug that will cause the blood vessels to contract again, to restore the blood pressure. We hope that’s what we have found. If you restore the blood pressure, antibiotics can then get rid of the infection,” says Professor Leiper.

For the past 20 years, Professor Leiper’s research has centred on a chemical called nitric oxide. This is a vasodilator, which means it relaxes the inner muscles of your blood vessels, causing the vessels to widen. In this way, it increases blood flow and lowers blood pressure.

Professor Leiper’s work began with his team finding out exactly how nitric oxide is regulated in sepsis. “We started to understand that if we could inhibit that pathway of relaxation, we could have something that would be useful in treating sepsis,” Professor Leiper explains.

In the years that followed, they made and tested different drugs in rats until they ultimately developed a potential drug called L-257. It blocks the action of an enzyme in the body called DDAH1, which regulates how nitric oxide is released in blood vessels. They found that L-257 blocks the fatal drop in blood pressure in rats and mice with sepsis, improving blood flow and survival rate.

But because there are no sepsis treatments of this type, it was uncertain what the cost and size of the clinical trials would be. This meant that they couldn’t get drug companies or other commercial investors to fund the research. It was a real problem. “Research is difficult because you can’t predict what’s going to happen,” says Professor Leiper. “There are more challenging times than there are eureka moments of discovery. But if you’re interested in the process and the knowledge that you accumulate along the way, then it keeps you going.”

As soon as we knew what we needed to do to get the new drug onto the market, investors were happy to get involved.

Professor James Leiper

So they kept on going. Professor Leiper and his team successfully applied for a BHF grant that allowed them to test different forms of L-257 and work with the regulatory authorities to find out how the clinical trials needed to be designed.

“We got venture capital investment of £10 million, which is enough to fund us right the way through to the second phase of clinical trials, which is where you show that, in patients, your drug has a beneficial effect.”

Before the end of 2021, they hope to start clinical trials to demonstrate that the drug is effective and safe in humans. At the end of the second phase of the trials, the hope is that a major pharmaceutical company will take up the drug and do the large-scale trials needed for it to be licensed for patients.

“If we manage to get a new medicine onto the market, it would be a great testament to the people who have done the work,” says Professor Leiper. “It would also be a great testament to funders like the BHF. It’s so important that funders have a long-term view: they invest in science today that may not yield a new medicine for 20 years. But if they invest wisely in good science, it increases the chances that research will identify new treatments.”

If this new medicine proves successful, it could prevent thousands of sepsis-related deaths every year.