Surviving sepsis

K. GANESAN

Interview with Prof. Gordon R. Bernard.

"Sepsis kills nearly half of the patients in intensive care units and several more who do not reach hospital," says Prof. Gordon R. Bernard, Assistant Vice-Chancellor for Research, Melinda Owen Bass Professor of Medicine and Director, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, United States.

Prof. Bernard has been researching the medical condition for nearly 25 years and is the coordinator of the International Sepsis Forum. He has been Chairman, Assembly on Critical Care, the American Thoracic Society (1995-1997); Chairman, International Sepsis Forum (1995-1999); Chairman, Committee on Pulmonary Artery Catheterisation and Clinical Outcomes, sponsored by American College of Chest Physicians, the American Thoracic Society, and the American Society of Critical Care Medicine (1999); Medical Director, Institutional Review Board, Vanderbilt University Medical Centre (1999 on); and member of the National Institute of Health Advisory Council (2002-2006).

The honours he has won include the Alfred Soffer Award (for best original research), Annual Meeting, American College of Chest Physicians, 1989; the Vanderbilt University Grant W. Liddle Research Appreciation Award, 1992 (awarded by the Vanderbilt University Medical Centre house staff to recognise faculty members who demonstrate exemplary leadership skills in promoting scientific research at Vanderbilt); the Vanderbilt University Department of Medicine Distinguished Teacher Award, 1992; and the Society of Critical Care Medicine President's Citation Award, Society of Critical Care Medicine, 1997.

Distinguished Lecturer of the Roger C. Bone Memorial meeting, American College of Chest Physicians, 2002, Prof. Bernard has authored several research papers and is a reviewer of several international journals. Prof. Bernard, who was in India to attend an international conference on `Critical Care Interventions', spoke to Asha Krishnakumar on the symptoms, causes and treatment methods of sepsis.

Excerpts from the interview:What is sepsis?

It is a systemic response to infection - usually serious. Sepsis usually leads to multi-organ failure and hence needs critical care at an ICU [Intensive Care Unit].

The most common are of a person suffering from pneumonia. Most people who are able to have access to a hospital remain in bed for a couple of weeks, take antibiotics and go their way thereafter. But a small percentage of those with pneumonia get into serious problems - they go into a shock, need drugs to keep their blood pressure up, their kidneys may fail, and so on - requiring hospitalisation for more than a month.

But if you look at a patient with pneumonia you cannot tell the difference between the one who had antibiotics and recovered from the one who had to go to the ICU. It can happen to anyone with an infection such as pneumonia. This is one of the most common causes for sepsis in the U.S.

In countries like India, there may be other causes for sepsis such as malaria, which can lead to multi-organ failure. Undoubtedly, many with malaria are not terribly sick but there are those who die because of it. So, sepsis is more at the end of the scale when people are dying of infection. And without intensive care, they would die.

What are the symptoms of sepsis?

Systemic problems such as rapid heart and respiratory rates, altered mineral status when the brain does not work properly, unstable blood pressure and so on. The symptoms are not found where the infection is - it is elsewhere. It is not the spread, but the reaction to the infection. For instance, you may have a sinus infection, but the response to that can happen anywhere in the body.

Are there studies on how the response to an infection actually happens?

Oh yes, it is well studied because with antibiotics even severe infections can be treated adequately but it is much more difficult to treat the systemic response because a tissue injury like a burn or a broken bone takes time to heal.

What triggers sepsis?

The most common trigger would be endotoxin from gram-negative bacteria that typically causes renal infections. But one can also get it from gram-positive bacteria that usually causes pneumonia or meningitis. Those products in the cell wall from the bacteria trigger this response. So even if you kill the organism, you get the same response. Thus it is not the organism itself that is necessarily causing the problem, but the reaction to it.

Why does the body react that way? Has gene make-up got anything to do with it?

The second question is the more difficult one to answer. It appears there are certain kinds of genetic predispositions that make them more likely to react more violently to an infection. But the other reason is the `sleeping dog theory', as I would like to describe it.

What is the sleeping dog theory?

When a dog is sleeping and you come near it, it wakes up and reacts violently as opposed to when it is awake. In the latter situation, it watches you and can size up what you are doing as you approach him. Similarly, for people with slightly suppressed immune systems because of alcoholism, diabetes, cancer treatment, some post-operative situations and so on, the infection gets further along before the body recognises that there is a problem. But then when it does, it reacts violently. And when that happens you get multi-organ - heart, lung, kidneys, and so on - failure situations.

What is the percentage of survival for people with such a condition?

In a good ICU, we can save most such patients. But still one-third die, even if they were healthy before.

Have the genes that cause sepsis been identified?

Some such as the Tumournicosis factor (TNF) have been identified. When the immune system is exposed to a foreign and invading organism, it produces TNF that sort of marshals the immune system. It tells the immune system, "There is trouble, get ready to fight the bacterium." And there are people with a certain genetic make-up who produce much more TNF than normal when that happens, and that causes problems. There are other similar types of genetic make-up that cause sepsis. But they are all polygenetic genes - not just one gene. So it involves multiple genes and is more complicated.

Has the Human Genome Project been able to identify the genes responsible for causing sepsis?

It is getting there. There are several studies now involving tens of thousands of pneumonia patients in which they pull their genetic material to see which genes are turned `on', `off' or which have not changed at all. Through the various new software programmes they are trying to interpret a thousand genes among 20,000 people. They are beginning to be able to pin down some of the patterns of genetic responses to sepsis, mostly with respect to pneumonia, as it is the most common cause.

Does environment play a role in inducing sepsis?

Not exactly environment, but alcoholism, smoking, pollution, pulmonary problems like asthma and so on can cause sepsis. And, of course, contagious diseases such as malaria, dengue and so on put a person at great risk for sepsis.

What is the incidence of sepsis?

In the U.S., it is estimated to be around 750,000 cases a year. And, mortality is about a third. So, some 250,000-300,000 die every year of sepsis. About half to two-thirds of patients in the ICU die because of severe sepsis. Also, several cases of death after surgery, due to complications arising from pneumonia, or due to extended illness are all terms that usually describe severe sepsis. The root cause may be an infection that had happened two to three weeks before death. That infection may have been treated but the patients may go in for multi-organ failure and it sounds complicated.

It is very difficult to have a count of sepsis even in the U.S. because patients may come into the ICU with pneumonia and die owing to severe sepsis but it would be counted as a pneumonia death. Similar is the case with death due to organ failures.

During the intervening period, that is, between the affliction of an infection and the body's reaction to it, is there a way to detect the onset of sepsis?

That is an excellent question. This happens pretty much after the detection of infection. So we can culture the bacteria, look at it under the microscope and so on. But, as I said earlier, just having the bacteria does not mean it is sepsis; it is only an infection. There is no specific blood test for sepsis. It remains a clinical diagnosis.

How do you diagnose a person with sepsis?

When a person comes down with pneumonia and he just has symptoms of fever one does not suspect he has sepsis. But when he starts to develop oxygenation problem - that is, when he does not have enough oxygen in the blood - when he has an unstable blood pressure, when his urine output starts to fall... all these lead to organ failures or dysfunction. If one or more of these symptoms occur, then that is diagnosed as sepsis.

You have an infection, the body reacts to it, and then that leads to a multi-organ failure - within this process, is there no way to detect sepsis before it strikes the patient?

This is a good question too. If you just read about sepsis you feel that it is a progression that has a window of time between the infection and multi-organ failure. But most often it happens all at once, or at least within a matter of hours.

Can precautions be taken against sepsis?

Once you have the infection the risk is pretty much all there. So, the way to deal with sepsis is not to get infected in the first place. And certainly in a hospital environment there is a lot we can do to reduce the chances of infection though we cannot get rid of them altogether.

For example, one has to be very careful during surgery; if the patient is on ventilator, care should be taken not to contaminate the airways; washing hands and wiping [floors] constantly will prevent the spread of infection in the hospital, and so on. On the patient side, what is expected of him/her is to do away with predispositions such as smoking, alcoholism, obesity, and so on.

So, what a normal person can do is just to practise common sense and lead a healthy lifestyle. And if one gets infected, it is going to be the job of the medical system to figure out how to minimise the infection and treat it as soon as possible so that it does not lapse into a severe sepsis. But it does not necessarily happen that way as, at times, particularly in the case of meningitis, it happens within a few hours - from going to bed at night and waking up at midnight. In the case of meningitis, people who are perfectly healthy in the morning can be nearly dead by night time.

At what level should there be awareness about sepsis - at the hospital, at the ICU or at the public level? In a country like India, where most people who are critically ill cannot make it to an ICU, how can sepsis be avoided?

If you can get to an ICU then it is useful for people there to be aware of how a sepsis patient would look like because without intervention, the patient usually dies. The hospital staff in a nursing home or a non-ICU setting also needs to recognise the symptoms of sepsis as against that of a common flu or other illnesses. In the case of the latter the patient may feel terribly ill, but he may still be breathing comfortably and his brain working normally. But if the patient's heart is beating 130 times a minute, he is breathing fast, his skin is cold and clammy, and he is hallucinating, is disoriented or does not speak clearly - these are all indications that this is going way beyond a common flu or cold and leading to sepsis. Sometimes, people describe it as impending doom. The patients know they are in trouble. And, in a matter of hours they die.

What are the pharmacological developments in sepsis?

This is one of the really stubborn areas where even after several clinical trials no major headway has been made. I have been working on it for 25 years. Some five years ago there was some study on recombinant antibodies against TNF. But it did not work. An Xigris trial on activated Protein-C was our first positive trial. And till today it is the only positive one.

What are the recent research findings in sepsis that enable us to understand it better?

What we have found in the last four to five years is that patients with sepsis have coagulopathy - that is, their coagulation system is not normal. Clots start forming in small blood vessels in their body. And that is probably how the organs get damaged because blood flow is being cut off here and there. And we did not pay much attention to it because the typical laboratory tests that we used were not very sensitive to this and they did not pick up these small clots. Only when we started looking more carefully at not common but clinically available tests did we find that everybody who had severe sepsis had coagulopathy.

Activated Protein-C works to prevent these clots. There is a natural system in the body which works to dissolve clots fairly quickly when you have them. But when you have sepsis this system is messed up as well. Activated Protein-C helps that system to work properly.

I have not, until the last four to five years, thought of this problem as being related to sepsis. I only thought of it as an inflammatory problem. Somebody then pointed out that there are primitive organisms that have a coagulation system though they do not have circulating blood like ours. Why do they have a coagulation system? Presumably to fight infection. So, when you start to get infected in a certain place you coagulate the blood around that to stop it from spreading. That is the normal phenomena. But when it goes beyond that area and gets under the rest of the system, then it gets out of control and causes a lot of problems.

Is there a residue in sepsis survivors who have had multi-organ failures or dysfunctions?

Most people return to normal or near-normal lives even if they have had severe organ failures. But a few people (some 1 per cent) have residual renal failure and may have to remain on dialysis forever. A few may have persistent cognitive problems - they cannot think clearly and so on. We are just beginning to understand this after studying sepsis patients 12 months after their recovery. The brains of some of them never seem to get back to normal. Regular conversations may not be a problem for most. But when you have to use logic and connect pieces of information that are not obviously related to each other, then there is a problem. There are standardised methods now to test this.

Occasionally, there is a disaster situation when the clotting is so severe that the fingers and toes die - they become black and fall off; they self-amputate. Sometimes patients can lose some other parts like a part of the nose and so on.

But that is rare. Most surviving patients come back to being normal. That is why we need to find a treatment for it.

Is sepsis a topic of study in medical schools?

It is now taught. We did not have a standardised definition of sepsis until the early 1990s. Even now, many think sepsis is a bad infection. It is not. It is bad response to an infection.

We have launched a worldwide campaign called Surviving Sepsis. It is to educate people on what it is, how to recognise it and so on. It also aims at providing a standardised approach to treating sepsis.

There are a lot of things - 10 to15 - that needs to be done for a sepsis patient. For example, simple things like heparin to remove blood clot, Zantac for ulcers, inclining the bed at 45 degrees if the patient is on ventilator to prevent secondary pneumonia, and so on. Every time you leave out something from the list, you reduce the chance of the patient's survival. We teach them to put a checklist and go through each one of them carefully.

Is sepsis a specialty?

No. There is no specialty called sepsis. It is part of critical care. This has its problems.

I do research in sepsis but it does not belong to any one group. The heart specialist says, "that is not my problem" and the lungs expert says, "that is not mine either". But it really is their problem. You think sepsis belongs to the infection group. But they have an entirely different focus and do not work in the ICU, where severe sepsis is a major problem.

So, though sepsis need not be a specialty, critical care experts need to be aware and tuned into it. All critical-care doctors who deal with multi-organ failures need to specialise in sepsis. Things really changed by the end of 2001 when activated Protein-C was developed to treat sepsis. As treatment was available the doctors in critical care had to make the diagnosis. That was a challenge. Apart from just attending to organ failures and putting patients on ventilator or dialysis, doctors also had to treat severe sepsis.

Is activated Protein-C the only available treatment for severe sepsis?

Yes. It is the only specific treatment for sepsis. But there are a whole lot of other anti-coagulators being tested. Sepsis is recognised in the U.S. as the greatest unmet medical needs we have. Even with activated Protein-C nearly a quarter of patients still die. The health care burden or the sheer cost of intensive care owing to sepsis in the U.S. adds up to tens of billions of dollars every year. So a lot of effort is going into finding treatment options for it.