Standing on the weighting scales

Anders Perner MD PhD, Institute for Clinical Medicine, Rigshospitalet, Copenhagen

‘Blood transfusions are obviously a costly procedure and I think that not only society but also patients would like to restrict them,’ explained Prof. Perner. Apart from that, all the evidence from high quality randomised trials indicate harm caused by liberal transfusions, he said. ‘Although not yet statistically significant, the potential is a 10 percent relative risk increase in mortality, which again will favour a restrictive strategy.’

Dr. Sakr holds the opposite view: ‘Blood transfusions are like any medical treatment. They should be applied optimally. Blood is not a medicine that you can simply buy from the pharmacy. It’s of human origin and an expensive treatment and therefore we all have an interest to restrict blood transfusions as much as we can, but not in a way that deprives  patients from a useful therapy.’

A surrogate oxygen supply
‘We usually give blood transfusions with ultimate goals, for example to improve the oxygen supply or oxygen delivery to patients. This supply depends on several variables,such as cardiac output, haemoglobin levels and much more. This actually was the reason for different studies that looked at haemoglobin being a surrogate for the oxygen supply to patients. Some of the observational studies have shown that in critically ill patients one gets a better outcome with blood transfusions It seems that the restrictive strategy may not be optimal for all ICU patients.’

Involved in a major high-quality trial involving intensive care patients with blood poisoning, Prof. Perner pointed out the researchers showed there was no benefit fromblood transfusion. ‘We added the outcomes to a meta-analysis of all trials done in all patient groups and the outcomes were quite common and indicated the same effects we saw in our trial,’ he said. ‘The outcomes from observational data in the context of critically ill patients are based on whether the patient is transfused or not, which is very difficult to interpret in terms of benefit, because severely ill patients are always transfused more.’ Trying to clarify this through statistical methods doesn’t work.‘The sickest patients will always receive more transfusions, which will make interpretation difficult.’

Dr. Sakr noted that 20 years ago several small studies looked at the liberal blood transfusion strategy compared to the restricted blood transfusion strategy. Results from the biggest study, TRICC, were published in the New England Journal of Medicine in 1999. ‘This study,’ he said, ‘was quite a landmark concerning critically ill patients, because it showed that a restricted transfusion strategy may be as good as the liberal strategy. There are studies just concentrating on patients with a septic shock or other special illnesses, but all these studies often do not mimic the situations we are confronted with in a clinic. People often argue against the results of observational studies showing better outcomes in some subgroups of critically ill patients receiving blood transfusions, but they present the situations we deal with in every day clinical life. You cannot ignore such signals from observational studies; you also must always consider pragmatism in the design of large randomized control trials.’

Transfusion risks
Blood transfusion transplants foreign cells and will affect the recipient’s immune system, increasing the risk of infection, Prof. Perner cautioned. ‘There are some well-known rare side effects, which are viral infections or allergic reactions,such as red cells being destroyed in circulation. There are also potential side effects that are more immunological. There are also more complex interactions with the immune system, particularly in patients whose immune system is already infected. These are very complex interactions that we don’t fully understand and therefore I would rely on data from high quality randomised trials, because they show the full effects of two different strategies – more restrictive vs. more liberal – in outcomes that are important for patients.’

Dr. Sakr spoke hypothetically of a young, clinically stable patient coming to the ICU after coma, with most organ functions preserved. Here, he said, restrictive transfusion strategies may be adopted because the benefit for that patient would be less than the risk –the TRICC-study showed that younger ’healthier’ patients have a higher risk of death compared to older or critically ill patients. ‘If you give blood to someone who doesn’t need it he only has the risk of blood transfusion, but no benefit – and you might experience a bad outcome. So you are actually more liberal in patients who are severely ill and in this case you can expect these patients to have more benefits than risks from blood transfusions.’
 

No safer alternatives
Developing safe alternatives to blood transfusions is extremely difficult, said Prof. Perner. ‘I believe all artificial blood transfusions failed in randomised trials, so the majority of development programmes were stopped. Some companies still push an artificial product, but observations from earlier trials were that this artificial blood infects and harms patients. It’s very complex to design these drugs. I thinkit will take many years before we see a realistic artificial product.

‘Blood transfusions can never be completely without side effects. One will always have to balance between the harmful effects of not receiving a transfusion vs. the side effects of receiving a transfusion. So we should still give blood transfusions, but we should restrict them.’

He also hopes that improving surgical and blood-sampling techniques could help to minimise blood loss during surgery and blood sampling. Particularly, he hopes for more trials to identify patients who would benefit from transfusions.

Dr. Sakr believes the new trend in clinical studies and medicine is shaping an intelligent design for clinical trials, adapting clinically relevant algorithms. ‘Pragmatic studies don’t provide clear answers to all clinically relevant research questions and usually look at the global effects of therapy on the patient, independent of the possible individual effect . The future will consider more the disease-specific interindividual variations and additional parameters  that influence the indication of blood transfusion such as indices of microvascular tissue oxygenation and perfusion .’
 

A legal question
‘I’m no friend of mixing law and practical medicine,’ Prof. Perner protests. ‘The way to go is to produce evidence through medicine, which means doing more and better trials, because no patient or doctor would want to receive or give a transfusion where it’s not needed. The problem has been lack of knowledge until now. This can only be improved through more research.’

Agreement: ‘It would be catastrophic to create legal regulations for blood transfusions based on fixed haemoglobin levels,’ Dr Sakr said. ‘Critically ill patients suffer mostly from syndromes, not from single diseases.’ Pointing to many existing guidelines about blood transfusion, he added, ‘A regulation about whether the liberal or restrictive strategy should be used is not a good idea.’

PROFILES
Anaesthetist and holder of the European Diploma in intensive care, Anders Perner MD PhD has worked at Rigshospitalet, Copenhagen since 2007. He is also Professor in Intensive Care Medicine, University of Copenhagen, Chair of Scandinavian Critical Care Trials Group, Deputy Editor of Intensive Care Medicine and recently Chair of the Centre for Research in Intensive Care – CRIC.  

Yasser Sakr MD, consultant in the Anaesthesiology and Intensive Care department at Friedrich Schiller University, Jena, Germany, formerly spent two years as a research fellow in the intensive care department at Erasme Hospital (Free University of Brussels).
He focuses on clinical research and investigating innovative methods to assess the microcirculation in critically ill patients.

16.03.2015