MANAGING MITOCHONDRIAL DYSFUNCTION

Interview with Arthur Van Zanten M.D. by Meg Marquardt, Nestlé Health Science.

From the Metabolic and Nutritional Issues in the ICU Workshop – 29-30 May 2018, Brussels, Belgium.

MB: I’m here with Dr Arthur Van Zanten who’s an intensivist Netherlands, here at the Metabolism and Nutritional Issues in ICU course in Brussels. He is a specialist in intensive care with a special interest in critical care nutrition and sepsis and he’s also chairman of the Surviving Sepsis campaign in the Netherlands. Now, Dr Van Zanten you’ve presented very elegantly yesterday the endogenous energy production in the ICU which could potentially leave lead to overfeeding in your mitochondrial dysfunction talk. What are the consequences of over feeding?

AVZ: Well, it’s important to notice that when we are healthy and we start eating we suppress our endogenous energy production. So there is no breakdown or proteins, there is no breakdown of glycogen or lipids, but in the critically ill patient this process is going on all always because they’re in a catabolic state. When we add to the endogenous production, and it can be as large as over 1000-1500kcal/day during the first few days, if we add enteral or parenteral nutrition on top of that in a high dose we can overfeed the patient. The consequences of that are that there can be induction of organ failure. So there can be steatosis of the liver, it can be hyperglycaemia, it can be increased insulin resistance and a need for a high dose of insulin, more renal failure, also the immune system is affected so we will see more infections. So in general by all the key opinion leaders and based on literature it has been shown that overfeeding during critical illness is associated with worse outcome.

MB: So it’s actually a very, very important aspect to consider in the intensive care patient?

AVZ: Yes it is, and of course it’s also important not to underfeed our patients, but it’s a rather narrow balance between under and overfeeding.

MB: How prevalent do you think overfeeding is, or how well understood do you think it is?

AVZ: Well we have to learn much more about this topic because there’s not much research on overfeeding in critical illness, but there’s some papers and I think it’s most important during the first few days of ICU admission. Then the endogenous production is high due to the catecholamines, to the distress hormones that are prevalent in the patient, and over days this response gradually disappears. And then we can also advance feeding to the target. So previously we felt that this energy and protein deficiency should be avoided and we should aggressively feed the patients during the first few days. Now we believe it’s better to gradually increase and maybe meet a target on day four or five. To prevent the negative effects of overfeeding, both by calories and what is new as we have shown in another study, also by giving too many of the proteins, because high protein doses during the first few days also were associated with worse outcome. However, on the other hand during the rest of the first week a high protein intake is beneficial for our patient, because it prevents muscle mass loss and we hope in the end we can also prove that by doing this we can reduce disability and loss of functionality in our patients, because we create more survivors in medicine now in critical care. Also sepsis patients have a better survival over the years, but we create victims because they’re disabled, not able to go back to work, or back home, they have to go to nursing homes and they suffer from all kinds of distress and problems after ICU and hospital discharge. So I think feeding is essential also to solve this problem in the future.

MB: So there’s more evidence emerging all the time that’s helping us understand the situation?

AVZ: Yes. I think we need more understanding of the basic physiology during critical illness and the interaction with our nutritional support, because it’s completely different compared to the healthy situation.

MB: You explained the mitochondrial dysfunction can be a result of some common ICU practices, such as the use of propofol. Do you think that ICU acquired weakness is a consequence of some of these actions?

AVZ: I think it is. ICU acquired weakness is common and can be as common as over 90% of the patients with severe sepsis and septic shock and lead to complete paralysis of our patients, and, well in part it’s due to the severity of illness of the patients and the inflammatory response and the consequences of their diseases. But we probably can add to that and make damage. So for long it’s known that maybe neuromuscular blocking agents have an effect from ICU acquired weakness but we also know that glucose regulation is important. So hyperglycaemia is not beneficial for ICU acquired weakness, but there is an unclear association between protein intake and ICU acquired weakness. And there are some recent papers showing that in the first few days after admission the glucagon levels in patients can be very high, and when you give a lot of proteins during that phase there is more breakdown of proteins in the liver. And that’s a rather counterintuitive to understand, but it’s also abnormal because in healthy situations when you start feeding and insulin levels go up, glucagon will go down, but it’s not the case in critical illness. So we have to understand this basic path of physiological processes better to know when it’s safe to advance our feeding to the full targets. And the problem is probably in the first few days, but there is an abundance of literature showing that after a few days, so after the acute phase, day five to day seven, that feeding up to the target is essential for the outcome. And I think during that period more proteins, exercise, and the combination of exercise and protein and optimal caloric intake can prevent ICU acquired weakness while the glucose is optimally regulated. We also wrote a paper, a review, on which macro and micro nutrients are associated with mitochondrial dysfunction because we believe that the mitochondria as essential for energy production in cells. They start dysfunctioning during critical illness, and we know that around many co-factors, so macronutrients, micronutrients, that are essential for optimal function of mitochondria. And there is almost no research on this topic. So we believe that maybe in the future we are able to design cocktails of maybe vitamins and trace elements that can help to resuscitate the mitochondria and maybe to improve the functional outcome of our patients. So probably in the future it will be a combination of optimal feeding with macronutrients, so proteins and carbohydrates and lipids, combined with maybe some essential micronutrients that are important for mitochondrial function.

MB: Fascinating. So watch this space for what happens in the scientific research coming up?

AVZ: Well we do more work on this, we study mitochondrial dysfunction in leukocytes and try to find out what is the connection or the association with nutritional intake. Does it improve the outcome or can it reduce the duration of mitochondrial dysfunction? But it’s still in its infancy because it’s a new field of research. Another area of interest is what happens with the patients after ICU discharge, because now we focus on longterm outcomes, so after three or six months, and we only have data on nutrition during the first week of ICU stay. And what happens in between with respect to feeding, with respect to exercise, we don’t know. So we need more data on that and for sure that will be helpful to know how to better well help our patients to recover from critical illness.

MB: Moving onto another talk you had on capnometry, I’m wondering if perhaps you could explain what this is and why it is important.

AVZ: Well capnometry is just a way of using the mechanical ventilator to get an impression of the energy expenditure of the patient. Of course when there is metabolism CO₂ is produced, and ventilation can measure the amount of CO₂ that’s produced per minute as a reflection of the metabolism. The best way to measure metabolism is using indirect calorimetry, and then you use the VO₂, the oxygen that is consumed by the body and the exhaled, or the produced CO₂. But then you need a metabolic cart a little bit more complex to do, but the more simple way is to use the VCO₂ of the mechanical ventilator. It’s available in most commercial ventilators nowadays in the ICU, so it could be helpful. And there is an equation that if you use the VCO₂ in L/min x 8.19 then you have a reflection of the 24 hours energy expenditure in the patient. We did some research on that and found that it is not as accurate as indirect calorimetry, but it’s better than the equations we use like Harris Benedict or the Penn State University equation, because you can understand this also that the energy expenditure of the patient is not always the same, it’s varying over days and so it’s important to have repeated measurements. Indirect calorimetry can be done everyday but it’s some work to do, and when it’s available from the ventilator automatic it’s very simple to do. But it’s a little bit imperfect compared to indirect calorimetry.

MB: And it doesn’t take into account the endogenous energy production by the patient?

AVZ: Yes that’s right, but it is the same for indirect calorimetry. You get an expression of the total energy expended and you don’t know whether it’s induced by feeding or metabolism, or from the feeding or endogenously. So we recommend during the first days of ICU stay not to try to meet the energy expenditure that’s provided by the device because if you go there and you add up the endogenous production this will lead to overfeeding. But as a target for maybe day four or five it’s excellent to have this readings of your patients.

MB: So given there are some controversy around that area, what do you recommend practically to your ICU colleagues?

AVZ: Well at this time we recommend to gradually build up feeding to the target on day four/five and maybe to aim during the first week at the energy expenditure measured of around 80%, or when you take a calculated target take 80% of the target and what we do after the first week we increase to the full target, and I think that’s maybe the most safe way to prevent overfeeding and also not to have prolonged underfeeding.

MB: You talked about precision medicine, is not all medicine precision medicine, or how is this distinguished from standard practice?

AVZ: Well I think it’s important because one size doesn’t fit all in the ICU and all our patients are different, all metabolism of the patients is different, the disease stage and also the pre-morbid conditions are different. So we have to take that all into account and to design the optimal feeding strategy. And of course when we have feedback from the patients that’s important. We know that in many ICUs the patient gets like one litre of enteral feed, or one litre of PN or two litres, and just standard protocol. It’s not individualised. In our ICU we have a very sophisticated computer system, we calculate the individual targets, we have hourly feedback of proteins and calories, also from non-nutritional sources like propofol, citrate or glucose/dextrose, and by having this we can adjust the optimal intake in the patients on an hourly basis. So our nurses are empowered to make changes to the feeding protocol, it’s called volume based feeding, they try to achieve the target every day and by doing this our feeding performance has been shown to be better than many other units. So our average protein intake is around 1.2g/kg/day, while in the international surveys it’s around 0.7-0.8 g/kg.day. And we can achieve this without overfeeding the patients.

MB: Excellent. So that’s the way of the future, in your view?

AVZ: I think so, and when we learn more about metabolism for instance we also did studies on the refeeding syndrome and found that when there is a drop in phosphate levels that it’s important to restrict the calories and provide electrolytes and thiamine (vitamin B1) to the patients and I think that’s, that’s a way to use your computer system and your protocol to optimise individually for your patients. Because now it’s impossible to identify those patients who will have refeeding syndrome during their ICU stay on ICU admission because well, commonly used risk factors seem not to predict refeeding syndrome in critically ill patients. So maybe in other patients, but not in the ICU. So I think the only way to circumvent this problem is to measure phosphate on a daily basis and when there is a marked drop in phosphate levels restrict your calories because this is refeeding syndrome and this has been shown to be associated with worse long-term outcome if you continue to give full support.

MB: That’s a very good example of precision medicine.

AVZ: Yes.

MB: Thank you very much for your time Dr Van Zanten, it’s been a pleasure.

AVZ: You’re welcome. Thank you.