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Lactate levels are often used in the ICU to predict outcome. Especially in acute sepsis or septic shock lactate is used frequently to guide treatment. More and more studies show that the inability of the patient to lower lactate levels is a strong predictor of outcome, even at slightly higher levels. However, there are also patinets with low levels that have a bad outcome and patinets with high lactate levels that survive. A better understanding of the underlying mechanism for the high lactate levels and the inability to lower this is needed. To facilitate this better we validated a 3-pool labelled lactate model to measure skeletal muscle lactate metabolism in humans in more detail. In this study adranaline was used to increase lactate production Results show that the 3-pool model can be used but is due to the large variation and high invasiveness not usefull in all situations and a 2-pool model can be used. The 3-pool model however suggest that the adrenaline induced increase lactate release from muscle is the result of a redirection of a very high lactate turnover intramuscular. In addition we show that adrenaline increases the state 3 respiration of mitochondria in vivo. For all details see here.
There is a lot of believe around that critically ill patients need more protein but the proof for this is weak. We have recently published 2 papers that address this issue. In a first paper we study the effect of early low protein enteral nutrition on whole body protein metabolism. For this study we collaborated with Luc van Loon from Maastricht in the Netherlands and used intrinsically labeled milk protein to study this. Results show even this very low dose of enteral protein has a positive effect on protein balance. For all details see here. The second study investigates whether an extra infusion of amaino acids affects protein metabolism in patients with ongoing nutrition. These patients received a 3 hour extra iv amino acid supplementation during the first week of their ICU stay. Results clearly show that this short infusion of amino acids improves protein balance already in the first week of ICU stay. We also observed a very strong correlations between the total protein feeding and the net protein balance, with many patients receiving over 1.2 gram protein/kg/day having a positive protein balance. Article can be found here.
In 2012 we published a paper showing that initial glutamine values are predictive for mortality is adult ICU patients. We wanted to know whether this is the same for critically ill children. Fortunately mortality of criticaly ill children is much lower than for adults but this meant that for the study mortality is a probablematic outcome measure. We decided therefore to use orgam failure as the outcome. Organ failue was assessed as a PELOD score. Results show that children with a low glutamine level in plasma when arriving to the pediatric ICU have a higher PELOD score and also have more organs failing. This study opens up the need for glutamien intervention studies also in critically ill children. For all details see here.
From a clinical trail that the group performed a few years agao on glutamine supplementation in Scandinavia it was suggested that glutamine supplementation inproved ICU mortality but not post-ICU mortality. This raised the question whether glutamine levels drop fast again after patinets leave the ICU, due to taht the supplementation is stopped, and that this affects the mortality negatively. To investigate this we performed a study to investiga eglutamien levels after teh ICU and whether the post-ICU glutamine levels are related to mortality. Results show that post-ICU plasma glutamine levels are within normal range and are not predictive for mortality outcome. Plasma glutamine level at discharge, on the other hand, is within normal limits but higher in nonsurvivors. In addition, it added prediction value to discharge SOFA scores for post-ICU mortality. For all details see here.
Another anesthesiology residents finished his research project recently. Bashar Dabbagh studied the levels of citrulline in plasma of critically ill patients. Citrulline has been suggested as a marker of intestinal function possibly also in the critically ill. Since no good measure for intestinal funstion is available in the critically ill and this is desperately needed, citrulline needs to be validated for this. However little is known about citrulline levels in the crtically ill and Bahar has studies this using 4 older studies with citrulline analyses available. From these studies citrulline levels were studies at admission, the changes in and after ICU treatment and in patients with liver failure. The results show that critically ill patients have low citrulline levels at admission compared to a reference group of young and middele aged healthy volunteers, that the levels on average do not change in and following ICU ward and that liver failure increases citrulline levels. An intereresting observation is that about 20% of all the patients have lower levels then the lowest reference value. The clinical relevance of these finding needs to be elucidated in directly designed studies. For all details see the poster that Bashar produced.
We have recently published 2 articles on glutamine kinetics in humans. The first one is where we establish the techniques using abolus injection of labelled glutamine and the calculation of glutamine kinetics from the decay of the labelled glutamine in plamsa over 90 minutes. This was done since glutamine has a very large intracellular pool which excludes a steady state of the labelled glutamine when infused continuously. The results from this first study show that the bolus method can be used relaibly, but also that it is very similar to rates measured withe continuous infusion technique. This indicated that both methods measure a rate of apperance of glutamine representing a transport rate through pthe plasma pool. In a second study we used this technique to measure glutamine rate of apperance in critically ill patients in the basel state and during extra glutamine supplementation (as alanyl-glutamine). The results show that the extra glutamine does not inhibit the glutamine rate of appearance, but rather results in a small but significant increase in the rate of appearance. We hypothesize that this is due to the extra amino acids and alanine given at the same time. For all details see the papers here and here.
One of the anesthesiology residents finished his research project recently. Imad Almahfoodh studied the effect of lactate changes in critically ill patinets treated in the ICU in Huddinge in relation to mortality. All patients treated in 2013 were screened retospectively and patients with high lactate levels at admission (>3 mM) were inlcuded. Patinets were devided in differemt gropup depending on the time to reach "normal" lacatte levels (<2mM). The results show that patients with a slow or no decrease in lactate have a higher mortality and that this in an independent predictor from APACHE. For all details see the poster that Imad produced.
Finally we published our first study on whole body protein turnover in critically ill patinets with MOF. This study was merely to establish the measurements in critically ill patinets to later use it to study the handling of extra parenteral and eneteral protein feeding. In this study we investiagted healthy volunteers fasted and during parenteral nutrition ans show that this results in a anabolic state. We also included 8 patients with MOF. The results show that patients with MOF have a higher protein turnover (both high synthesis and breakdown)andd have a negative protein balance. In addition, we show that the amount of parenteral amaino acids is positively correlated to a positive protein balance. However we used 2 different tracers in this study that gave conflicting results; both showed that parenteral amino acids results in anlbolism but one by increasing synthesis and one by decreasing breakdown. For all details see the paper here.
Amino acid metabolism is dramatically changed during critical illness. This is mainly described as changes in plasma concentrations. However, these concentrations in the central circulation are the result of metabolism and feeding (either parenterally and/or enterally). Little is known about the interaction between these and the resulting amino acid profiles. Our research group has published on amino acid levels in plasma during critical illness but the main focus has always been on one amino acid: glutamine. We are however planning to investigate the meaning of the whole amino acid profile more in relation to critical illness and feeding. One of the first studies in this is that we looked at the amino acid profiles in critically ill patinets and how these are related to feeding, length of stay and insulin treatment. This study was doen in collaboration with Greet vanden Berghe's group in Leuven and samples from their large intervention study on intensive insulin treatment nin critically ill children was used for analysing amino acid profiles. The results show that non-surviving children have a higher total amino acid concentratio and that isnulin treatment lowers total amino acid concentration. In addition individual amino acids seem to be related to state of disease, age and insulin treatment. For all details see the paper here.
Obesity is an increasing problem in society. A large part of obese subjects are insulin resistance for glucose metabolism, however also a resitance to feeding, better known as an anabolic resistance has been suggested for obese subjects. In this study we tested the hypothesis that insulin resistant obese subjects are also analbolically resistance in response to a mixed meal. To test this hypothesis we compared whole body and leg muscle protein kinetics in upper and lower body obese women with the presumption that the upper body women are more insluin resistant for glucose metabolism. The results show that the upper body obese women are more insulin resistant but also more analboilically resistance in response to a continuous enteral feeding on whole body level but not in leg muscle. For all details please see here.
Muscle wasting is a problem in many diseases but during the more severe diseases (like critical illness and cancer cachexia) this loss negatively affects morbidity and mortality. In the more severe diseases this loss is mostly driven by an increased protein breakdown rather than an decreased protein synthesis in skeletal muscle. Protein breakdown is regulated by several proteolytic systems with the lysosomal-autophagy and the ubiquitin-proteasome systems as the major ones. In a recent study we show that muscle wasting in patients with severe cancer cachexia is driven by an increased activation of the lysosomal-autophagy system rather then the proteasome system. This finding is different from most animal models for cancer cachexia in which the proteasome system has been found to be activated. The increased activation of the lysosomal-autophagy system was assessed by lysosomal enzyme activities and confirmed by protein levels of severeal key regulators of the system. The article can be found here.
One of the most characterist feature of critically ill patients treated in the ICU is the loss of lean body mass, also refered to as catabolism. This loss of body protein is progressive and eventually affects outcome and succes of recovery. The idea is that appropriate feeding of protein at the right time and with the right amount can prevent or at least reduce this loss of body protein. Recommendations for protein feeding for this type of patients is sub-optimal and more research is needed to improve the recommendations. Our approach is that we study the effect of different feeding regimes on a direct measure of the patient's protein turnover (synthesis, breakdown and balance) using stable isotope tracers. Recently we have published the first results of this new line of research. In this study we investigated the effect of hypo-caloric feeding of patients with head trauma treated in the ICU on their protein turnover. The study shows that feeding patinets a hypo-caloric diet (with less protein as well) results in a more negative protein balance (patients loose more body protein) compared with normo-caloric feeding (based on individual indirect calorimetry measurements) in a cross over design. The results have recently been published in a open-access journal, Critical Care, and can be found here.
As mentioned below continuous glucose monitoring is critically needed in the ICU for performing better studies and for better clinical glucose control. In 2 earlier papers (see bleow) we have been validating an intravenous micordialysis technique in combination with an on-line analyser and monitor for continuous glucose monitoring. Now in our latest paper we have used a central vein cathater with a microdialysis membrane in combination with an on-line analysed and minotor for glucose and lactate. Both plasma glucose and lactate are shown continuously witha 5 minutes dalay. The study performed in 10 surgical patients over 20 hours shown very promissing results justifying further validation of this approach. Paper is open access and can be found here.
Continuous glucose monitoring is something that is urgently needed in the ICU to enable better studies and improved clinical care in relation to intensive insulin treatment to prevent hyperglycemia. Soon our second paper in a series of papers testing and validating intravenous microdialysis for continuous glucose monitoring in critically ill patients. In a first paper published in 2010 we show that this an intravenous catheter with a microdialysis membrane works nicely over several days but that the agreement with plasma references values is not good. We also showed that many critically ill patients actually have very limited peripheral veins allowing for this to facilitate continuous glucose monitoring. In a second paper we show that increasing the membrane length and decreasing the perfusion flow rate actually significantly imporve the agreement to plasma reference values. See paper here.
Recent results show that if one keeps glucose at lower levels during major surgery that the patients are less insulin resistant following surgery. In this study glucose was kept under 8 mM during surgery using insulin. Since post-surgical insulin resistance is clearly related to compålications this finding may have effects on the outcome for the patient. For details, see the paper.
In a recent paper published in Clinical Science we describe how low glutamine levels at admittance to the ICU predicts a worsen outcome independent from APACHE II score. In this paper we also describe that a low percentage of blood glutathione rather then a high percentage is related to a worsen outcome in ICU patients. For details, see the paper.
In another recent paper in Clinical Science we show that the loss of muscle mass in ICU patients with multiple organ failure is due to a dramatic increase in protein breakdown rates and NO change in protein synthesis rates. We also show that this increased breakdown is due to increased activities of both the proteasome and the lysosomes. You find the paper here.
We have recently compared 3 different machines for measuring energy expenditure with indirect calorimetry in ICU patients that are mechanically ventilated. This project was done by a medical student (Martin Sundström). Results shown rather large differences between the machines. We have written a preliminary report on this that we make available on an individual base to those interested. The on-line version of the paper is available now.
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