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Pharmaconutrition in critically ill patients

Historically, starvation was a commonly accepted approach to treat critical illness, with water deprivation frequently being an integrated part of therapy. This changed in the 1880s, when medical doctors started prescribing nutrients to seriously ill patients. In modern times, adequate nutritional support is state of the art to improve and speed up patient recovery.

Recently, the novel concept of “pharmaconutrition” has further revolutionised clinical nutrition therapy strategies. Over the last decades the primary goal of clinical nutrition was to cover a patient’s needs for energy, proteins (nitrogen),fluids and essential nutrients based on recommended dietary allowances (RDAs) for healthy humans. Today we know that some nutrients do not only possess nutritive properties but also display pharmacological effects, especially when given at high dosages.

Moreover, we have learned that critical illness is accompanied by deficiencies, antagonisms or imbalances in particular compartments or various organs, selectively requiring the extra supply of one or more nutrients to prevent tissue damage. This knowledge opens a new therapeutic dimension: in addition to a standard nutritional regimen, active therapeutic measures can be performed by giving extra pharmaconutrients specifically to support target cells and organs with impaired functions.

Diagnostic tools (eg, analyses of biomarkers) are now available, in addition to clinical judgement, to recognise the need for pharmaconutrition. Similarly to drugs, pharmaconutrients exhibit “pharmacokinetic” characteristics: target and/or extent of metabolic effects depend on dosage (often related to the severity of the disease) and mode of administration.

Glutamine and antioxidative nutrients
Information and clinical evidence within the concept of pharmaconutrition are now available for the amino acid glutamine (Gln), the most prevalent free amino acid in the human body, and for antioxidative nutrients (AOX).

In hypermetabolic and hypercatabolic situations, the endogenous need for Gln is dramatically enhanced: rapidly proliferating cells such as lymphocytes and macrophages and organs such as the intestinal tract switch to use Gln as a major energy substrate (in addition to or instead of glucose) and nitrogen donor to maintain structure and function. The sick organism reacts (through a pathway mediated by stress hormones) with a quantitatively higher Gln efflux from muscle tissue as a result of expanded protein hydrolysis and/or de-novo synthesis from branched-chain amino acids. Since the liberation of Gln from muscle is metabolically limited, the increased needs of the Gln-consuming tissues cannot, however, be completely covered. Consequently, critical illness leads to important Gln deprivation: intracellular concentrations are decreased by almost 50%, and extracellular levels are often below the normal physiological range.(1-3) Gln-depleted patients develop various signs of metabolic disorders: impaired gut structure and function (eg, increased bacterial translocation or toxin uptake), weakened cellular immune response and a highly negative nitrogen balance. More importantly, Gln deprivation is associated with poor outcome.(4) There is now convincing clinical evidence available that a parenteral administration of Gln (approximately 0.5g/kg body weight/day, mostly in form of Gln-containing dipeptides) in addition to standard nutritional regimen (parenteral or enteral) improves not only biomarkers such as endogenous protein synthesis, lymphocyte proliferation rate, cytokine release and membrane integrity, but also beneficially influences clinical outcome in critically ill patients (reduced number of infectious complications, reduced length of hospital stay, and lower morbidity and mortality rates).(5-8) Early enteral Gln supplements reduce morbidity in patients with multiple trauma.(9) A combination of both parenteral and enteral glutamine is recommended to cover the high metabolic needs of high-risk intensive care unit patients.(10) The use of Gln-rich products in pharmaconutrition is safe; in clinical routine, serum urea concentrations should be followed.

Several studies demonstrated that patients with adult respiratory distress syndrome (ARDS), septic shock, systemic inflammatory response syndrome (SIRS) and polytrauma often exhibit a low total antioxidative capacity in plasma.(11,12) This observation can be related to decreased levels of micronutrients such as vitamin C, vitamin E, β-carotene, zinc and selenium. It can be speculated that inadequate levels of these AOX in the body are one of the reasons for the occurrence of radical-related clinical symptoms such as ischaemia and reperfusion damage. In any case, persistence of a low antioxidative status in these patients will worsen the pathophysiological situations and may contribute to increased mortality rates.(12,13) Several intervention studies in critically ill patients confirm that enteral/parenteral administration of high-dose vitamin C, vitamin E, β-carotene, zinc and selenium positively influence extracellular substrate levels and total antioxidative capacity.(14,15) Moreover, supply of an AOX cocktail in addition to the basic nutritional support reduces the occurrence of hyperinflammation and cellular dysfunction and diminishes oxidative stress.(16,17) According to the Canadian Clinical Practical Guidelines,(18) “in critically ill patients supplementation with a mixture of antioxidative nutrients (vitamins and minerals) should be taken into account”. The use of AOX cocktails in amounts not exceeding the accepted daily upper intake levels is considered to be safe.

The concept of pharmaconutrition clearly opens new possibilities for therapeutic interactions and implications. Growing knowledge of the metabolic effects of nutrients on the cellular and molecular levels will further increase the list of pharmaconutrients that can be used.

Industry has already taken over the message from basic science and medicine, and the number of products available is steadily increasing. Their controlled use in clinical practice may further improve patient healing and outcome.


Peter Stehle
Department of Nutrition and Food Sciences � Nutrition Physiology
University Bonn
E:[email protected]


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