Impact of anabolic manipulations in ICU patients Claude Pichard Clinical Nutrition and Dietetics, Geneva University Hospital, Switzerland Email: claude.pichard@medecine.unige.ch Key words : stress, Intensive Care Medicine, catabolism, lean body mass, growth hormone, insulin, insulin-like growth factor-1, testosterone. Metabolic stress in ICU patients results in catabolism and muscle wasting, which depends on the initial stress level, then on stress-related to medical and surgical procedures as well as to secondary complications. Prolonged metabolic stress and immobilization lead to major muscle wasting and dysfunctions. Current therapeutical progress in ICU patients allow prolonged patient survival in spite of major catabolism which results in decreased immune function, defective healing, respiratory and peripheral muscle dysfunctions. In turn, these dysfunctions contribute to difficult weaning from the respirator and prolonged physical rehabilitation. All together, catabolism-related wasting unfavourably influences both global prognosis and kinetics of patients recovery. In these conditions, optimal nutrition support is aimed at limiting protein catabolism, but its effect is generally insufficient, and systematic administration of anabolic compounds seems to be desirable. This observation has stimulated investigations on the combined effects of anabolic compounds, physical mobilization and nutritional support to reduce the negative effects of stress and immobilization related to critical illness and intensive treatment. Promoting anabolism of the lean body mass, or limiting its catabolism, during acute illness necessitates direct action on the pathological protein kinetic occurring in muscle tissues and major organs. A few anabolic pharmacological compounds can potentially limit the stress-related catabolism due to severe illness: recombinant human growth hormone (rhGH), insulin-like growth factor-1 (rhIGF-1), testosterone derivatives, insulin and other drugs acting along catecholamine-atypical axis ( adrenoceptor agonists). In addition, physical active/passive anticatabolic therapies are also important. Indeed, when contractile tissue is considered, muscle tone is also a critical factor influencing both protein synthesis and degradation. This statement is easily observed in case of muscle atrophy observed during prolonged bed rest (a daily loss of about 0.3 kg, representing about 2% of body protein), leg cast immobilization, microgravity or muscle atrophy following nerve section. At the opposite, muscle hypertrophy is observed in case of regular physical exercise or muscle contraction in response to electrical stimulation. Unfortunately, medical applications of such mechanical muscle stimulation are generally not feasible in most ICU patients. Both experimental and clinical results indicate that rhGH, insulin, rhIGF, testosterone and its derivates can significantly limit stress-related catabolism. In addition to its anticatabolic effect, insulin has been shown to reduce morbidity and mortality in ICU patients. The true clinical value of rhGH to ameliorate catabolic conditions remains to be defined, except in burns where the positive effect has been demonstrated. Indeed, we and others have occasionally found significant improvements of metabolic parameters such as nitrogen retention, without functional improvement. The beneficial metabolic effects of anabolic compounds in terms if clinical outcome deserves further investigations. Careful selection of patients to be potentially treated, and close monitoring of both adequacy of protein-energy support and modality of anabolic agents administration are mandatory to allow for their safe utilization in critical care settings. In conclusion, limitation of catabolism during the initial phase of stress resolution, and promotion of anabolism as soon as the catabolic phase is over, are among the major nutritional therapeutic goals in ICU patients with severe and prolonged illness. Nowadays, testosterone derivates offer too many limited clinical advantages to be recommended for routine use. rhGH treatment potentiates the anticatabolic effect of nutrition support, but a better understanding of potential adverse effects of rhGH treatment is urgently required as well as the demonstration of its impact in shortening ICU stay and on risk-benefit and cost-benefit ratio before it can be recommended for clinical routine. Identification of patients who could benefit from rhGH, as well as dose and timing of administration are all still required to be clarified. Meanwhile, the use of rhGH should be strictly reserved to clinicians with extensive experience in its utilization. Combination with other therapeutic agents (e.g. rhIGF-I, rhIGF-I -I/BP3 complex, beta 3-receptor agonists) are attractive but are still under investigation.