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Weakness and wasting in the critically ill patient
Current Anaesrhesia and Critical Care (1996) 7, 81-86
© 1996 Pearson Professional Ltd
Focus on: Gut and nutritional failure in the critically ill
Weakness and wasting in the critically ill patient
M. J. O'Leary and J. H. Coakley
Introduction
Immobilization of a fractured limb has been shown to result in a reduction of mean muscle fibre area of approximately 40% in healthy young adults over a 6-7 week period. During critical illness wasting generally occurs much more rapidly, often being apparent as early as 10 days after admission to intensive care. This puts in doubt the role of immobilization as a sole aetiological factor. Although rehabilitation physiotherapy has been shown to accelerate recovery, it is unlikely that immobilization is a major cause of muscle wasting and weakness in critically ill patients but clearly its presence may exacerbate other causes.
Cachexia, associated with critical illness, has for a long time been a recognized clinical entity and may in part be explained by the combined effects of malnutrition, immobilization and the hypercatabolism seen after surgery, trauma and sepsis. The failure of hyperalimentation to reverse muscle wasting and negative nitrogen balance during critical illness has led to a re-evaluation of the causes of wasting and of the therapeutic strategies that might be employed to prevent it. Although muscle wasting and negative nitrogen balance is clearly of concern to the intensive care physician, the muscle weakness which accompanies wasting (but which may also occur in its absence) is the dominant clinical problem. Weakness and wasting of skeletal muscles is often obvious and has been shown to delay mobilization and prolong recovery time. Weakness of respiratory musculature, however, may not always be appreciated as a major cause of prolonged weaning from ventilatory support, despite resolution of the underlying condition leading to intensive care unit (ICU) admission. Prolonged ventilation is not without complications such as development of nosocomial pneumonias and sepsis which may ultimately lead to death. In this article we will summarize our current understanding of the causes of weakness and wasting in critically ill patients and highlight the latest attempts to reverse these processes by therapeutic intervention.
Malnutrition Muscle wasting and weakness is a major feature of malnutrition. Many patients on the ICU are malnourished on admission because of anorexia owing to illness or fasting in preparation for surgery. This may be exacerbated by delays in commencing nutritional support following ICU admission. Hepatic glycogen stores are only sufficient for 24 h glycogenolysis and after this a decrease in insulin secretion and increase in glucagon result in protein and fat breakdown to provide energy. Protein catabolism leads to increased urinary urea and negative nitrogen balance. In uncomplicated starvation lean body mass is generally preserved until late as fat breakdown is the main source of calories. The administration of sufficient nutritional substrate will thus convert the starved patient to an anabolic state. Initially, once intensive care physicians became aware of the importance of nutritional support, it was assumed that wasting and negative nitrogen balance would be reversed by hyperalimentation in critically ill patients but this was found not to be the case. In fact, overfeeding led to hepatic steatosis, abnormal liver function, and excess carbon dioxide production which
Causes of muscle wasting in critical illness Immobilization Muscle wasting is a common accompaniment of disuse. Dr M. J. O'Leary FRCA, ResearchFellow in IntensiveCare Medicine. Dr J. H. Coakley MRCP, Consultant, IntensiveCare Unit, St. Bartholomew'sHospital,West Smithfield,LondonEC1A 7BE, UK. 81
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was thought by some to be detrimental to weaning from ventilatory support. Over the past 20 years the energy intake recommended for critically ill patients receiving parenteral nutrition has fallen by approximately 60%, and it appears that the energy requirements of these patients are in fact similar to those of normal healthy people. 1 These requirements still reflect hypermetabolism but this is balanced by the effects of reduced physical activity. Why does nutritional support fail to prevent muscle wasting and a negative nitrogen balance in critical illness? Recent attention has focused on certain nutrients such as glutamine, alanine, cysteine and tyrosine which are deficient or missing from nutritional formulae and which may become conditionally essential in critical illness, In the absence of these substances muscle turnover may be deranged and essential body functions limited. Enrichment of nutrition with these substances, therefore, may be of therapeutic value, and is discussed later in this article. It may be, however, that nutritional support alone is insufficient to reverse negative nitrogen balance associated with critical illness because of the special metabolic response seen following trauma, surgery and sepsis. Furthermore, the various neuromuscular disorders described below would not be expected to be amenable to treatment by nutritional support alone. The metabolic response to trauma, surgery and sepsis
Following a major insult there is increased secretion of catecholamines and glucocorticoids with reduced secretion of insulin. Initially there is a period of decreased energy catabolism but this is followed by an accelerated catabolic phase which does not demonstrate the adaptation to fat metabolism seen during starvation. There is weight loss and muscle wasting which leads to an increased loss of nitrogen in the urine most of which originates from muscle proteins. Whole body protein turnover and its response to trauma, surgery and sepsis has been extensively investigated. Following relatively mild trauma, for example, an uncomplicated open cholecystectomy, protein synthesis is generally depressed but with increasing severity of insult protein synthesis and breakdown may both be enhanced with breakdown predominating over synthesis, zNet muscle protein breakdown in this situation may have several short-term advantages including provision of amino-acids such as glutamine for protein synthesis within the cells of the immune system, for repair processes and for hepatic gluconeogenesis. In addition to the well recognized effects of catecholamines and glucocorticoids, it is now clear that cytokine release and changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis also are of considerable importance in the metabolic response to trauma, surgery and sepsis. Cytokines released as part of the inflammatory response to injury or sepsis affect whole body nutrition and metabolism and are responsible for many nutritional effects, including fever, hyper-
metabolism, anorexia, protein catabolism, cachexia, and altered fat, glucose and trace mineral metabolism? It has been postulated that derangement of the GH/ IGF-1 axis may partly explain muscle loss and negative nitrogen balance in critical illness. GH is a polypeptide hormone with both direct fuel regulating effects (lipolysis and insulin antagonism) and indirect growth promoting actions (anabolism) which influence amino acid uptake and protein synthesis. Its anabolic actions are mediated through IGF-1, which is secreted principally by cells of the liver under the control of GH. Critically ill patients are relatively resistant to GH, and circulating levels of IGF-1 are reduced despite increased basal secretion of GH. 4 These changes occur early and usually persist until clinical recovery begins. The derangement in the GH/ IGF-1 axis may have initial protective effects following injury, the fall in IGF-1 promoting muscle catabolism thus avoiding hypoglycaemia if nutritional intake is reduced, and the rise in GH promoting insulin antagonism and lipolysis. It is possible that this response may also explain the failure of standard nutritional regimes to prevent nitrogen loss in critical illness. The causes of muscle wasting in critical illness are summarized in Table 1.
Causes of muscle weakness in critical illness Acquired neuromuscular disorders
Causes of muscle weakness in critical illness are summarized in Table 2. In the past, weakness in critical illness has been principally attributed to muscle wasting and its causes as we have described. Increasing use of percutaneous muscle biopsy and neurophysiological studies in recent years have, however, characterized myopathies and peripheral neuropathies occurring in critical illness which may cause severe weakness. Immobilization and disuse atrophy, along with the catabolic response to trauma, surgery and sepsis generally induce non-specific changes on muscle histological appearance, such as type 11 fibre atrophy. Nerve conduction studies and creatine phosphokinase (CK) levels are characteristically normal. Myopathies have been described in patients requiring ventilation for acute severe asthma and attributed to steroids, terbutaline and/or the use of muscle relaxants. 5 Histological features of muscle biopsies included vacuolar myopathy, which is seen in steroid-induced myopathies,
Table 1--Causes of muscle wasting in critical illness. 1. Immobilization and disuse atrophy 2. Malnutrition • starvation - premorbid factors (e.g. anorexia, malignancy) - delayed initiation of feeding on ICU • deficiencies of 'conditionally essential' nutrients - glutamine 3. Metabolic response to trauma, surgery and sepsis • (hormones) • cytokines • derangement of the GH/IGF-1 axis.
WEAKNESS AND WASTINGIN THE CRITICALLYILL PATIENT 83 Table 2~Canses of muscleweaknessin critical illness. 1. Acquiredneuropathies - Critical illness neuropathyand variants 2. Acquiredmyopathies Muscle wasting- disuse atrophy/catabolic myopathy,(causes as describedin Table 1) - Acute myositis - Necrotisingmyopathy 3. Concomitantmedicalconditions - Guillain-Barresyndrome Myastheniagravis Metabolicmyopathies - CNS damage 4. Drug induced conditions Muscle relaxants Steroids - Aminoglycosideantibiotics Hypermagnesaemia - Rhabdomyolysis - Terbutaline 5. Metabolic - Hypokalaemia Hypophosphataemia. -
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and rhabdomyolysis, which sometimes occurs following subcutaneous terbutaline. Rhabdomyolysis has also been reported in two patients with asthma who received steroids and muscle relaxants but not terbutaline, 6 and we have reported another case of a patient who developed an acute necrotising myopathy in association with acute severe asthma who did not receive terbutaline. 7 Infection, trauma or drugs may induce an acute myositis. The onset of weakness is acute, CK is greatly elevated and muscle biopsy shows muscle necrosis, or microabscesses (pyomyositis). Rarely, muscle weakness in a critically ill patient may be due to a pre-existing undiagnosed myositis or metabolic myopathy. Helliwell and co-workers described histological muscle abnormalities in 31 critically ill patients. 8Twelve had atrophy of type I or II fibres in serial muscle biopsies, and 15 had a necrotising myopathy. In only nine patients was muscle histology normal. Rhabdomyolysis is usually seen in the context of severe muscle damage following trauma, but is a well recognised complication of sepsis and drug overdose. In Helliwell's study the presence of necrosis on muscle biopsy was associated with a 70% mortality and an increased incidence of renal failure. A raised CK level may help in the early identification of these patients with muscle necrosis, but CK may also be normal. We have reported muscle biopsy features from 23 critically ill patients? All but one biopsy demonstrated abnormal histological features (fibre atrophy, myopathy, neurogenic atrophy and necrosis), and on electron microscopy myofibrillar disruption and abnormalities of mitochondrial structure were seen. In patients followed up with sequential biopsies, progressive histological changes occurred, consistent with a worsening myopathy. Critical illness neuropathy is a condition characterized by a flaccid weakness which may be profound, with diminished or absent reflexes? ° Neurophysiological studies characteristically demonstrate normal nerve conduction velocities with reduced compound muscle
action potentials and reduced sensory action potentials, consistent with an axonal neuropathy. Muscle biopsy findings are of denervation atrophy, and CK levels are normal or only mildly elevated. The condition can be differentiated from Guillain-Barr6 syndrome by finding normal spinal fluid protein concentrations. Critical illness neuropathy is common in patients with sepsis and multiple organ failure, occurring in 70% of such patients. The natural history of the condition is for slow recovery to occur if the patient survives the condition which necessitated ICU admission, although some patients followed up over long periods still had abnormal electro myograms a few years after ICU discharge. A number of variants of this condition have been described. We reported three patients after prolonged periods of mechanical ventilation for chronic airways disease with a predominantly motor syndrome, two of whom had markedly reduced compound muscle action potentials with preservation of the sensory action potentials. There was diffuse fibrillation in all muscles studied suggesting neuropathic damage. Nerve conduction velocities were normal. In one of the patients, repetitive stimulation failed to demonstrate evidence of neuromuscular block, and in another the abnormalities w e r e not reversed by anticholinesterase administration. In these patients the lesion appeared to be either in the distal portion of the motor neurone or at the neuromuscular junction, and we designated this syndrome 'Critical Illness Neurological Syndrome'.9 A similar syndrome was reported by Gorson and colleagues.11 The cause of these neuromuscular disorders is unclear. Early reports attempted to link their presence to persisting effects of neuromuscular blocking agents but, in retrospect, the patients reviewed in these reports demonstrated features indistinguishable from critical illness neuropathy which may occur in patients who have never received muscle relaxants. In addition, most patients also demonstrated sensory abnormalities which are difficult to explain if neuromuscular junction blocking drugs are being blamed as the cause. A prospective study also failed to demonstrate a link with antibiotic or steroid use, but a peripheral nerve function index derived from electrophysiological measurements showed a significant negative correlation with the time in the critical care unit, and a significant positive correlation with serum albumin level. 1° The authors postulated that the polyneuropathy was due to the same mechanisms which caused dysfunction of other organ systems in sepsis and multiple organ failure: a view supported by the finding that critical illness neuropathy usually improves once sepsis is brought fully under control. We have, however, identified critical illness neuropathy and abnormal muscle histology in patients who have not had sepsis and in patients with only single organ failure. 9 In prospective studies of neurophysiologicai abnormalities in critical illness, the incidence is as high as 70-80% after approximately 1 week of intensive care admission. The relationship between muscle histological abnormalities and findings on nerve conduction studies is also
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unclear. Profound reductions in compound muscle action potentials may be associated with histological features of denervation. In general, as the cause of these neuromuscular disorders is almost certainly multifactorial, both muscle biopsy and nerve conduction studies are needed to fully define the nature of a neuromuscular disorder in any individual patient. Drug-induced conditions Steroid use may precipitate a myopathy characterized by proximal weakness and wasting and diminished tendon reflexes. Muscle biopsy shows features of a vacuolar myopathy owing to glycogen accumulation. This myopathy may occur after acute or chronic administration and may explain weakness and difficulty in weaning from ventilation in some asthmatic patients. Aminoglycoside antibiotics are known to interfere with neuromuscular transmission and may sometimes lead to weakness in the critically ill patient, especially if used concomitantly with neuromuscular blocking drugs in patients with renal or hepatic failure. Magnesium therapy for pre-eclampsia may lead to disruption of neuromusclar transmission and muscle weakness. This can be a serious side-effect of an important therapy and emphasises the necessity for regular monitoring of serum levels during therapy. Metabolic causes of weakness Hypokalaemia and hypophosphataemia are not uncommon on the ICU, and are sometimes iatrogenic. Significant hypokalaemia may cause a severe muscle weakness. There is generally associated cardiac rhythm abnormalities and a metabolic alkalosis. Muscle biopsy reveals a vacuolar myopathy.
Table 3--Therapeutic optionsfor the preventionof weakness and
wasting in critical illness. 1. Ameliorationof inflammatoryresponse - debridementof wounds - aggressivediagnosis and treatmentof sepsis (- blockadeof inflammatorycascade/cytokines) 2. Nutritional support - novel substrates glutamine glutamine dipeptides 3. Growthfactor administration - recombinanthuman growth hormone - insulin-like growthfactor-1 4. Rehabilitationphysiotherapy 5. Carefuluse of steroids and musclerelaxants.
these conditions is unclear and is probably multifactorial. Therapeutic options in the prevention of wasting and weakness are listed in Table 3. It is clear that the metabolic response to trauma, surgery and sepsis is a major factor in causation of negative nitrogen balance and thus muscle protein loss. It is important, therefore, that effective therapy for the underlying condition is instituted rapidly, so that the inflammatory response is limited. This will involve early and effective resuscitation to achieve adequate tissue oxygen delivery and may involve early surgical debridement or drainage. Early diagnosis and appropriate antibiotic treatment of infectious is also of importance. Recent interest in agents which block the inflammatory response at various stages, such as anti-endotoxin and anti-cytokine agents, have unfortunately not translated into useful therapies for sepsis. Should a suitable agent be identified, however, its use might help prevent the hypercatabolism seen in these patients. Nutrition
Concomitant medical conditions Although rare, concomitant conditions such as GuillainBarre syndrome, myasthenia gravis and acute central nervous system lesions must not be forgotten as potential causes for muscle weakness in the ICU. Careful clinical evaluation and investigation will ascertain the diagnosis. Further discussion of these conditions is beyond the scope of this review. Strategies to prevent wasting and weakness t h e c r i t i c a l l y ill
in
Muscle wasting and weakness is common in the critically ill and leads to prolonged requirement for respiratory support, prolonged stay on the ICU, increased susceptibility to the complications of critical illness and delayed rehabilitation following ICU stay. In addition to mortality and morbidity implications, this has significant psychosocial implications for patients and their relatives and an increased cost burden for the health care system. Prevention of wasting and weakness is important, therefore, but it is likely to be difficult as the aetiology of
Intuitively it is important to commence early nutritional support in critically ill patients. However, as we have already discussed, hyperalimentation does not prevent muscle wasting. Recently attention has shifted to certain 'novel' substrates not usually included, or only minireally included, in nutritional regimes for patients which may have advantages in reversing negative nitrogen balance. The substance which has received most attention is glutamine. Glutamine. Glutamine is a non-essential amino-acid which is the most abundant amino-acid in the body, and constitutes 60% of free intracellular amino-acids in skeletal muscle. Glutamine is unstable in solution and is, therefore, not normally included in parenteral nutrition regimes or enteral feeds stored as liquid. Endogenous sources of glutamine include the lung, adipose tissue and the liver, but skeletal muscle is thought to be most important site of glutamine synthesis and release. Glutamine is the most important carrier of ammonia from the peripheral tissues to the splanchnic area and serves as an oxidation fuel during cell division. It is a donor of nitrogen for deoxyribo nucleic acid (DNA) and
WEAKNESSAND WASTINGIN THE CRITICALLYILL PATIENT 85 ribonucleic acid (RNA) synthesis and hence is essential for the proliferation of cells. Glutamine is the principal metabolic fuel of gut mucosal cells, lymphocytes and monocytes. Studies have demonstrated a net flux of glutamine from peripheral to splanchnic tissue with increased hepatic and intestinal uptake after operative stress or in sepsis. 12 In illness glutamine requirements appear to increase markedly, and utilization may exceed capacity for endogenous production. In this situation, glutamine may become a conditionally essential aminoacid. If adequate dietary glutamine is not provided net catabolism of skeletal muscle will occur to supply the requirements of glutamine dependent tissue. Plasma and muscle glutamine levels fall in catabolic states. 13Muscle glutamine depletion in illness may be due to both reduced intracellular synthesis and increased efflux to supply glutamine dependent tissues. There is a positive correlation between muscle glutamine level and rate of muscle protein synthesis, and muscle protein breakdown is inhibited by providing glutamine. Recent studies in man have suggested that addition of glutamine to nutritional regimes may restore depleted plasma and muscle levels and improve nitrogen balance in patients with sepsis, following bone marrow transplant and post surgeryJ 4 In addition, the fall in muscle protein synthesis seen postoperatively (as assessed by ribosome analysis) was counteracted by glutamine enriched feeding. The effect of glutamine-enriched feeding in a heterogeneous group of critically ill patients has, however, not yet been elucidated. Other nutrients are also under study. In children receiving home intravenous nutrition, large doses of ornithine c~-ketoglutarate produced improvement in growth. Arginine has been promoted as an immunonutrient and reduced wound infections following major surgery.15 However, there is little information on whether these agents will be useful in ameliorating the catabolic state seen in critical illness.
Growth factors As there is evidence that the GH/IGF-1 axis is disrupted in critical illness, and recombinant techniques have allowed the preparation of GH and IGF-1 for therapeutic use, interest has risen in the potential use of these agents to reverse weakness and wasting in critical illnessJ 6
Growth hormone. Growth hormone has been shown to be associated with improved nitrogen balance and muscle function after elective abdominal surgery and to improve respiratory muscle function in patients withchronic airways disease. Animal and human studies have demonstrated that GH increases protein synthesis in skeletal muscle? 7 In patients undergoing open cholecystectomy protein synthesis was stimulated, along with an increase in the concentration of free glutamine in muscle. Fewer septic complications were reported in the GH group and length of hospital stay was reduced. Most studies of the use of GH in seriously ill humans have involved those with burns, although recently there have been reports of the use of GH following sepsis and
pancreatitis. Several studies have shown that once daily subcutaneous administration of low doses of recombinant human GH increase plasma levels of GH and IGF1, and that positive nitrogen balance can be promoted, even in the presence of hypocaloric nutrition. 18 GH administration to critically ill patients does not appear to be associated with any significant adverse effects, and a multi-centre trial of its use in critical illness is currently in progress.
IGF-1. Despite increased basal secretion of GH, critically ill patients have low levels of IGF-1, suggesting that their tissues may be resistant to the effects of GH. IGF-1 has insulin-like effects on most tissues, but also has major promoting effects on the proliferation and differentiation of cells. IGF-1 has been synthesized by recombinant techniques and may be useful in the amelioration of protein catabolism associated with critical illness. m IGF-1 has been given to postoperative patients and to critically ill patients without adverse effects, but as yet there is insufficient information on its use therapeutically in these groups. Other strategies There is no evidence implicating any particular group of drugs in the causation of weakness and wasting in critical illness. Corticosteroids appear to have no definite role in the development of neuromuscular disorders, except in very high doses. Although many have implicated muscle relaxants in the causation of prolonged weakness, prospective studies have shown that many cases of acquired neuromuscular disorders are unrelated to their use. Clearly, short acting agents are to be preferred, and atracurium is clearly the agent of choice in patients with renal and/or hepatic failure. Monitoring neuromuscular blockade, regularly stopping infusions to check for recovery, and limiting duration of infusions to the minimum time necessary will avoid complications from the use of these agents. Early institution of rehabilitation physiotherapy may help reduce weakness and wasting and promote more rapid recovery following critical illness. Many patients will, however, need prolonged ventilatory support, and will remain in hospital for a considerable time following ICU discharge owing to immobility. It should not be forgotten, however, that the natural history of wasting and weakness in these patients is for recovery to occur.
Conclusion Muscle wasting and weakness are extremely common in critically ill patients. Although wasting is usually obvious, weakness is commonly unrecognized and yet is of major importance to morbidity and outcome. The causes of wasting and weakness are multiple, but inadequate nutritional support, the metabolic response to trauma, surgery and sepsis and acquired neuromuscular disorders are probably of most importance. Correct diagnosis requires neurophysiological studies and muscle biopsy. Preven-
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tion of wasting and weakness involves prompt and appropriate treatment to limit the inflammatory response, early nutritional support which may include novel substrates such as glutamine, consideration of the use of growth factors, and aggressive rehabilitation physiotherapy as soon as it is appropriate. There is no conclusive evidence implicating any drugs in the causation of these disorders.
References 1. Elia M. Changing concepts of nutrient requirements in disease: Implications for artificial nutritional support. Lancet 1995; 345: 1279-1289. 2. Arnold J, Campbell I T, Samuels T A, et al. Increased whole body protein breakdown predominates over increased whole body protein synthesis in multiple organ failure. Clin Sci 1993; 84: 655-661. 3. Souba W. Cytokine control of nutrition and metabolism in critical illness. Curr Probl Surg 1994; 31(7): 577-643. 4. Ross R, Miell J, Freeman E, et al. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-1. Clin Endocrinol 1991; 35: 47-54. 5. Douglass J, Tuxen D, Home M, Sheinkestel C. Myopathy in severe asthma. Am Rev Respir Dis 1992; 146: 517-519. 6. Barrett S, Mourain S, Villareal C, Gonzales J, Zimmerman J. Rhabdomyolysis associated with status asthmaticus. Crit Care Med 1993; 21: 151-153. 7. O'Leary M, Honavar M, Coakley J. Acute necrotizing myopathy and acute renal failure in association with acute severe asthma. Anaesth Intensive Care 1994; 22: 729-732.
8. Helliwell T, Coakley J, Wagenmakers A, et al. Necrotizing myopathy in critically ill patients. J Pathol 1991; 164: 307-314. 9. Coakley J H, Nagendran K, Honavar M, Hinds C J. Preliminary observations on the neuromuscular abnormalities in critically ill patients. Int Care Med 1993; 19(6): 323-328. 10. Witt N, Zocbodne D, Bolton C, et al. Peripheral nerve function in sepsis and multiple organ failure. Chest 1991; 99(1): 176-184. 11. Gorson K, Ropper A. Acute respiratory failure neuropathy: A variant of critical illness polyneuropathy. Crit Care Med 1993; 21(2): 267-271. 12. Souba W W, Austgen T R. Interorgan glutamine flow following surgery and infection. JPEN 1990; 14(suppl 4): 90S-93S. 13. Parry-Billings M, Baigrie R J, Lamont P M, Morris P J, Newsholme E A. Effects of major and minor surgery on plasma glutamine and cytokine levels. Arch Surg 1992; 127: 1237-1240. 14. Efia M. Glutamine in parenteral nutrition. Int J Food Sci Nutr .... 1992; 43: 47-49. 15. Daly M, Liekerman M, Foldfine J, et al. Enteral nutrition with supplemental arginine, RNA and omega-3 fatty acids in patients after operation: Immunologic, metabolic and clinical outcomes. Surgery 1992; 112: 56-57. 16. Coaldey J, Yarwood G, Ross R. The pathophysiology of neuromuscular weakness: Potential of treatment with growth factors. In: Vincent J-L, (ed) Intensive Care and Emergency Medicine Update 1993. Springer Verlag, 1993: 178-184. 17. Hammarqvist F, Strrmberg C, vonder Decken A, Vinnars E, Wemerman J. Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole body nitrogen economy after operation. Ann Surg 1992; 16(2): 184-191. 18. Manson J M, Smith R J, Wilmore D W. Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Ann Surg 1988; 208: 136-142. 19. Ross R, Yarwood G, Coakley J. Prospective therapeutic use of growth hormone and IGF-1 in ICU patients. In: Intensive Care Britain 1993. London: Greycote Publishing, 1993: 45-48.
© 1996 Pearson Professional Ltd
Focus on: Gut and nutritional failure in the critically ill
Weakness and wasting in the critically ill patient
M. J. O'Leary and J. H. Coakley
Introduction
Immobilization of a fractured limb has been shown to result in a reduction of mean muscle fibre area of approximately 40% in healthy young adults over a 6-7 week period. During critical illness wasting generally occurs much more rapidly, often being apparent as early as 10 days after admission to intensive care. This puts in doubt the role of immobilization as a sole aetiological factor. Although rehabilitation physiotherapy has been shown to accelerate recovery, it is unlikely that immobilization is a major cause of muscle wasting and weakness in critically ill patients but clearly its presence may exacerbate other causes.
Cachexia, associated with critical illness, has for a long time been a recognized clinical entity and may in part be explained by the combined effects of malnutrition, immobilization and the hypercatabolism seen after surgery, trauma and sepsis. The failure of hyperalimentation to reverse muscle wasting and negative nitrogen balance during critical illness has led to a re-evaluation of the causes of wasting and of the therapeutic strategies that might be employed to prevent it. Although muscle wasting and negative nitrogen balance is clearly of concern to the intensive care physician, the muscle weakness which accompanies wasting (but which may also occur in its absence) is the dominant clinical problem. Weakness and wasting of skeletal muscles is often obvious and has been shown to delay mobilization and prolong recovery time. Weakness of respiratory musculature, however, may not always be appreciated as a major cause of prolonged weaning from ventilatory support, despite resolution of the underlying condition leading to intensive care unit (ICU) admission. Prolonged ventilation is not without complications such as development of nosocomial pneumonias and sepsis which may ultimately lead to death. In this article we will summarize our current understanding of the causes of weakness and wasting in critically ill patients and highlight the latest attempts to reverse these processes by therapeutic intervention.
Malnutrition Muscle wasting and weakness is a major feature of malnutrition. Many patients on the ICU are malnourished on admission because of anorexia owing to illness or fasting in preparation for surgery. This may be exacerbated by delays in commencing nutritional support following ICU admission. Hepatic glycogen stores are only sufficient for 24 h glycogenolysis and after this a decrease in insulin secretion and increase in glucagon result in protein and fat breakdown to provide energy. Protein catabolism leads to increased urinary urea and negative nitrogen balance. In uncomplicated starvation lean body mass is generally preserved until late as fat breakdown is the main source of calories. The administration of sufficient nutritional substrate will thus convert the starved patient to an anabolic state. Initially, once intensive care physicians became aware of the importance of nutritional support, it was assumed that wasting and negative nitrogen balance would be reversed by hyperalimentation in critically ill patients but this was found not to be the case. In fact, overfeeding led to hepatic steatosis, abnormal liver function, and excess carbon dioxide production which
Causes of muscle wasting in critical illness Immobilization Muscle wasting is a common accompaniment of disuse. Dr M. J. O'Leary FRCA, ResearchFellow in IntensiveCare Medicine. Dr J. H. Coakley MRCP, Consultant, IntensiveCare Unit, St. Bartholomew'sHospital,West Smithfield,LondonEC1A 7BE, UK. 81
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was thought by some to be detrimental to weaning from ventilatory support. Over the past 20 years the energy intake recommended for critically ill patients receiving parenteral nutrition has fallen by approximately 60%, and it appears that the energy requirements of these patients are in fact similar to those of normal healthy people. 1 These requirements still reflect hypermetabolism but this is balanced by the effects of reduced physical activity. Why does nutritional support fail to prevent muscle wasting and a negative nitrogen balance in critical illness? Recent attention has focused on certain nutrients such as glutamine, alanine, cysteine and tyrosine which are deficient or missing from nutritional formulae and which may become conditionally essential in critical illness, In the absence of these substances muscle turnover may be deranged and essential body functions limited. Enrichment of nutrition with these substances, therefore, may be of therapeutic value, and is discussed later in this article. It may be, however, that nutritional support alone is insufficient to reverse negative nitrogen balance associated with critical illness because of the special metabolic response seen following trauma, surgery and sepsis. Furthermore, the various neuromuscular disorders described below would not be expected to be amenable to treatment by nutritional support alone. The metabolic response to trauma, surgery and sepsis
Following a major insult there is increased secretion of catecholamines and glucocorticoids with reduced secretion of insulin. Initially there is a period of decreased energy catabolism but this is followed by an accelerated catabolic phase which does not demonstrate the adaptation to fat metabolism seen during starvation. There is weight loss and muscle wasting which leads to an increased loss of nitrogen in the urine most of which originates from muscle proteins. Whole body protein turnover and its response to trauma, surgery and sepsis has been extensively investigated. Following relatively mild trauma, for example, an uncomplicated open cholecystectomy, protein synthesis is generally depressed but with increasing severity of insult protein synthesis and breakdown may both be enhanced with breakdown predominating over synthesis, zNet muscle protein breakdown in this situation may have several short-term advantages including provision of amino-acids such as glutamine for protein synthesis within the cells of the immune system, for repair processes and for hepatic gluconeogenesis. In addition to the well recognized effects of catecholamines and glucocorticoids, it is now clear that cytokine release and changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis also are of considerable importance in the metabolic response to trauma, surgery and sepsis. Cytokines released as part of the inflammatory response to injury or sepsis affect whole body nutrition and metabolism and are responsible for many nutritional effects, including fever, hyper-
metabolism, anorexia, protein catabolism, cachexia, and altered fat, glucose and trace mineral metabolism? It has been postulated that derangement of the GH/ IGF-1 axis may partly explain muscle loss and negative nitrogen balance in critical illness. GH is a polypeptide hormone with both direct fuel regulating effects (lipolysis and insulin antagonism) and indirect growth promoting actions (anabolism) which influence amino acid uptake and protein synthesis. Its anabolic actions are mediated through IGF-1, which is secreted principally by cells of the liver under the control of GH. Critically ill patients are relatively resistant to GH, and circulating levels of IGF-1 are reduced despite increased basal secretion of GH. 4 These changes occur early and usually persist until clinical recovery begins. The derangement in the GH/ IGF-1 axis may have initial protective effects following injury, the fall in IGF-1 promoting muscle catabolism thus avoiding hypoglycaemia if nutritional intake is reduced, and the rise in GH promoting insulin antagonism and lipolysis. It is possible that this response may also explain the failure of standard nutritional regimes to prevent nitrogen loss in critical illness. The causes of muscle wasting in critical illness are summarized in Table 1.
Causes of muscle weakness in critical illness Acquired neuromuscular disorders
Causes of muscle weakness in critical illness are summarized in Table 2. In the past, weakness in critical illness has been principally attributed to muscle wasting and its causes as we have described. Increasing use of percutaneous muscle biopsy and neurophysiological studies in recent years have, however, characterized myopathies and peripheral neuropathies occurring in critical illness which may cause severe weakness. Immobilization and disuse atrophy, along with the catabolic response to trauma, surgery and sepsis generally induce non-specific changes on muscle histological appearance, such as type 11 fibre atrophy. Nerve conduction studies and creatine phosphokinase (CK) levels are characteristically normal. Myopathies have been described in patients requiring ventilation for acute severe asthma and attributed to steroids, terbutaline and/or the use of muscle relaxants. 5 Histological features of muscle biopsies included vacuolar myopathy, which is seen in steroid-induced myopathies,
Table 1--Causes of muscle wasting in critical illness. 1. Immobilization and disuse atrophy 2. Malnutrition • starvation - premorbid factors (e.g. anorexia, malignancy) - delayed initiation of feeding on ICU • deficiencies of 'conditionally essential' nutrients - glutamine 3. Metabolic response to trauma, surgery and sepsis • (hormones) • cytokines • derangement of the GH/IGF-1 axis.
WEAKNESS AND WASTINGIN THE CRITICALLYILL PATIENT 83 Table 2~Canses of muscleweaknessin critical illness. 1. Acquiredneuropathies - Critical illness neuropathyand variants 2. Acquiredmyopathies Muscle wasting- disuse atrophy/catabolic myopathy,(causes as describedin Table 1) - Acute myositis - Necrotisingmyopathy 3. Concomitantmedicalconditions - Guillain-Barresyndrome Myastheniagravis Metabolicmyopathies - CNS damage 4. Drug induced conditions Muscle relaxants Steroids - Aminoglycosideantibiotics Hypermagnesaemia - Rhabdomyolysis - Terbutaline 5. Metabolic - Hypokalaemia Hypophosphataemia. -
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and rhabdomyolysis, which sometimes occurs following subcutaneous terbutaline. Rhabdomyolysis has also been reported in two patients with asthma who received steroids and muscle relaxants but not terbutaline, 6 and we have reported another case of a patient who developed an acute necrotising myopathy in association with acute severe asthma who did not receive terbutaline. 7 Infection, trauma or drugs may induce an acute myositis. The onset of weakness is acute, CK is greatly elevated and muscle biopsy shows muscle necrosis, or microabscesses (pyomyositis). Rarely, muscle weakness in a critically ill patient may be due to a pre-existing undiagnosed myositis or metabolic myopathy. Helliwell and co-workers described histological muscle abnormalities in 31 critically ill patients. 8Twelve had atrophy of type I or II fibres in serial muscle biopsies, and 15 had a necrotising myopathy. In only nine patients was muscle histology normal. Rhabdomyolysis is usually seen in the context of severe muscle damage following trauma, but is a well recognised complication of sepsis and drug overdose. In Helliwell's study the presence of necrosis on muscle biopsy was associated with a 70% mortality and an increased incidence of renal failure. A raised CK level may help in the early identification of these patients with muscle necrosis, but CK may also be normal. We have reported muscle biopsy features from 23 critically ill patients? All but one biopsy demonstrated abnormal histological features (fibre atrophy, myopathy, neurogenic atrophy and necrosis), and on electron microscopy myofibrillar disruption and abnormalities of mitochondrial structure were seen. In patients followed up with sequential biopsies, progressive histological changes occurred, consistent with a worsening myopathy. Critical illness neuropathy is a condition characterized by a flaccid weakness which may be profound, with diminished or absent reflexes? ° Neurophysiological studies characteristically demonstrate normal nerve conduction velocities with reduced compound muscle
action potentials and reduced sensory action potentials, consistent with an axonal neuropathy. Muscle biopsy findings are of denervation atrophy, and CK levels are normal or only mildly elevated. The condition can be differentiated from Guillain-Barr6 syndrome by finding normal spinal fluid protein concentrations. Critical illness neuropathy is common in patients with sepsis and multiple organ failure, occurring in 70% of such patients. The natural history of the condition is for slow recovery to occur if the patient survives the condition which necessitated ICU admission, although some patients followed up over long periods still had abnormal electro myograms a few years after ICU discharge. A number of variants of this condition have been described. We reported three patients after prolonged periods of mechanical ventilation for chronic airways disease with a predominantly motor syndrome, two of whom had markedly reduced compound muscle action potentials with preservation of the sensory action potentials. There was diffuse fibrillation in all muscles studied suggesting neuropathic damage. Nerve conduction velocities were normal. In one of the patients, repetitive stimulation failed to demonstrate evidence of neuromuscular block, and in another the abnormalities w e r e not reversed by anticholinesterase administration. In these patients the lesion appeared to be either in the distal portion of the motor neurone or at the neuromuscular junction, and we designated this syndrome 'Critical Illness Neurological Syndrome'.9 A similar syndrome was reported by Gorson and colleagues.11 The cause of these neuromuscular disorders is unclear. Early reports attempted to link their presence to persisting effects of neuromuscular blocking agents but, in retrospect, the patients reviewed in these reports demonstrated features indistinguishable from critical illness neuropathy which may occur in patients who have never received muscle relaxants. In addition, most patients also demonstrated sensory abnormalities which are difficult to explain if neuromuscular junction blocking drugs are being blamed as the cause. A prospective study also failed to demonstrate a link with antibiotic or steroid use, but a peripheral nerve function index derived from electrophysiological measurements showed a significant negative correlation with the time in the critical care unit, and a significant positive correlation with serum albumin level. 1° The authors postulated that the polyneuropathy was due to the same mechanisms which caused dysfunction of other organ systems in sepsis and multiple organ failure: a view supported by the finding that critical illness neuropathy usually improves once sepsis is brought fully under control. We have, however, identified critical illness neuropathy and abnormal muscle histology in patients who have not had sepsis and in patients with only single organ failure. 9 In prospective studies of neurophysiologicai abnormalities in critical illness, the incidence is as high as 70-80% after approximately 1 week of intensive care admission. The relationship between muscle histological abnormalities and findings on nerve conduction studies is also
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unclear. Profound reductions in compound muscle action potentials may be associated with histological features of denervation. In general, as the cause of these neuromuscular disorders is almost certainly multifactorial, both muscle biopsy and nerve conduction studies are needed to fully define the nature of a neuromuscular disorder in any individual patient. Drug-induced conditions Steroid use may precipitate a myopathy characterized by proximal weakness and wasting and diminished tendon reflexes. Muscle biopsy shows features of a vacuolar myopathy owing to glycogen accumulation. This myopathy may occur after acute or chronic administration and may explain weakness and difficulty in weaning from ventilation in some asthmatic patients. Aminoglycoside antibiotics are known to interfere with neuromuscular transmission and may sometimes lead to weakness in the critically ill patient, especially if used concomitantly with neuromuscular blocking drugs in patients with renal or hepatic failure. Magnesium therapy for pre-eclampsia may lead to disruption of neuromusclar transmission and muscle weakness. This can be a serious side-effect of an important therapy and emphasises the necessity for regular monitoring of serum levels during therapy. Metabolic causes of weakness Hypokalaemia and hypophosphataemia are not uncommon on the ICU, and are sometimes iatrogenic. Significant hypokalaemia may cause a severe muscle weakness. There is generally associated cardiac rhythm abnormalities and a metabolic alkalosis. Muscle biopsy reveals a vacuolar myopathy.
Table 3--Therapeutic optionsfor the preventionof weakness and
wasting in critical illness. 1. Ameliorationof inflammatoryresponse - debridementof wounds - aggressivediagnosis and treatmentof sepsis (- blockadeof inflammatorycascade/cytokines) 2. Nutritional support - novel substrates glutamine glutamine dipeptides 3. Growthfactor administration - recombinanthuman growth hormone - insulin-like growthfactor-1 4. Rehabilitationphysiotherapy 5. Carefuluse of steroids and musclerelaxants.
these conditions is unclear and is probably multifactorial. Therapeutic options in the prevention of wasting and weakness are listed in Table 3. It is clear that the metabolic response to trauma, surgery and sepsis is a major factor in causation of negative nitrogen balance and thus muscle protein loss. It is important, therefore, that effective therapy for the underlying condition is instituted rapidly, so that the inflammatory response is limited. This will involve early and effective resuscitation to achieve adequate tissue oxygen delivery and may involve early surgical debridement or drainage. Early diagnosis and appropriate antibiotic treatment of infectious is also of importance. Recent interest in agents which block the inflammatory response at various stages, such as anti-endotoxin and anti-cytokine agents, have unfortunately not translated into useful therapies for sepsis. Should a suitable agent be identified, however, its use might help prevent the hypercatabolism seen in these patients. Nutrition
Concomitant medical conditions Although rare, concomitant conditions such as GuillainBarre syndrome, myasthenia gravis and acute central nervous system lesions must not be forgotten as potential causes for muscle weakness in the ICU. Careful clinical evaluation and investigation will ascertain the diagnosis. Further discussion of these conditions is beyond the scope of this review. Strategies to prevent wasting and weakness t h e c r i t i c a l l y ill
in
Muscle wasting and weakness is common in the critically ill and leads to prolonged requirement for respiratory support, prolonged stay on the ICU, increased susceptibility to the complications of critical illness and delayed rehabilitation following ICU stay. In addition to mortality and morbidity implications, this has significant psychosocial implications for patients and their relatives and an increased cost burden for the health care system. Prevention of wasting and weakness is important, therefore, but it is likely to be difficult as the aetiology of
Intuitively it is important to commence early nutritional support in critically ill patients. However, as we have already discussed, hyperalimentation does not prevent muscle wasting. Recently attention has shifted to certain 'novel' substrates not usually included, or only minireally included, in nutritional regimes for patients which may have advantages in reversing negative nitrogen balance. The substance which has received most attention is glutamine. Glutamine. Glutamine is a non-essential amino-acid which is the most abundant amino-acid in the body, and constitutes 60% of free intracellular amino-acids in skeletal muscle. Glutamine is unstable in solution and is, therefore, not normally included in parenteral nutrition regimes or enteral feeds stored as liquid. Endogenous sources of glutamine include the lung, adipose tissue and the liver, but skeletal muscle is thought to be most important site of glutamine synthesis and release. Glutamine is the most important carrier of ammonia from the peripheral tissues to the splanchnic area and serves as an oxidation fuel during cell division. It is a donor of nitrogen for deoxyribo nucleic acid (DNA) and
WEAKNESSAND WASTINGIN THE CRITICALLYILL PATIENT 85 ribonucleic acid (RNA) synthesis and hence is essential for the proliferation of cells. Glutamine is the principal metabolic fuel of gut mucosal cells, lymphocytes and monocytes. Studies have demonstrated a net flux of glutamine from peripheral to splanchnic tissue with increased hepatic and intestinal uptake after operative stress or in sepsis. 12 In illness glutamine requirements appear to increase markedly, and utilization may exceed capacity for endogenous production. In this situation, glutamine may become a conditionally essential aminoacid. If adequate dietary glutamine is not provided net catabolism of skeletal muscle will occur to supply the requirements of glutamine dependent tissue. Plasma and muscle glutamine levels fall in catabolic states. 13Muscle glutamine depletion in illness may be due to both reduced intracellular synthesis and increased efflux to supply glutamine dependent tissues. There is a positive correlation between muscle glutamine level and rate of muscle protein synthesis, and muscle protein breakdown is inhibited by providing glutamine. Recent studies in man have suggested that addition of glutamine to nutritional regimes may restore depleted plasma and muscle levels and improve nitrogen balance in patients with sepsis, following bone marrow transplant and post surgeryJ 4 In addition, the fall in muscle protein synthesis seen postoperatively (as assessed by ribosome analysis) was counteracted by glutamine enriched feeding. The effect of glutamine-enriched feeding in a heterogeneous group of critically ill patients has, however, not yet been elucidated. Other nutrients are also under study. In children receiving home intravenous nutrition, large doses of ornithine c~-ketoglutarate produced improvement in growth. Arginine has been promoted as an immunonutrient and reduced wound infections following major surgery.15 However, there is little information on whether these agents will be useful in ameliorating the catabolic state seen in critical illness.
Growth factors As there is evidence that the GH/IGF-1 axis is disrupted in critical illness, and recombinant techniques have allowed the preparation of GH and IGF-1 for therapeutic use, interest has risen in the potential use of these agents to reverse weakness and wasting in critical illnessJ 6
Growth hormone. Growth hormone has been shown to be associated with improved nitrogen balance and muscle function after elective abdominal surgery and to improve respiratory muscle function in patients withchronic airways disease. Animal and human studies have demonstrated that GH increases protein synthesis in skeletal muscle? 7 In patients undergoing open cholecystectomy protein synthesis was stimulated, along with an increase in the concentration of free glutamine in muscle. Fewer septic complications were reported in the GH group and length of hospital stay was reduced. Most studies of the use of GH in seriously ill humans have involved those with burns, although recently there have been reports of the use of GH following sepsis and
pancreatitis. Several studies have shown that once daily subcutaneous administration of low doses of recombinant human GH increase plasma levels of GH and IGF1, and that positive nitrogen balance can be promoted, even in the presence of hypocaloric nutrition. 18 GH administration to critically ill patients does not appear to be associated with any significant adverse effects, and a multi-centre trial of its use in critical illness is currently in progress.
IGF-1. Despite increased basal secretion of GH, critically ill patients have low levels of IGF-1, suggesting that their tissues may be resistant to the effects of GH. IGF-1 has insulin-like effects on most tissues, but also has major promoting effects on the proliferation and differentiation of cells. IGF-1 has been synthesized by recombinant techniques and may be useful in the amelioration of protein catabolism associated with critical illness. m IGF-1 has been given to postoperative patients and to critically ill patients without adverse effects, but as yet there is insufficient information on its use therapeutically in these groups. Other strategies There is no evidence implicating any particular group of drugs in the causation of weakness and wasting in critical illness. Corticosteroids appear to have no definite role in the development of neuromuscular disorders, except in very high doses. Although many have implicated muscle relaxants in the causation of prolonged weakness, prospective studies have shown that many cases of acquired neuromuscular disorders are unrelated to their use. Clearly, short acting agents are to be preferred, and atracurium is clearly the agent of choice in patients with renal and/or hepatic failure. Monitoring neuromuscular blockade, regularly stopping infusions to check for recovery, and limiting duration of infusions to the minimum time necessary will avoid complications from the use of these agents. Early institution of rehabilitation physiotherapy may help reduce weakness and wasting and promote more rapid recovery following critical illness. Many patients will, however, need prolonged ventilatory support, and will remain in hospital for a considerable time following ICU discharge owing to immobility. It should not be forgotten, however, that the natural history of wasting and weakness in these patients is for recovery to occur.
Conclusion Muscle wasting and weakness are extremely common in critically ill patients. Although wasting is usually obvious, weakness is commonly unrecognized and yet is of major importance to morbidity and outcome. The causes of wasting and weakness are multiple, but inadequate nutritional support, the metabolic response to trauma, surgery and sepsis and acquired neuromuscular disorders are probably of most importance. Correct diagnosis requires neurophysiological studies and muscle biopsy. Preven-
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tion of wasting and weakness involves prompt and appropriate treatment to limit the inflammatory response, early nutritional support which may include novel substrates such as glutamine, consideration of the use of growth factors, and aggressive rehabilitation physiotherapy as soon as it is appropriate. There is no conclusive evidence implicating any drugs in the causation of these disorders.
References 1. Elia M. Changing concepts of nutrient requirements in disease: Implications for artificial nutritional support. Lancet 1995; 345: 1279-1289. 2. Arnold J, Campbell I T, Samuels T A, et al. Increased whole body protein breakdown predominates over increased whole body protein synthesis in multiple organ failure. Clin Sci 1993; 84: 655-661. 3. Souba W. Cytokine control of nutrition and metabolism in critical illness. Curr Probl Surg 1994; 31(7): 577-643. 4. Ross R, Miell J, Freeman E, et al. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-1. Clin Endocrinol 1991; 35: 47-54. 5. Douglass J, Tuxen D, Home M, Sheinkestel C. Myopathy in severe asthma. Am Rev Respir Dis 1992; 146: 517-519. 6. Barrett S, Mourain S, Villareal C, Gonzales J, Zimmerman J. Rhabdomyolysis associated with status asthmaticus. Crit Care Med 1993; 21: 151-153. 7. O'Leary M, Honavar M, Coakley J. Acute necrotizing myopathy and acute renal failure in association with acute severe asthma. Anaesth Intensive Care 1994; 22: 729-732.
8. Helliwell T, Coakley J, Wagenmakers A, et al. Necrotizing myopathy in critically ill patients. J Pathol 1991; 164: 307-314. 9. Coakley J H, Nagendran K, Honavar M, Hinds C J. Preliminary observations on the neuromuscular abnormalities in critically ill patients. Int Care Med 1993; 19(6): 323-328. 10. Witt N, Zocbodne D, Bolton C, et al. Peripheral nerve function in sepsis and multiple organ failure. Chest 1991; 99(1): 176-184. 11. Gorson K, Ropper A. Acute respiratory failure neuropathy: A variant of critical illness polyneuropathy. Crit Care Med 1993; 21(2): 267-271. 12. Souba W W, Austgen T R. Interorgan glutamine flow following surgery and infection. JPEN 1990; 14(suppl 4): 90S-93S. 13. Parry-Billings M, Baigrie R J, Lamont P M, Morris P J, Newsholme E A. Effects of major and minor surgery on plasma glutamine and cytokine levels. Arch Surg 1992; 127: 1237-1240. 14. Efia M. Glutamine in parenteral nutrition. Int J Food Sci Nutr .... 1992; 43: 47-49. 15. Daly M, Liekerman M, Foldfine J, et al. Enteral nutrition with supplemental arginine, RNA and omega-3 fatty acids in patients after operation: Immunologic, metabolic and clinical outcomes. Surgery 1992; 112: 56-57. 16. Coaldey J, Yarwood G, Ross R. The pathophysiology of neuromuscular weakness: Potential of treatment with growth factors. In: Vincent J-L, (ed) Intensive Care and Emergency Medicine Update 1993. Springer Verlag, 1993: 178-184. 17. Hammarqvist F, Strrmberg C, vonder Decken A, Vinnars E, Wemerman J. Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole body nitrogen economy after operation. Ann Surg 1992; 16(2): 184-191. 18. Manson J M, Smith R J, Wilmore D W. Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Ann Surg 1988; 208: 136-142. 19. Ross R, Yarwood G, Coakley J. Prospective therapeutic use of growth hormone and IGF-1 in ICU patients. In: Intensive Care Britain 1993. London: Greycote Publishing, 1993: 45-48.