995

Nutrition and the Metabolic

Response to InjuryWHEN, in the mid-nineteenth century, Robert

Graves of Dublin showed that the mortality fromtyphus fever could be reduced by giving food anddrink to his patients, he not only overturnedestablished dogma that the treatment of fever shouldconsist of bleeding, purging, and starvation, but alsoheralded modern interest in nutritional support to aidsurvival and recovery from acute illness or injury. Theresponse to injury consists of a brief "ebb" or shockphase followed by a catabolic "flow" phase1 whichgives way, during recovery, to an anabolicconvalescent phase. Increased food intake can be usedduring the convalescent phase to restore tissue lost inthe flow phase. This response is mediated in two ways.First, afferent nerve sensors and spinal pathwaysconvey stimuli to the hypothalamus, causing a

neuroendocrine response characterised by increasedsympathetic activity, enhanced cortisol, glucagon, andgrowth hormone secretion, and initial suppression ofinsulin release followed by insulin resistance. Thisresponse can be attenuated after lower abdominal

surgery by spinal anaesthetic blockade .2 During majorinjury and sepsis, the inflammatory cascade itself maygenerate cytokines or other substances that stimulatethe hypothalamus directly and have local effects oncell metabolism although some studies have notshown such an effect.4 Is the response to injury adesirable and necessary way of diverting the body’sresources away from activity and feeding towards therepair of injury, or an archaic and undesirable

1. Cuthbertson DP. Observations on the disturbance of metabolism produced by injuryto the limbs. Q J Med 1932; 1: 233-46.

2. Kehlet H, Schulze S. Modification of injury responses. In: Little RA, Frayn KN, eds.The scientific basis for the care of the critically ill. Manchester: Manchester

University Press, 1986: 153-68.3. Clowes GHA, George BC, Viltec CH, et al Muscle proteolysis induced by a

circulating peptide in patients with sepsis or trauma. N Enql J Med 1983; 308:545-52.

4. Moldawer LL, Svaninger G, Gelin J, Lundholm KG. Interleukin 1 and tumornecrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol1987; 253: V766-73.

mechanism to be suppressed and counteracted at allcosts? John Hunters perceived the answer when hewrote "Impressions are capable of producing orincreasing natural actions and are then called stimuli:but they are likewise capable of producing too muchaction, as well as depraved, unnatural, or what wecommonly call diseased actions". He saw that a

necessary physiological response can , when extreme,carry the seeds of destruction.

During the metabolic response to acute illness, netbreakdown of muscle protein occurs, not to meetenergy requirements, 80-90% of which are providedby fat, but to supply precursors for the acceleratedgluconeogenesis necessary to meet the dependence ofinjured tissue on anaerobic glycolysis.6,7 Muscle

protein also acts as a reserve of aminoacids for normalprotein turnover and for the special aminoacid

requirements of other tissues. Whilst these processesmay be beneficial in the previously well-nourishedindividual who sustains a modest injury from traumaor surgery, they may cause fatal wasting in those whoare already depleted or have sustained major injurycombined with sepsis and starvation. Nitrogenbalance has been a traditional yardstick of themetabolic response to injury and to feeding, but it is acrude measure, and describes only the net result ofchanges in synthesis and catabolism without

distinguishing between them. Uncomplicatedabdominal surgery is associated with diminished

protein synthesis,8 whereas in major injury withsepsis, increased catabolism may predominate.9Nitrogen balance measurements also fail to accountfor important differences between tissues-eg, thebranched-chain aminoacids leucine, isoleucine, andvaline have a special role in muscle.1O Theiraccelerated breakdown after injury was at first thoughtto contribute to the energy requirements of thattissue," but the process may be even more importantfor the synthesis of glutamine. This aminoacid is notonly a precursor for renal ammonia production, butalso a crucial substrate for the rapidly dividing cells ofthe gut mucosal2 and immune system,13 in which itmay provide both energy and a source for nucleic acidsynthesis. After injury, glutamine, comprising 50% ofthe free aminoacid pool, is released from muscle cells,

5. Hunter J. A treatise on the blood, inflammation and gunshot wounds. G. Nicol, 17946. Kinney JM, Duke JH Jr, Long CL, Gump FE. Tissue fuel and weight loss after

injury. J Clin Pathol 1970; 23 (suppl 4): 65-72.7. Wilmore DW, Aulick LH, Mason AD, et al. Influence of the bum wound on local and

systemic responses to injury Ann Surg 1977; 186: 444-58.8. O’Keefe SJD, Sender PM, James WPT. "Catabolic" loss of body nitrogen in response

to surgery. Lancet 1974; ii: 1035-38.9. Yamamori H, Tashiro T, Mashima Y, Okui K. Effects of seventy of surgical trauma

on whole body protein turnover in patients receiving total parenteral nutrition.J Parent Ent Nutr 1987; 11: 454-57.

10. Smith R, Williamson DH Biochemical effects of human injury. Trends Biochem Sci1983; 198: 142-46.

11. Vinnars E, Bergstrom J, Furst P. Influence of the postoperative state on the

intracellular free aminoacids pool in human muscle tissue. Ann Surg 1975; 182:665-71.

12. Windmueller HG, Spaeth AE. Uptake and metabolism of plasma glutamine by thesmall intestine. J Biol Chem 1974; 249: 5070-79.

13 Newsholme EA, Crabtree B, Ardawi MSM. Glutamine metabolism in lymphocytes:its biochemical, physiological and clinical importance. Q J Exp Physiol 1985; 70:473-89.

996

in which its concentration falls by 50%." Theseobservations, and studies showing direct correlationbetween muscle glutamine and the rate of proteinsynthesis,14 suggest that the supply of this normallynon-essential aminoacid might become rate limitingin muscle and other tissues.

Advances in our understanding of metabolism havebeen paralleled by technical developments in methodsof delivering nutritional support by both enteral andintravenous routes. Uncritical enthusiasm for these

techniques has now given way to a more rationalapproach. Most well-conducted controlled trials,whilst showing a positive effect of feeding on nitrogenbalance, have failed to show much clinical benefitfrom the routine use of perioperative intravenousfeeding in patients undergoing gastrointestinalsurgery .15 However, there is increasing evidence thatselected patients may derive considerable benefit,particularly those with antecedent weight loss of 15%or more and those with prolonged postoperativegastrointestinal failure or anorexia.16 Supplementaryenteral nutrition may shorten the rehabilitation timeof very thin patients after operation for fractured neckor femur, 17 and nutritional treatment has also made animportant contribution to survival from bum injuryand other major trauma.18 These clinical observationssuggest that nutritional support during illness mayhelp to counteract, even if it does not abolish, theresponse to injury. Such support may providesubstrate when reserves are depleted from antecedentmalnutrition or when they are used up more rapidlyby the response to injury.

Nutritional therapy is not only being more

selectively applied, but also has become more selectivein its composition. Although enteral tube feeding is awell-established procedure, commercially availablematerials for intravenous use are a comparativelyrecent development. A casein hydrolysate mixture ofaminoacids and peptides (’Aminosol’) and a lipidemulsion (’Intralipid’) were introduced in the 1950sby Wretlind19 and both preparations provedsuccessful in clinical practice. Because of toxicreactions to early American fat emulsions, a

satisfactory source of fat for intravenous use was notallowed onto the United States market for another

twenty years. The only available energy source wasconcentrated glucose solution, which Dudrick et al20gave in combination with aminoacids via central

14. Jepson MM, Bates PC, Broadbent P Pell JM, Millward DJ Relationship betweenglutamine concentrations and protein synthesis in rat skeletal muscle. Am J Physiol1988; 255: E166-72.

15. Buzby GP, Williford WO, Peterson OL, et al A randomized clinical trial of totalparenteral nutrition in malnourished surgical patients’ the rationale and impact ofprevious clinical trials and pilot study on protocol design. Am J Clin Nutr 1988; 47(suppl): 357-65.

16 Sitges-Serra A, Rafecas A, Jaurrieta E. Malnutrition, resectability and postoperativeoutcome in gastnc cancer patients. Br J Clin Pract 1988; 42, 63 (suppl) 15-19

17 Bastow MD, Rawlings J, Allison SP Benefits of supplementary feeding after fracturedneck of femur a randomised controlled trial. Br Med J 1983; 287: 1589-92.

18 Wilmore DW. Metabolic management of the critically ill. New York. Plenum, 1978.19. Shenkin A, Wretlind A Parenteral nutrition. World review of nutrition and dietetics,

vol 28. Basel: Karger, 1978: 1-111.20 Dudnck SJ, Wilmore DW, Vars HM, Rhoads JE. Long term parenteral nutrition

with growth, development and positive nitrogen balance Surgery 1968, 64: 134-41.

venous catheters. This approach came to be known as"hyperalimentation" and was later used not only toremove the element of starvation but also to try toreverse the negative nitrogen balance of injury.Kinney’s group21 later showed that excessive amountsof glucose could be dangerous in catabolic patients,leading to excessive CO2 production and increasingoxygen demand, so exceeding the gas exchangecapacity of failing lungs. These workers also showedthat the increased gluconeogenesis and lipolysis afterinjury are insensitive to inhibition by infused glucose.

Attempts have also been made to block and divertthe flow phase of injury by use of hormones to sparethe patient’s own tissues, while providing necessarysubstrates by appropriate feeding. Insulin,22 growthhormone/3 and anabolic steroids24 have positiveeffects on nitrogen balance but have not yet foundtheir way into routine clinical practice for this

purpose. Aggressive attempts to bludgeon the patientinto positive nitrogen balance during the flow phase ofinjury, via excessive energy intake, have given way to amore defensive strategy. Fat and carbohydrate aregiven in equal proportions to supply little more thanthe patient’s measured or estimated energy needs.Simultaneously, the catabolic drive is reduced bybetter anaesthetic and surgical techniques, by moreefficient control of infection and fluid balance, and byremoval of other stimuli to thermogenesis, such as acool environment. This defensive approach aims tominimise the worst ravages of the flow phase of injury,and recognises that true restoration of lean body massmust await the onset of convalescence.

Protein metabolism is influenced by energy intakebut also depends on the amount and form of nitrogensupply. Greig et al,25 using a balanced aminoacidsolution, showed that increasing the nitrogen inputabove 191 mg/kg per day when the energy intake was1-35 times energy expenditure had no additional

positive effect on nitrogen balance. They pointed outthat this result is hardly surprising in catabolic

patients lying immobile in bed in whom significantpositive nitrogen balance is unlikely to be achieved.Enterally absorbed aminoacids first pass the gut andthen the liver, which act as a carburettor, taking whatthey require and allowing 90% of the branched-chainaminoacids into the systemic circulation for muscleprotein synthesis. It is difficult to mimic thisdifferential aminoacid distribution by intravenousfeeding and, moreover, there are technical limitationsto the formulation of suitable aminoacid solutions.The proportion of branched-chain aminoacids can

21 Askanazi J, Carpentier Y, Elwyn DH, et al. Influence of total parenteral nutrition onfuel ultilization in injury and sepsis Ann Surg 1980; 191: 40-46.

22 Woolfson AMJ, Heatley RV, Allison SP. Insulin to inhibit protein catabolism afterinjury. N Engl J Med 1979; 300: 14-17.

23. Wilmore DW, Moylan JA, Bristow BF, Mason AD, Pruitt BA Jr Anabolic effects ofhuman growth hormone and high caloric feedings following thermal injury. SurgGynecol Obstet 1974; 138: 875-84.

24 Tweedle D, Walton C, Johnston IDA The effect of an anabolic steroid on

postoperative nitrogen balance Br J Clin Pract 1973, 27: 130-32.25 Greig PD, Elwyn DH, Askanazi J, Kinney JM. Parenteral nutrition in septic patients

effect of increasing nitrogen intake Am J Clin Nutr 1987, 46: 1040-47.

997

easily be increased in such solutions to try to meet theextra demands of muscle. Unfortunately, if energyand total nitrogen supplies are adequate, additionalbranched-chain aminoacids have little effect on either

nitrogen balance or outcome.26 Physiologicalarguments for providing additional glutamine havebeen presented but this aminoacid is unstable insolution. Furst’s group27 in Stuttgart lately discussed anew approach to this problem. Relying on the fact thataminoacids are more stable in solution in the form of

dipeptides, they gave intravenous infusions to

postoperative patients of an aminoacid solution

containing alanylglutamine and found that nitrogenbalance was much better than in those receiving anidentical regimen apart from the substitution of

glycine for glutamine. They also showed that theintramuscular glutamine concentration was restoredto normal. It remains to be seen whether these

developments will lead to improved outcome in

seriously ill patients, but they certainly form anexciting new approach to the old problem of how bestto counteract the worst effects of protein catabolismafter injury.

It is ironic that, when the casein hydrolysates weresuperseded by synthetic aminoacid preparations ofconsistent composition, the peptides containingglutamine and the otherwise insoluble cysteine werethereby eliminated. We are now beginning to think ofputting them back again.

Ascariasis"Your worm is your only emperor for diet; we fat all creatures else to fat

us."-SHAKESPEARE; Hamlet.

Ascaris lumbricoides, the large roundworm,averaging 25 cm in length, is the most abundant andprolific of all helminths with more than a billionpeople infected, mostly in developing countries in thetropics and subtropics. The worm burden is so

enormous that if placed head to tail they would spanthe world fifty times. The Romans were well

acquainted with Ascaris but confused them withearthworms and called them Lumbricus teres. Theywere given specific status by Linnaeus in 1758, butwere clearly recognised as distinct parasites in ancientChina where they were known to cause intestinalobstruction and were even used as "catheters" to cure

impotence. Man must have acquired his Ascaris fromclose contact with wild or domestic pigs and notphylogenetically from his prehominid ancestors

because this helminth is not a natural parasite ofmonkeys or apes. Pigs are universally infected with

26 Hammarqvist F, Wernerman J, von den Decken A, Vinnars E. The effects of branchedchain amino acids upon postoperative muscle protein synthesis and nitrogenbalance. Clin Nutr 1988; 7: 171-75.

27. Stehle P, Zander J, Mertes N, et al. Effects of parenteral glutamine peptidesupplements on muscle glutamme loss and nitrogen balance after major surgery.Lancet 1989; i: 231-33.

Ascaris suum, a parasite which, apart from minordifferences in morphology and biochemistry, is almostidentical to A lumbricoides. Although man can beinfected with A suum and pigs with A lumbricoides,there is now very little evidence of cross transmission.A lumbricoides is a man-adapted parasite maintained innature by interhuman transmission.Each day the female worm produces 200 000 large,

thick-shelled eggs that can survive for months or even

years in the environment. The parasite is disseminatedunder insanitary conditions where there isindiscriminate defaecation and where human faecesare used as a fertiliser. There is no direct transmissionbecause the larvae inside the eggs require several daysin moist shady conditions at a temperature between22° and 30°C for their development. Infection is

acquired by mouth from contaminated food or water,so everyone in the endemic areas is infected at sometime in their lives. There is evidence of resistance to

superinfection in adults and heavy worm burdens areusually seen only in children. There is surprisinglylittle transmission through vegetables and fruit

imported from endemic areas into Europe, althoughin one incident an especially heavy infection occurredin an English "health addict" who consumed largequantities of "bran" imported from West Africa.The stimulus provided by the Rockefeller

Foundation’s programme on the great neglecteddiseases of mankind and the Parasitic DiseasesDivision of the World Health Organisation has led torenewed interest in Ascaris and other intestinal

parasites. The proceedings of two conferences onascariasis organised by WHO are now available;1,2 thefirst was based on a meeting in New York in 1985, andthe second on a similar meeting in Penang, Malaysia,in 1988. These two volumes provide the first extensiveand authoritative account of the biology, diagnosis,epidemiology, clinical features, treatment, and controlof ascariasis, including a summary of prevalence datafrom all over the world. Because the worms produce somany eggs each day reliable prevalence data can beobtained by simple faecal examination, but it is muchmore difficult to obtain data about morbidity andmortality. Hospital records indicate that between 8000and 100 000 children may die each year from intestinalobstruction and other abdominal complicationscaused by the adult worms; there is surprisingly littleinformation on the effects of the parasite on the other999 900 000 individuals in the world who are infected.There is no evidence to show that the worms cause

malabsorption or that they consume significantcalories or essential elements in the diet, but they canreduce the appetite in children and in this way theymay contribute to malnutrition.3 Heavy infections

1. Crompton DWT, Nesheim MC, Pawlowski ZS, eds. Ascariasis and its public healthsignificance London: Taylor and Francis, 1985.

2. Crompton DWT, Nesheim MC, Pawlowski ZS, eds. Ascariasis and its prevention andcontrol. London: Taylor and Francis, 1989.

3 Stephenson LS, Holland C Impact on helminth infections on human nutrition.London- Taylor and Francis, 1987