263
and Metabolism RENEWED interest in assessing the value of different electrolyte and nutrient regimens for use after surgery comes at a time when most surgeons believe they
Postoperative Feeding
have settled the problems of postoperative support. A simple system for rotating 5% dextrose with physiological saline is often used; solutions may also be combined as a single dextrose-saline mixture or even prepared to local specifications by a helpful pharmacy department anxious to minimise the bacterial contamination of fluid to which potassium is often added at the bedside. These standardised regimens work well, are readily understood by nursing staff, and, since they are needed only for a day or two before most patients resume eating, the failure to provide for a patient’s nutritional requirements is unimportant. This approach to postoperative management may not be appropriate for many patients undergoing gastrointestinal surgery, and neglects new evidence linking the metabolic response after surgery to the type of fluid given. A simple dextrose-saline regimen is often assumed to do no harm even if full nutritional support is needed after 5-7 days in those who, because of gastrointestinal problems, cannot resume eating. The assumption that the catabolic loss of nitrogen after surgery derives from increased breakdown of muscle proteins 1,2 and is an inevitable consequence of stress has helped to inhibit those enthusiasts who aim at a complete supply of nutrient as soon as the patient returns from The dangers accompanying intravenous feeding are also firmly fixed in surgeons’ minds from the early days when fat solutions proved to be toxic. BLACKBURN and his colleagues in Boston 3,4 have now stimulated the enthusiasts by showing that the catabolic loss of nitrogen is not inevitable and that nitrogen balance can be maintained in the immediate postoperative period by the provision of aminoacids
requirements theatre.
1.
Cuthbertson, D. P., Fell, G. S., Smith, C. M., Tilstone, W. J. Br. J. Surg. 1972, 59, 925. 2. Cuthbertson, D. P. in Parenteral Nutrition (edited by A. W. Wilkinson); p. 4. London, 1972. 3. Blackburn, G. L., Flatt, J. P., Clowes, G. H. A., O’Donnell, T. E. Am. J. Surg. 1973, 125, 447. 4. Blackburn, G. L. Congres International de Nutrition Parentérale, Montpellier, 1974, abstract, p. 80 (in the press).
without additional energy-a concept which incidentally destroys another established nutritional/ principle that nitrogen balance can only be maintained if the body is in a state of energy balance.5,6 BLACKBURN claims4 that a daily infusion of 100 g. of glucose leads to a greater loss of body nitrogen (8-8 g. daily) than an electrolyte solution alone (6-8 g.) and that infusing 30-60 g. aminoacids leads to a daily nitrogen loss of only 1-3 g. Previous studiesagain with short-term balance periods conducted immediately after surgery, showed that infusing a solution of 70 g. of aminoacids produced a positive nitrogen balance, but that combining the aminoacids with glucose led to net loss of body nitrogen. This work comes at a time when it is being realised once more that fat oxidation provides 70-80% of energy needs postoperativelyand that glucose has limited importance as a source of energy in postabsorptive man.8 If fasting man needs only 180 g. glucose daily and two-thirds of this is oxidised by the brain, then it would seem reasonable to provide 100 g. of glucose postoperatively to limit gluconeogenesis and urea formation. This view, however, neglects the fact that the brain can readily oxidise ketones if their circulating levels are sufficiently high 9,10; and that carbohydrate feeding may induce insulin resistance in hepatic and peripheral tissues. If ketones can be used by the brain in the postoperative state then this will substantially reduce the need for gluconeogenesis. BLACKBURN et al. noted that patients infused with aminoacids alone had a low plasma-insulin with high levels of free fatty acids, and concentrations of ketone bodies which were three to five times higher than those found in
patients receiving glucose alone. reasonable to assume that the postoperative ketonoemia is beneficial, with the brain joining other tissues in relying, albeit indirectly, on fat as a source of energy. The traditional view that even mild ketosis and ketonuria should be avoided then becomes difficult to defend. SMITH and his colleagues 11 have also produced evidence suggesting that ketosis is beneficial by showing that those patients with severe trauma who have ketosis lose less nitrogen than those who fail to generate ketones in sufficient quantity to substantially increase their blood ketone levels. O’KEEFE et al.12 have now argued that the " catabolic " response with nitrogen losses after surgery reflects predominantly a fall in protein synthesis and not a rise in breakdown rates; if synthesis were restored to normal, then nitrogen It thus
5. 6. 7. 8. 9. 10. 11. 12.
seems
Miller, D. S., Payne, P. R. J. theoret. Biol. 1963, 5, 1398. Payne, P. R., Waterlow, J. C. Lancet, 1971, ii, 210. Tweedle, D., Johnston, I. D. A. Br. J. Surg. 1971, 58, 771. Cahill, G. F. New Engl. J. Med. 1970, 282, 668. Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., Cahill, G. F. J. clin. Invest. 1967, 46, 1589. Hawkins, R. A., Williamson, D. H., Krebs, H. A. Biochem. J. 1971, 122, 13. Smith, R., Fuller, D. J., Wedge, J. H., Williamson, D. H., Alberti, K. G. G. M. Lancet, 1975, i, 1. O’Keefe, S. J. D., Sender, P. M., James, W. P. T. ibid. 1974, ii, 1035.
_
264
balance would be achieved. Although muscle synthesis can be maintained by ketone bodies 13 and aminoacid solutions postoperatively seems increase body-protein synthesis,14 the relationship in stress between ketone-body metabolism and protein turnover is unclear. Recent evidence suggests that ketones may limit the oxidation of the essential branched-chain aminoacids in muscle,15 and this could help to maintain protein synthesis or limit protein breakdown. 16 If ketones can to a large degree take the place of glucose oxidation by cerebral tissues, then continued gluconeogenesis will depend on the remaining need for glucose by glycolytic tissues such as the erythrocytes. The continued catabolism of aminoacids in liver and muscle by oxidative enzymes which have a minimum oxidative activity also requires the infusion of aminoacids if nitrogen balance is to be preserved. This view of metabolic regulation would logically lead to the Boston group’s practice of providing aminoacids to cover both the inevitable oxidative loss of aminoacids and the substrate for gluconeogenesis but in amounts sufficiently small to prevent the stimulation of insulin secretion with its tendency to limit both lipolysis and ketogenesis. Thus patients could remain in nitrogen balance while relying on their reserves of fat as a source of energy. Malnourished patients or those who require intravenous fluids for more than a week or two need the additional supply of energy and an early consideration of their requirements for minerals, vitamins, and trace elements. In their efforts to provide additional energy, workers in the United States have been at a severe disadvantage because they are limited to carbohydrate sources of energy rather than fat emulsions which have been used safely for years, particularly in Sweden.17 The fat emulsions, such as ’Intralipid’, eliminate the problems of hyperosmolar solutions of dextrose with the need for cannulating large vessels and its attendant risks-the risks of thrombosing veins and the suggestion that hypertonic dextrose predisposes to bacterial and fungal infections perhaps because of the high circulating levels of glucose. 18 The lower infection-rate in countries where therapy involves the use of fat emulsions has not been assessed formally with a controlled trial, but it seems to occur despite the difficulties in using bacterial filters in intravenous lines when infusing fat emulsions. More clear-cut are the demonstrations that hypo-
infusing
to
E., Hjalmarson, A. C., Morgan, H. E. Am. J. Physiol. 1974, 226, 528. 14. O’Keefe, S. J. D., Sender, P. M., James, W. P. T. Congrès International de Nutrition Parentérale, Montpellier, 1974; abstract, p. 76 (in the press). 15. Sherwin, R. S., Hendler, R. G., Felig, P. J. clin. Invest. 1975, 55, 13. Rannels, D.
phosphatxmia 19 and essential-fatty-acid deficiency 20 be avoided by using fat emulsions which are readily metabolised both in normal and postoperative subjects .21 It seems logical, therefore, to try intralipid and aminoacid solutions without a carbohydrate source to see whether patients are able to maintain both energy and nitrogen balance. It is, of course, known that some patients seem able to achieve nitrogen balance despite carbohydrate infusions provided the energy input is high,22 and, once the postoperative state is over, long-term maintenance of energy and protein homoeostasis with infusions containing carbohydrate can work well. The ketogenic regimen for postoperative care is also unsuitable for diabetics since the induction of ketosis by the high glucagon levels in the postoperative state 23,24 would be uncontrolled in the absence of appropriate circulating insulin levels. can
In view of the relative costs of solutions of aminoacids and dextrose, widespread substitution of aminoacids for dextrose in routine postoperative care is unlikely, but the recent availability of aminoacid solutions without a carbohydrate source should permit an assessment of the Boston group’s work and a reappraisal of the type of parenteral feeding used for both very ill patients and those in whom there is a possibility that oral feeding will be delayed after operation.
Drug Levels in Epilepsy TECHNICAL advances in the measurement of small of chemical substances in biological fluidsparticularly by gas chromatography, and more recently by radioimmunoassay and enzyme-immunoassay-have made regular monitoring of serum levels of a number of drugs a practical proposition. The antiepileptic drugs are among those which present the least difficulty in measurement, largely because full therapeutic doses produce relatively high concentrations. Does the clinical value of these estimations justify the expense and labour involved in performing them ? The chief reason why measuring drug levels is potentially of value is that serum levels produced by standard doses of some drugs vary widely from patient to patient.25,26 This variation is due to amounts
19. 20. 21. 22.
23. 24.
1382.
Ricour, C., Millot, M., Balsan, S. Acta Pœdiat. scand. 1975, 64, 385. Paulsrud, J. R., Pensler, L., Whitten, C. F., Stewart, S. L., Holman, R. T. Am. J. clin. Nutr. 1972, 987, 904. Hallberg, D., Schuberth, O., Wretlind, A. Nutr. Diet. 1966, 8, 245. Wang, C. W. V., Meng, H. C., Sandstead, H. H. Archs Surg. 1975, 110, 272. Russell, R. C. G., Walker, C. J., Bloom, S. R. Br. med. J. 1974, iv, 10. Gerich, J. E., Lorenzi, M., Bier, D. M., Schneider, V. S., Tsalikian, E., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1975, 292, 985.
R.
M., Li, J. B., Goldberg, A. L. J. biol. Chem. 1975, 250,
16.
Fulks,
17. 18.
Wretlind, A., Nutr. Metab. 1972, 14, suppl. 1. Brennan, M. F., Goldman, M. H., O’Connell, R. R., Kundsin, R. B., Moore, F. D. Ann. Surg. 1972, 176, 265.
290.
25.
Lascelles, P. T., Kocen, R. S., Reynolds, E. H. J. Neurol. Neurosurg. Psychiat. 1970, 33, 501. 26. Lund, L. in Biological Effects of Drugs in Relation to their Plasma Concentrations (edited by D. S. Davies and B. N. C. Prichard); p. 227. London, 1973.
and Metabolism RENEWED interest in assessing the value of different electrolyte and nutrient regimens for use after surgery comes at a time when most surgeons believe they
Postoperative Feeding
have settled the problems of postoperative support. A simple system for rotating 5% dextrose with physiological saline is often used; solutions may also be combined as a single dextrose-saline mixture or even prepared to local specifications by a helpful pharmacy department anxious to minimise the bacterial contamination of fluid to which potassium is often added at the bedside. These standardised regimens work well, are readily understood by nursing staff, and, since they are needed only for a day or two before most patients resume eating, the failure to provide for a patient’s nutritional requirements is unimportant. This approach to postoperative management may not be appropriate for many patients undergoing gastrointestinal surgery, and neglects new evidence linking the metabolic response after surgery to the type of fluid given. A simple dextrose-saline regimen is often assumed to do no harm even if full nutritional support is needed after 5-7 days in those who, because of gastrointestinal problems, cannot resume eating. The assumption that the catabolic loss of nitrogen after surgery derives from increased breakdown of muscle proteins 1,2 and is an inevitable consequence of stress has helped to inhibit those enthusiasts who aim at a complete supply of nutrient as soon as the patient returns from The dangers accompanying intravenous feeding are also firmly fixed in surgeons’ minds from the early days when fat solutions proved to be toxic. BLACKBURN and his colleagues in Boston 3,4 have now stimulated the enthusiasts by showing that the catabolic loss of nitrogen is not inevitable and that nitrogen balance can be maintained in the immediate postoperative period by the provision of aminoacids
requirements theatre.
1.
Cuthbertson, D. P., Fell, G. S., Smith, C. M., Tilstone, W. J. Br. J. Surg. 1972, 59, 925. 2. Cuthbertson, D. P. in Parenteral Nutrition (edited by A. W. Wilkinson); p. 4. London, 1972. 3. Blackburn, G. L., Flatt, J. P., Clowes, G. H. A., O’Donnell, T. E. Am. J. Surg. 1973, 125, 447. 4. Blackburn, G. L. Congres International de Nutrition Parentérale, Montpellier, 1974, abstract, p. 80 (in the press).
without additional energy-a concept which incidentally destroys another established nutritional/ principle that nitrogen balance can only be maintained if the body is in a state of energy balance.5,6 BLACKBURN claims4 that a daily infusion of 100 g. of glucose leads to a greater loss of body nitrogen (8-8 g. daily) than an electrolyte solution alone (6-8 g.) and that infusing 30-60 g. aminoacids leads to a daily nitrogen loss of only 1-3 g. Previous studiesagain with short-term balance periods conducted immediately after surgery, showed that infusing a solution of 70 g. of aminoacids produced a positive nitrogen balance, but that combining the aminoacids with glucose led to net loss of body nitrogen. This work comes at a time when it is being realised once more that fat oxidation provides 70-80% of energy needs postoperativelyand that glucose has limited importance as a source of energy in postabsorptive man.8 If fasting man needs only 180 g. glucose daily and two-thirds of this is oxidised by the brain, then it would seem reasonable to provide 100 g. of glucose postoperatively to limit gluconeogenesis and urea formation. This view, however, neglects the fact that the brain can readily oxidise ketones if their circulating levels are sufficiently high 9,10; and that carbohydrate feeding may induce insulin resistance in hepatic and peripheral tissues. If ketones can be used by the brain in the postoperative state then this will substantially reduce the need for gluconeogenesis. BLACKBURN et al. noted that patients infused with aminoacids alone had a low plasma-insulin with high levels of free fatty acids, and concentrations of ketone bodies which were three to five times higher than those found in
patients receiving glucose alone. reasonable to assume that the postoperative ketonoemia is beneficial, with the brain joining other tissues in relying, albeit indirectly, on fat as a source of energy. The traditional view that even mild ketosis and ketonuria should be avoided then becomes difficult to defend. SMITH and his colleagues 11 have also produced evidence suggesting that ketosis is beneficial by showing that those patients with severe trauma who have ketosis lose less nitrogen than those who fail to generate ketones in sufficient quantity to substantially increase their blood ketone levels. O’KEEFE et al.12 have now argued that the " catabolic " response with nitrogen losses after surgery reflects predominantly a fall in protein synthesis and not a rise in breakdown rates; if synthesis were restored to normal, then nitrogen It thus
5. 6. 7. 8. 9. 10. 11. 12.
seems
Miller, D. S., Payne, P. R. J. theoret. Biol. 1963, 5, 1398. Payne, P. R., Waterlow, J. C. Lancet, 1971, ii, 210. Tweedle, D., Johnston, I. D. A. Br. J. Surg. 1971, 58, 771. Cahill, G. F. New Engl. J. Med. 1970, 282, 668. Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., Cahill, G. F. J. clin. Invest. 1967, 46, 1589. Hawkins, R. A., Williamson, D. H., Krebs, H. A. Biochem. J. 1971, 122, 13. Smith, R., Fuller, D. J., Wedge, J. H., Williamson, D. H., Alberti, K. G. G. M. Lancet, 1975, i, 1. O’Keefe, S. J. D., Sender, P. M., James, W. P. T. ibid. 1974, ii, 1035.
_
264
balance would be achieved. Although muscle synthesis can be maintained by ketone bodies 13 and aminoacid solutions postoperatively seems increase body-protein synthesis,14 the relationship in stress between ketone-body metabolism and protein turnover is unclear. Recent evidence suggests that ketones may limit the oxidation of the essential branched-chain aminoacids in muscle,15 and this could help to maintain protein synthesis or limit protein breakdown. 16 If ketones can to a large degree take the place of glucose oxidation by cerebral tissues, then continued gluconeogenesis will depend on the remaining need for glucose by glycolytic tissues such as the erythrocytes. The continued catabolism of aminoacids in liver and muscle by oxidative enzymes which have a minimum oxidative activity also requires the infusion of aminoacids if nitrogen balance is to be preserved. This view of metabolic regulation would logically lead to the Boston group’s practice of providing aminoacids to cover both the inevitable oxidative loss of aminoacids and the substrate for gluconeogenesis but in amounts sufficiently small to prevent the stimulation of insulin secretion with its tendency to limit both lipolysis and ketogenesis. Thus patients could remain in nitrogen balance while relying on their reserves of fat as a source of energy. Malnourished patients or those who require intravenous fluids for more than a week or two need the additional supply of energy and an early consideration of their requirements for minerals, vitamins, and trace elements. In their efforts to provide additional energy, workers in the United States have been at a severe disadvantage because they are limited to carbohydrate sources of energy rather than fat emulsions which have been used safely for years, particularly in Sweden.17 The fat emulsions, such as ’Intralipid’, eliminate the problems of hyperosmolar solutions of dextrose with the need for cannulating large vessels and its attendant risks-the risks of thrombosing veins and the suggestion that hypertonic dextrose predisposes to bacterial and fungal infections perhaps because of the high circulating levels of glucose. 18 The lower infection-rate in countries where therapy involves the use of fat emulsions has not been assessed formally with a controlled trial, but it seems to occur despite the difficulties in using bacterial filters in intravenous lines when infusing fat emulsions. More clear-cut are the demonstrations that hypo-
infusing
to
E., Hjalmarson, A. C., Morgan, H. E. Am. J. Physiol. 1974, 226, 528. 14. O’Keefe, S. J. D., Sender, P. M., James, W. P. T. Congrès International de Nutrition Parentérale, Montpellier, 1974; abstract, p. 76 (in the press). 15. Sherwin, R. S., Hendler, R. G., Felig, P. J. clin. Invest. 1975, 55, 13. Rannels, D.
phosphatxmia 19 and essential-fatty-acid deficiency 20 be avoided by using fat emulsions which are readily metabolised both in normal and postoperative subjects .21 It seems logical, therefore, to try intralipid and aminoacid solutions without a carbohydrate source to see whether patients are able to maintain both energy and nitrogen balance. It is, of course, known that some patients seem able to achieve nitrogen balance despite carbohydrate infusions provided the energy input is high,22 and, once the postoperative state is over, long-term maintenance of energy and protein homoeostasis with infusions containing carbohydrate can work well. The ketogenic regimen for postoperative care is also unsuitable for diabetics since the induction of ketosis by the high glucagon levels in the postoperative state 23,24 would be uncontrolled in the absence of appropriate circulating insulin levels. can
In view of the relative costs of solutions of aminoacids and dextrose, widespread substitution of aminoacids for dextrose in routine postoperative care is unlikely, but the recent availability of aminoacid solutions without a carbohydrate source should permit an assessment of the Boston group’s work and a reappraisal of the type of parenteral feeding used for both very ill patients and those in whom there is a possibility that oral feeding will be delayed after operation.
Drug Levels in Epilepsy TECHNICAL advances in the measurement of small of chemical substances in biological fluidsparticularly by gas chromatography, and more recently by radioimmunoassay and enzyme-immunoassay-have made regular monitoring of serum levels of a number of drugs a practical proposition. The antiepileptic drugs are among those which present the least difficulty in measurement, largely because full therapeutic doses produce relatively high concentrations. Does the clinical value of these estimations justify the expense and labour involved in performing them ? The chief reason why measuring drug levels is potentially of value is that serum levels produced by standard doses of some drugs vary widely from patient to patient.25,26 This variation is due to amounts
19. 20. 21. 22.
23. 24.
1382.
Ricour, C., Millot, M., Balsan, S. Acta Pœdiat. scand. 1975, 64, 385. Paulsrud, J. R., Pensler, L., Whitten, C. F., Stewart, S. L., Holman, R. T. Am. J. clin. Nutr. 1972, 987, 904. Hallberg, D., Schuberth, O., Wretlind, A. Nutr. Diet. 1966, 8, 245. Wang, C. W. V., Meng, H. C., Sandstead, H. H. Archs Surg. 1975, 110, 272. Russell, R. C. G., Walker, C. J., Bloom, S. R. Br. med. J. 1974, iv, 10. Gerich, J. E., Lorenzi, M., Bier, D. M., Schneider, V. S., Tsalikian, E., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1975, 292, 985.
R.
M., Li, J. B., Goldberg, A. L. J. biol. Chem. 1975, 250,
16.
Fulks,
17. 18.
Wretlind, A., Nutr. Metab. 1972, 14, suppl. 1. Brennan, M. F., Goldman, M. H., O’Connell, R. R., Kundsin, R. B., Moore, F. D. Ann. Surg. 1972, 176, 265.
290.
25.
Lascelles, P. T., Kocen, R. S., Reynolds, E. H. J. Neurol. Neurosurg. Psychiat. 1970, 33, 501. 26. Lund, L. in Biological Effects of Drugs in Relation to their Plasma Concentrations (edited by D. S. Davies and B. N. C. Prichard); p. 227. London, 1973.
