- Email: [email protected]
Planning Intravenous Alimentation of Surgical Patients
Planning Intravenous Alimentation of Surgical Patients ALEXANDER DOOLAS, M.D. *
It has become apparent that preoperative and postoperative malnutrition is associated with an increased morbidity and mortality rate. Patients who have lost large amounts of weight due to disease or inability to eat have low protein reserves in spite of a seemingly normal serum protein concentration. The protein concentration will be misleadingly high in those patients who are dehydrated and who have a constricted blood volume. It is generally accepted that edema follows protein concentrations below 5.5 gm. per 100 ml. or an albumin concentration below 3 gm. per 100 ml. 12 Open wounds in dogs being fed adequate amounts of proteins and carbohydrates have no quiescent period in their healing, whereas those dogs being fed only fat have a quiescent period of 6 days. 6 Some other deleterious effects of hypoproteinemia include: (1) an increased mortality after gastrectomy for obstructing duodenal ulcers associated with weight 10ss,34 (2) a decreased resistance to infections,5 (3) a decreased tolerance to acute blood 10ss,32 (4) a decreased stomach-to-cecuni emptying time,28. 31 and (5) an increased rate of dehiscence. 35 Although the advantages of adequate nutrition have been recognized, surgeons make only token attempts at improving the nutrition of their patients. The reasons for this are: (1) the past teachings that protein hydrolysates administered parenterally are promptly excreted in the urine with no gain in lean tissue mass, (2) the invariable development of chemical phlebitis in peripheral veins when hypertonic solutions of dextrose and protein hydrolysates are administered, and (3) the high rate of infection in peripherally placed catheters. In 1968 Dudrick et al,15. 16 reported that by supplying large quantities of protein hydrolysates and dextrose through a catheter inserted into the subclavian vein and threaded to the superior vena cava, they could consistently and safely achieve a positive nitrogen balance and gain in weight over extended periods of time. By employing this method in 300 *Instructor in Surgery, University of Illinois College of Medicine; Assistant Attending Surgeon, Presbyterian-St. Luke's Hospital, Chicago, Illinois
Surgical Clinics of North America- Vol. 50, No.1, February, 1970
103
104
ALEXANDER DOOLAS
patients they have induced weight gain with healing of fistulas and wounds in those in whom they were present.!8 The intravenous administration of sufficient quantities of the necessary nutrients to maintain a positive metabolic state has been called parenteral hyperalimentationY In view of this exciting development in the preoperative and postoperative care of patients, a review of some basic concepts of nutrition and intravenous alimentation is indicated.
THE CATABOLIC STATE Cuthbertson9 in 1930 demonstrated that bony and soft tissue injury is followed by a general breakdown of body proteins in great excess of the amount of tissue injured, as demonstrated by urinary nitrogen losses. He interpreted the catabolic process as being a favorable, physiologic response supplying the calories and protein which are immediately needed in amounts greater than are available with diets. The severity of the nitrogen loss depends on the extent and duration of injury, starvation, and immobilization, on the presence of sepsis, and on the nutritional status and muscle development of the patient. Malnourished persons who are injured lose little nitrogen since their labile protein stores are depleted.! It is thought that this is an unfavorable response, since adequate quantities of nutrients are not made available to the injured areas. The role of starvation in the catabolic response is not entirely clear. Generally, the nitrogen loss in minor injuries such as herniorrhaphy, hemorrhoidectomy, and appendectomy is equal to that of starvation, and it was shown that by maintaining an adequate diet the negative nitrogen balance can be prevented. 29 Holden et al.2 3 have similarly shown that patients undergoing the above operations lose 12 to 13 gm. of nitrogen daily, an amount equal to that lost by healthy, starving young males. In three patients subjected to somewhat more severe trauma (cholecystectomy), Brunschwig et al.,2 in 1942, achieved a 5 day nitrogen balance of -8.5 gm., +20.39 gm., and +4.97 gm., by supplementing parenterally the regular postoperative dietary management with 18 gm. of nitrogen and 75 to 300 gm. of dextrose daily during the first 5 postoperative days. The conclusion was that starvation played a very important role in the catabolic state. A different picture is seen in patients subjected to major trauma. Cuthbertson lO in 1936 could not alter, with adequate diets, the extent of nitrogen loss during the first 8 days after severe fractures, but this regimen did induce attainment of an earlier metabolic balance. Howard et al.,24 in 1944, described a great loss of body nitrogen in patients whose daily diets contained 6.5 gm. of nitrogen and 900 calories per 1. 73 square meters of body surface. This loss was not reduced by daily diets containing 15 gm. of nitrogen and 2400 calories per 1. 73 square meters of body surface daily. They concluded that a certain amount of protein breakdown is necessary after major injury, but they did not exclude the possibility that with much greater quantities of nutrients a positive
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
105
nitrogen balance could not be attained. It was their feeling, however, that the nutrients would have to be supplied parenterally, since in the early postoperative period patients are not able to tolerate large quantities of gastrointestinal feedings. In 1947 Riegel et al. 33 attained a positive nitrogen balance during the first 5 days after gastric and cranial surgery by giving gastrojejunal feedings containing 0.3 gm. of nitrogen per kg. and 30 calories per kg. daily. These findings were reaffirmed by Koop et al.,25 who achieved a positive nitrogen balance after major operations by administering parenterally 0.40 to 0.47 gm. of nitrogen per kg. and 12 to 30 calories per kg. daily in the first 5 days. Holden et al. 23 demonstrated that a positive nitrogen balance can be more easily achieved in females than in males. While a positive nitrogen balance has been achieved by others, the complications of their methods and inconsistency of their results has discouraged the widespread clinical use of intense parenteral alimentation. It was not until 1967 that Dudrick et al. 14 demonstrated that longterm parenteral nutrition was practical by achieving normal growth and development in starving beagle puppies over a 255 day period. In 196815 they reported on six surgical patients in whom long-term parenteral therapy resulted in a significant positive nitrogen balance. Dudrick's studies indicate that although the greatly increased breakdown of body proteins cannot be stopped after injury, the availability of large quantities of nutrients results in an anabolic response with nitrogen retention and gain in lean tissue mass, as had been envisioned by Howard et al. 24 much earlier.
BODY CONSTITUENTS The body weight of a 70 kg. man, in general, consists of 40 kg. of water, 10 kg. of protein, 10 kg. of fat, and 10 kg. of bone. The carbohydrate content is less than 0.5 kg., and most of it is utilized within 24 hours. The energy requirements after trauma and starvation are supplied by the protein and fat. Two kg. of protein and 8.5 kg. of fat are labile and are readily broken down for utilization. Further protein loss requires the breakdown of lean tissues. The ratio of nitrogen to protein is 1 :6, and the ratio of nitrogen to lean tissue is 1 :30. Thus, 10 kg. of protein contain 1.66 gm. of nitrogen and represent 50 kg. of lean tissue such as muscle and viscera. After severe injury and sepsis, as much as 500 gm. oflean tissue and 500 gm. of fat can be broken down daily. After most major surgery the usual weight loss is approximately 1 to 2 pounds daily for 8 to 10 days.
NUTRITIONAL REQUIREMENTS A great step in parenteral nutrition was taken when Elman20 in 1937 demonstrated in hypoproteinemic dogs that parenterally infused amino acids and dextrose were rapidly utilized. In 1939 he and Weinerl
106
ALEXANDER DOOLAS
achieved in eight patients an increase in serum proteins, a loss of nutritional edema, and a decrease in the negative nitrogen balance by supplying intravenously 1600 calories and 0.5 gm. of nitrogen per kg. daily for 2 or more days. In 1943 Brunschwig3 demonstrated that protein hydrolysates were utilized similarly when given through the intravenous or the gastrointestinal route in major abdominal procedures, by supplying 15 gm. of nitrogen and 780 to 1200 calories daily. Werner in 194736 discovered that the relatively low amounts of 10 to 14 gm. of nitrogen given intravenously as amino acids were not sufficient to maintain a metabolic equilibrium, whereas the same amount of nitrogen given as food did result in a metabolic balance in preoperative patients. This may be due, in part, to the presence of d-amino acids and polypeptides in the protein hydrolysates, which are not readily utilized and result in an 11 per cent urinary protein 10ss.19 The minimum oral daily requirement of hydrolyzed proteins in normal individuals is approximately 0.7 gm. per kg. of protein. 30 Protein hydrolysates administered alone without calories are broken down for energy. Calloway and Spector' showed that in protein-free diets calories spare nitrogen loss. However, quantities in excess of 750 calories daily in normal individuals do not result in further sparing of nitrogen. The optimum ratio of nitrogen to calories when both are administered parenterally is 1115029 to 11200. 26 Suggested quantities of nutrients in postoperative patients have been 0.3 gm. of nitrogen per kg. and 30 calories per kg. daily.33 More recently Dudrick et al.t 8 have used as much as 0.45 gm. of nitrogen per kg. and 60 calories per kg. daily with excellent results. McNair et al. 27 in 1954 stressed that the caloric supply and protein hydrolysates must be infused simultaneously, since when given metachronously there is a two to three fold increase in urinary nitrogen loss. It is also important that the infusion of these nutrients be evenly distributed over the 24 hours to avoid urinary loss. The utilization of glucose when given without protein hydrolysates is 0.5 gm. per kg. per hour.7 Rates faster than this result in glycosuria, dehydration, and hyperosmolality. Dudrick et a1. 18 recently have achieved a dextrose utilization of 1.2 gm. per kg. per hour when it was given with adequate quantities of protein hydrolysates. Exogenous insulin is usually not required, since endogenous insulin production is stimulated by dextrose and most amino acids. In the early postoperative period, however, insulin may be needed, since postoperative patients develop a transient diabetic tolerance curve. 22 Diabetics, of course, will require exogenous insulin. Potassium plays a very important role in parenteral nutrition. The intracellular ratio of K+ to nitrogen is 3:1. In the catabolic state much more K+ than nitrogen is lost, attaining at times a ratio of 15 mEq. of K+ to 1 gm. of nitrogen. Unless this additional K+ loss is replenished, the expected metabolic balance may not be attained. Other electrolytes such as Na+, Cl-, and Mg++ are supplied as necessary. Trace elements are required after a month of total parenteral nutrition and can be supplied by the administration of 1 unit of fresh frozen plasma weekly. Vitamin A, B, C, D, and E must be supplied daily.
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
107
INDICATIONS FOR PARENTERAL HYPERALIMENTATION Parenteral hyperalimentation may be employed in: 1. Surgical complications which render the gastrointestinal tract functionless, such as fistula, obstruction, and peritonitis. 2. Preoperative preparation of patients who are malnourished and unable to eat. 3. Gastrointestinal diseases which benefit by rest, such as ulcerative colitis and regional enteritis. 4. Preoperative preparation for major surgical procedures associated with a high morbidity. 5. Malabsorption. 6. Diseases which benefit by adequate nutrition, but in which, because of the peculiarities of the diet and a restricted volume of intake, such as in liver and renal failure, the nutrients are more easily administered parenterally. 7. Conditions associated with anorexia and inability to eat, such as carcinomatosis, cancer chemotherapy, anorexia nervosa, and cerebrovascular accident.
SAFETY OF PERCUTANEOUS SUBCLAVIAN CATHETERIZATION In the use of 500 subclavian catheters Dudrick13 has found no evidence of embolization. Corwin8 reported two instances of pneumothorax but no embolization in 98 subclavian catheterizations. In a series of 94 patients, Davidson l l had one pneumothorax and three hematomas and was unable to insert the catheter in six patients. Although peripheral catheterization is often associated with phlebitis and septicemia, Wilmore and Dudrick37 reported negative cultures of 15 subclavian catheters indwelling for an average of 19.7 days. Phlebitis or infection did not occur and did not necessitate removal of the subclavian catheters in his series. The catheters were removed electively with cessation of parenteral therapy. The reasons for the success of the subclavian vein approach are: (1) the subclavian vein is large and the catheter which courses through it does not cause irritation of the vein wall; (2) the rapid flow through the subclavian vein prevents clotting and bacterial growth; (3) the catheter courses through a relatively long tract of subcutaneous tissue and muscle, thus affording a greater inhibition of bacterial growth; (4) the necessary aseptic technique mininrizes initial contanrination; and (5) the placement of the catheter tip in the superior vena cava results in rapid dilution of the hypertonic solutions, thus preventing chenrical phlebitis.
TECHNIQUE OF PERCUTANEOUS SUBCLAVIAN CATHETERIZATION The patient is placed in the Trendelenburg position to promote maximum filling of the subclavian veins and to avoid air embolization
108
ALEXANDER DOOLAS
Figure 1. The subclavian vein lies between the clavicle and the first rib. The needle is inserted into the skin just below the midpoint of the clavicle. It is advanced under the clavicle, toward the suprasternal notch, and parallel to the frontal plane of the chest.
as the catheter is inserted. A folded towel placed between the scapulas allows extension of the shoulders so that the needle can assume a course parallel to the chest wall. The entire upper chest and shoulder area on the side to be catheterized is shaved and scrubbed with soap and water, defatted with ether, and painted with tincture of iodine or Zephiran or Betadine, and then is draped with sterile towels. After donning sterile gloves and mask, the surgeon makes a wheal with 1 per cent Xylocaine just lateral to the midpoint of the clavicle and 1 cm. below it. A 2 inch No. 14 needle is fitted onto a 3 ml. syringe. The needle is inserted through the wheal, advanced under the clavicle and parallel to the frontal plane of the chest wall toward the suprasternal notch (Fig. 1). A slight negative pressure is applied by slightly withdrawing the plunger. In muscular or fat patients the entire needle may have to be inserted below the skin before the vein is entered. Entrance into the vein is made obvious by a rush of venous blood into the syringe, after which the needle is advanced slightly further to assure complete insertion of the bevel. The syringe is removed and an 8 inch radiopaque No. 16 polyethylene catheter is inserted to its entire length. The needle is withdrawn so that 1 or 2 cm. of the catheter appear above the skin and the bevel is bent with a hemostat. The catheter is affixed to the skin with silk, and the intravenous tubing is inserted in the catheter. Gentamicin ointment is applied to the puncture site, and the needle and its connection with the intravenous tubing are covered with an occlusive dressing.
CARE OF THE CATHETER Blood, plasma, "riders," and other intravenous solutions should be avoided, since they lead to contamination. The occlusive dressing and
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
109
intravenous tubing are changed every 3 days. At this time the skin is defatted, painted with tincture of iodine or Zephiran or Betadine, gentamicin ointment is reapplied, and the area is redressed. In patients developing a fever of unknown origin, removal and culture of the catheter should be considered.
PREPARATIONS OF SOLUTIONS In Dudrick's manufacturing pharmacy the solutions are prepared in bulk with strict bacteriologic and pyrogenic control. Such elaborate facilities, however, are not commonly available or strictly necessary. There are two simple and relatively safe methods of mixing solutions: METHOD 1. Our pharmacy at Presbyterian-St. Luke's Hospital prepares the solution according to this method. Into a 2000 ml. Travenol vacuum plasma collection unit, which serves as the receiving container, 1000 ml. of 5 per cent dextrose/5 per cent amino acid and 500 ml. of 50 per cent dextrose in water are emptied through intravenous tubing inserted into the appropriate apertures of the containers. The resulting 1500 ml. solution contains 6 gm. of nitrogen and 1200 nonprotein calories, a nitrogen to calorie ratio of 1 :200. The quantity of amino acid solution may be increased, if needed, to 1500 ml. in each unit, thus supplying 8.5 gm. of nitrogen and 1300 calories with a nitrogen to calorie ratio of 1:150. Electrolytes and vitamins are simply added to the container. One thousand units of heparin may be added to each bottle to inhibit clotting of blood which may back up into the catheter. METHOD 2. An alternative method of preparation is as follows. Two hundred and fifty milliliters of amino acid solution are discarded from each of three 1000 ml. bottles of 5 per cent dextrose/5 per cent amino acid. To each bottle is added 350 ml. of 50 per cent dextrose in water. (This is possible because the 1000 ml. containers have a capacity of 1200 ml.) These three bottles supply 3300 ml. of fluid, 13.5 gm. of nitrogen, and 2560 calories, with a nitrogen to calorie ratio of 1: 190. The pouring of fluids must be conducted carefully in a clean room and preferably under a laminar flow hood to prevent airborne contamination. All other electrolytes, vitamins, etc., are added to each bottle. Dudrick13 has shown occasional positive cultures in solutions prepared by both techniques, but this seems to be of no clinical significance. In both methods room air enters the containers, thus forming an interface of room air and fluid as in all other intravenous fluid bottles.
MANAGEMENT OF NUTRITIONAL AND ELECTROLYTE BALANCE Patients who do not have severe liver or renal disease, and who have adequate tissue perfusion, may be started on approximately 3000 ml. of solution, supplying approximately 12 gm. of nitrogen, and 2400 calories. The usual requirements of K+ for the above quantities is 100 to 120
110
ALEXANDER DOOLAS
mEq. Sodium chloride may be added from a 5 per cent NaCl solution. Usually 100 to 200 ml. of this solution, supplying 75 to 150 mEq. of NaCl daily, is sufficient. Albumin may be infused initially to help raise the colloid osmotic pressure and reduce edema. Other minerals such as calcium, phosphorus, and iron may be added as needed. Magnesium is required daily in amounts of 5 to 10 mEq. Trace elements are not necessary for 3 or 4 weeks of total parenteral therapy. These can be supplied by administering 1 unit of fresh frozen plasma weekly. The following daily vitamin requirements must be supplied: Vitamin A Vitamin D Vitamin E Vitamin C Thiamine Riboflavin Pyridoxine Niacin Pantothenic acid
5000 U SP Units 500 USP Units 2.5 International Units 1000 mg. 50 mg. 10 mg. 5 mg. 100 mg. 25 mg.
Vitamin B 12 , folic acid, and vitamin K may be supplied periodically. As a rule insulin is not required. If the blood sugar remains above 200 mg. per 100 ml. or if there is a 2 per cent urinary loss, then insulin may be given. The recommended dose is 10 to 20 units of regular insulin subcutaneously every 6 hours for each 1000 calories. A longer lasting insulin may be used when the patient's requirements have stabilized. Electrolyte and blood sugar determinations are done daily, and adjustments are made. The patient is weighed daily and examined for edema and cardiorespiratory impairment. An initial weight loss is usually due to diuresis and is an encouraging finding. If facilities for urinary nitrogen quantitation are available, periodic checks should be made to evaluate the adequacy of the nutrients. The administration of fluids may be accelerated or more amino acid solution may be added to the vacuum collecting unit to achieve a proper balance. Some patients may require 0.45 gm. of nitrogen per kg. and 60 calories per kg. daily. Patients who have liver or renal failure cannot tolerate great quantities of proteins. It is recommended that parenteral nutrition be limited initially to 25 to 50 gm. of amino acids and 1500 calories, and increased slowly as the patient's condition allows. Patients with poor peripheral perfusion may develop severe acidosis and are poor candidates for parenteral hyperalimentation. Reactions to the amino acid solutions are infrequent. These are tachycardia, urticaria, pyrexia, and nausea. Decreasing the infusion rate or emplOying a different type of amino acid preparation may result in relief.
RESULTS Sixty subclavian catheters were inserted. There were three instances of pneumothorax which occurred in the first 15 cases at the time the
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
111
author was unfamiliar with the technique. Twenty-nine patients were started on hyperalimentation, and twenty-three were maintained on it for more than 9 days. The average duration of parenteral hyperalimentation before elective removal of the catheter was 29 days. The longest duration was 126 days. Eleven catheters which remained in the vein for an average of 20 days were cultured. Four of these had positive cultures, but all of these patients had severe pre-existing infection and in three there was a preexisting bacteremia The other patient from whom yeast was cultured had carcinomatosis and wound infection, and was on cancer chemotherapy. The sterile catheters were in the vein on the average of 38 days with the longest in place 126 days. Nineteen of 23 patients gained significant weight and four lost from 1 to 6 pounds. Healing of fistulas and wounds occurred when these were present, with an accompanying sense of well being and loss of edema. The fluid orders and the management of their administration was conducted by the house staff, but the solutions were mixed by the pharmacy. As a preliminary study, we felt satisfied that the approach is feasible and safe for routine clinicaL use by house staff. ACKNOWLEDGMENT
I am indebted to Mr. Louis Gdalman, Director of the Pharmacies at Presbyterian-St. Luke's Hospital, and his staff for devising the methodology and preparing the nutrient solutions.
REFERENCES 1. Abbott, W. E., and Albertsen, K.: The effect of starvation, infection and injury on the metabolic process and body composition. Ann. N.Y. Acad. Sci., 110:941, 1963. 2. Brunschwig, A., Clark, D. E., and Corbin, N.: Postoperative nitrogen loss and studies on parenteral nitrogen nutrition by means of casein digest. Ann. Surg., 115:1091, 1942. 3. Brunschwig, A., and Corbin, N.: Clinical study of relative efficiency for nitrogen metabolism of casein digest administered intravenously and protein ingested by mouth. Surgery, 14:898, 1943. 4. Calloway, D. H., and Spector, H.: Nitrogen balance as related to caloric and protein intake in active young men. Amer. J. Clin. Nutrition, 2:405, 1954. 5. Cannon, P. R.: The importance of proteins in resistance to infection. J.A.M.A., 128:360, 1945. 6. Clark, A. H.: Effect of diet on the healing of wounds. Bull. Johns Hopkins Hosp., 30:117, 1919. 7. Cooper, D. R., lob, V., and Coller, F. A.: Response to parenteral glucose of normal kidney and kidney of postoperative patients. Ann. Surg., 129: 1, 1949. 8. Corwin, J. H., and Moseley, T.: Subclavian vein puncture and central vp.nous pressure technique and application. Amer. Surgeon, 32:413, 1966. 9. Cuthbertson, D. P.: The disturbance of metabolism produced by bony and non-bony injury with notes on certain abnormal conditions of bone. Biochem. J., 24:1244, 1930. 10. Cuthbertson, D. P.: Further observations on the disturbance of metabolism caused by injury with particular reference to the dietary requirements of fracture cases. Brit. J. Surg., 23:505, 1936. 11. Davidson, J. T., Ben Hur, N., and Nathen, H.: Subclavian puncture. Lancet, 2:1139,1963. 12. Davis, H. H.: The routine use of protein digest intravenously following major surgical procedures. Surg. Gynec. Obstet., 81 :31, 1945. 13. Dudrick, S. J., personal communications. 14. Dudrick, S. J., Rhoads, J. E., and Vars, H. M.: Growth of puppies receiving all nutritional requirements by vein. Fortschr. parenteralen Ernahrung, 2: 16, 1967.
112
ALEXANDER DOOLAS
15. Dudrick, S. J., Wilmore, D. W., Vars, N. M., and Rhoads, J. E.: Long term parenteral nutrition with growth development and positive nitrogen balance. Surgery, 64:134, 1968. 16. Dudrick, S. J., Vars, H. M., and Rhoads, J. E.: Long term intravenous hyperalimentation. Fed. Proc., 27:486,1968. 17. Dudrick, S. J., and Wilmore, D. W.: Long term parenteral feeding. Hospital Practice, Oct. 1968, p. 65. 18. Dudrick, S. J., Wilmore, D. W., Vars, H. M., and Rhoads, J. E.: Can intravenous feedings as the sole means of nutrition support growth in the child and restore weight loss in the adult? Ann. Surg., 169:974, 1969. 19. Elman, R.: Amino acid mixtures as parenteral protein food. Amer. J. Med., 5:760, 1948. 20. Elman, R.: Intravenous i'liection of amino acids in regeneration of serum proteins following severe experimental hemorrhage. Proc. Soc. Exper. BioI., 36:867, 1937. 21. Elman, R., and Weiner, D.O.: Intravenous alimentation. J.A.M.A., 112:796, 1939. 22. Hayes, M. A, and Brandt, R. L.: Carbohydrate metabolism in the immediate postoperative period. Surgery, 32:819, 1952. 23. Holden, W. D., Krieger, H., Levey, S., and Abbott, W. E.: The effect of nutrition on nitrogen metabolism in the surgical patient. Ann. Surg., 146:563, 1957. 24. Howard, J. E., Winternit, J., Parson, W., Bigham, R. S., and Eisenberg, H.: Studies on fracture convalescence-The influence of-diet on post traumatic nitrogen deficit exhibited by fracture patients. Bull. Johns Hopkins Hosp., 75:209, 1944. 25. Koop, C. E., Riegel, C., Grigger, R. P., and Barnes, M. T.: A study of protein hydrolysates, ossein gelatin and glucose in parenteral nutrition. Surg. Gynec. Obstet., 84:1065,1947. 26. Lawson, J. L.: Parenteral nutrition in surgery. Brit. J. Surg., 52:795, 1965. 27. McNair, R. D., O'Donnell, D., and Quigley, W.: Protein nutrition in surgical patients. Time factor in protein sparing action of dextrose in parenteral feeding. Arch. Surg., 68: 76, 1954. 28. McCray, P. M., Borden, R. P., and Ravdin, 1. S.: Nutritional edema: Its effect on the gastric emptying time before and after gastric operations. Surgery, 1 :53, 1937. 29. Moore, F. D.: Metabolic Care of the Surgical Patient. Philadelphia, W. B. Saunders Co., 1959, p. 460. 30. Mueller, A. J., Fickas, D., and Cox, W. M., Jr.: Minimum maintenance requirements of an enzymatic casein hydrolysate. Bull. Johns Hopkins Hosp., 72: 110, 1943. 31. Ravdin, 1. S.: Factors involved in the retardation of gastric emptying after gastric operations. Pennsylvania M. T., 41 :695, 1937-1938. 32. Ravdin, 1. S., McNamee, H. G., Kamholz, J. H., and Rhoads, J. E.: Effect of hypoproteinemia on susceptibility to shock resulting from hemorrhage. Arch. Surg., 48:491, 1944. 33. Riegel, C., Koop, E..C., Drew, J., Stevens, L. W., and Rhoads, J. E.: The nutritional requirements for nitrogen balance in surgical patients during the early postoperative period. J. Clin. Invest., 26:18,1947. 34. Studley, H. 0.: Percentage of weight loss a basic indicator of surgical risk in patients with chronic peptic ulcer. J.AM.A., 106:458,1936. 35. Thompson, W. D., Ravdin, 1. S., and Frank, 1. L.: Effect of hypoproteinemia on wound disruption. Arch. Surg., 36:500, 1938. 36. Werner, S. C.: The use of a mixture of pure amino acids in surgical nutrition. Ann. Surg., 126:169,1947. 37. Wilmore, D. W., and Dudrick, S. J.: Cannula Sepsis. JAM.A., 277:433, 1967. 1725 W. Harrison Street Chicago, Illinois 60612
It has become apparent that preoperative and postoperative malnutrition is associated with an increased morbidity and mortality rate. Patients who have lost large amounts of weight due to disease or inability to eat have low protein reserves in spite of a seemingly normal serum protein concentration. The protein concentration will be misleadingly high in those patients who are dehydrated and who have a constricted blood volume. It is generally accepted that edema follows protein concentrations below 5.5 gm. per 100 ml. or an albumin concentration below 3 gm. per 100 ml. 12 Open wounds in dogs being fed adequate amounts of proteins and carbohydrates have no quiescent period in their healing, whereas those dogs being fed only fat have a quiescent period of 6 days. 6 Some other deleterious effects of hypoproteinemia include: (1) an increased mortality after gastrectomy for obstructing duodenal ulcers associated with weight 10ss,34 (2) a decreased resistance to infections,5 (3) a decreased tolerance to acute blood 10ss,32 (4) a decreased stomach-to-cecuni emptying time,28. 31 and (5) an increased rate of dehiscence. 35 Although the advantages of adequate nutrition have been recognized, surgeons make only token attempts at improving the nutrition of their patients. The reasons for this are: (1) the past teachings that protein hydrolysates administered parenterally are promptly excreted in the urine with no gain in lean tissue mass, (2) the invariable development of chemical phlebitis in peripheral veins when hypertonic solutions of dextrose and protein hydrolysates are administered, and (3) the high rate of infection in peripherally placed catheters. In 1968 Dudrick et al,15. 16 reported that by supplying large quantities of protein hydrolysates and dextrose through a catheter inserted into the subclavian vein and threaded to the superior vena cava, they could consistently and safely achieve a positive nitrogen balance and gain in weight over extended periods of time. By employing this method in 300 *Instructor in Surgery, University of Illinois College of Medicine; Assistant Attending Surgeon, Presbyterian-St. Luke's Hospital, Chicago, Illinois
Surgical Clinics of North America- Vol. 50, No.1, February, 1970
103
104
ALEXANDER DOOLAS
patients they have induced weight gain with healing of fistulas and wounds in those in whom they were present.!8 The intravenous administration of sufficient quantities of the necessary nutrients to maintain a positive metabolic state has been called parenteral hyperalimentationY In view of this exciting development in the preoperative and postoperative care of patients, a review of some basic concepts of nutrition and intravenous alimentation is indicated.
THE CATABOLIC STATE Cuthbertson9 in 1930 demonstrated that bony and soft tissue injury is followed by a general breakdown of body proteins in great excess of the amount of tissue injured, as demonstrated by urinary nitrogen losses. He interpreted the catabolic process as being a favorable, physiologic response supplying the calories and protein which are immediately needed in amounts greater than are available with diets. The severity of the nitrogen loss depends on the extent and duration of injury, starvation, and immobilization, on the presence of sepsis, and on the nutritional status and muscle development of the patient. Malnourished persons who are injured lose little nitrogen since their labile protein stores are depleted.! It is thought that this is an unfavorable response, since adequate quantities of nutrients are not made available to the injured areas. The role of starvation in the catabolic response is not entirely clear. Generally, the nitrogen loss in minor injuries such as herniorrhaphy, hemorrhoidectomy, and appendectomy is equal to that of starvation, and it was shown that by maintaining an adequate diet the negative nitrogen balance can be prevented. 29 Holden et al.2 3 have similarly shown that patients undergoing the above operations lose 12 to 13 gm. of nitrogen daily, an amount equal to that lost by healthy, starving young males. In three patients subjected to somewhat more severe trauma (cholecystectomy), Brunschwig et al.,2 in 1942, achieved a 5 day nitrogen balance of -8.5 gm., +20.39 gm., and +4.97 gm., by supplementing parenterally the regular postoperative dietary management with 18 gm. of nitrogen and 75 to 300 gm. of dextrose daily during the first 5 postoperative days. The conclusion was that starvation played a very important role in the catabolic state. A different picture is seen in patients subjected to major trauma. Cuthbertson lO in 1936 could not alter, with adequate diets, the extent of nitrogen loss during the first 8 days after severe fractures, but this regimen did induce attainment of an earlier metabolic balance. Howard et al.,24 in 1944, described a great loss of body nitrogen in patients whose daily diets contained 6.5 gm. of nitrogen and 900 calories per 1. 73 square meters of body surface. This loss was not reduced by daily diets containing 15 gm. of nitrogen and 2400 calories per 1. 73 square meters of body surface daily. They concluded that a certain amount of protein breakdown is necessary after major injury, but they did not exclude the possibility that with much greater quantities of nutrients a positive
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
105
nitrogen balance could not be attained. It was their feeling, however, that the nutrients would have to be supplied parenterally, since in the early postoperative period patients are not able to tolerate large quantities of gastrointestinal feedings. In 1947 Riegel et al. 33 attained a positive nitrogen balance during the first 5 days after gastric and cranial surgery by giving gastrojejunal feedings containing 0.3 gm. of nitrogen per kg. and 30 calories per kg. daily. These findings were reaffirmed by Koop et al.,25 who achieved a positive nitrogen balance after major operations by administering parenterally 0.40 to 0.47 gm. of nitrogen per kg. and 12 to 30 calories per kg. daily in the first 5 days. Holden et al. 23 demonstrated that a positive nitrogen balance can be more easily achieved in females than in males. While a positive nitrogen balance has been achieved by others, the complications of their methods and inconsistency of their results has discouraged the widespread clinical use of intense parenteral alimentation. It was not until 1967 that Dudrick et al. 14 demonstrated that longterm parenteral nutrition was practical by achieving normal growth and development in starving beagle puppies over a 255 day period. In 196815 they reported on six surgical patients in whom long-term parenteral therapy resulted in a significant positive nitrogen balance. Dudrick's studies indicate that although the greatly increased breakdown of body proteins cannot be stopped after injury, the availability of large quantities of nutrients results in an anabolic response with nitrogen retention and gain in lean tissue mass, as had been envisioned by Howard et al. 24 much earlier.
BODY CONSTITUENTS The body weight of a 70 kg. man, in general, consists of 40 kg. of water, 10 kg. of protein, 10 kg. of fat, and 10 kg. of bone. The carbohydrate content is less than 0.5 kg., and most of it is utilized within 24 hours. The energy requirements after trauma and starvation are supplied by the protein and fat. Two kg. of protein and 8.5 kg. of fat are labile and are readily broken down for utilization. Further protein loss requires the breakdown of lean tissues. The ratio of nitrogen to protein is 1 :6, and the ratio of nitrogen to lean tissue is 1 :30. Thus, 10 kg. of protein contain 1.66 gm. of nitrogen and represent 50 kg. of lean tissue such as muscle and viscera. After severe injury and sepsis, as much as 500 gm. oflean tissue and 500 gm. of fat can be broken down daily. After most major surgery the usual weight loss is approximately 1 to 2 pounds daily for 8 to 10 days.
NUTRITIONAL REQUIREMENTS A great step in parenteral nutrition was taken when Elman20 in 1937 demonstrated in hypoproteinemic dogs that parenterally infused amino acids and dextrose were rapidly utilized. In 1939 he and Weinerl
106
ALEXANDER DOOLAS
achieved in eight patients an increase in serum proteins, a loss of nutritional edema, and a decrease in the negative nitrogen balance by supplying intravenously 1600 calories and 0.5 gm. of nitrogen per kg. daily for 2 or more days. In 1943 Brunschwig3 demonstrated that protein hydrolysates were utilized similarly when given through the intravenous or the gastrointestinal route in major abdominal procedures, by supplying 15 gm. of nitrogen and 780 to 1200 calories daily. Werner in 194736 discovered that the relatively low amounts of 10 to 14 gm. of nitrogen given intravenously as amino acids were not sufficient to maintain a metabolic equilibrium, whereas the same amount of nitrogen given as food did result in a metabolic balance in preoperative patients. This may be due, in part, to the presence of d-amino acids and polypeptides in the protein hydrolysates, which are not readily utilized and result in an 11 per cent urinary protein 10ss.19 The minimum oral daily requirement of hydrolyzed proteins in normal individuals is approximately 0.7 gm. per kg. of protein. 30 Protein hydrolysates administered alone without calories are broken down for energy. Calloway and Spector' showed that in protein-free diets calories spare nitrogen loss. However, quantities in excess of 750 calories daily in normal individuals do not result in further sparing of nitrogen. The optimum ratio of nitrogen to calories when both are administered parenterally is 1115029 to 11200. 26 Suggested quantities of nutrients in postoperative patients have been 0.3 gm. of nitrogen per kg. and 30 calories per kg. daily.33 More recently Dudrick et al.t 8 have used as much as 0.45 gm. of nitrogen per kg. and 60 calories per kg. daily with excellent results. McNair et al. 27 in 1954 stressed that the caloric supply and protein hydrolysates must be infused simultaneously, since when given metachronously there is a two to three fold increase in urinary nitrogen loss. It is also important that the infusion of these nutrients be evenly distributed over the 24 hours to avoid urinary loss. The utilization of glucose when given without protein hydrolysates is 0.5 gm. per kg. per hour.7 Rates faster than this result in glycosuria, dehydration, and hyperosmolality. Dudrick et a1. 18 recently have achieved a dextrose utilization of 1.2 gm. per kg. per hour when it was given with adequate quantities of protein hydrolysates. Exogenous insulin is usually not required, since endogenous insulin production is stimulated by dextrose and most amino acids. In the early postoperative period, however, insulin may be needed, since postoperative patients develop a transient diabetic tolerance curve. 22 Diabetics, of course, will require exogenous insulin. Potassium plays a very important role in parenteral nutrition. The intracellular ratio of K+ to nitrogen is 3:1. In the catabolic state much more K+ than nitrogen is lost, attaining at times a ratio of 15 mEq. of K+ to 1 gm. of nitrogen. Unless this additional K+ loss is replenished, the expected metabolic balance may not be attained. Other electrolytes such as Na+, Cl-, and Mg++ are supplied as necessary. Trace elements are required after a month of total parenteral nutrition and can be supplied by the administration of 1 unit of fresh frozen plasma weekly. Vitamin A, B, C, D, and E must be supplied daily.
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
107
INDICATIONS FOR PARENTERAL HYPERALIMENTATION Parenteral hyperalimentation may be employed in: 1. Surgical complications which render the gastrointestinal tract functionless, such as fistula, obstruction, and peritonitis. 2. Preoperative preparation of patients who are malnourished and unable to eat. 3. Gastrointestinal diseases which benefit by rest, such as ulcerative colitis and regional enteritis. 4. Preoperative preparation for major surgical procedures associated with a high morbidity. 5. Malabsorption. 6. Diseases which benefit by adequate nutrition, but in which, because of the peculiarities of the diet and a restricted volume of intake, such as in liver and renal failure, the nutrients are more easily administered parenterally. 7. Conditions associated with anorexia and inability to eat, such as carcinomatosis, cancer chemotherapy, anorexia nervosa, and cerebrovascular accident.
SAFETY OF PERCUTANEOUS SUBCLAVIAN CATHETERIZATION In the use of 500 subclavian catheters Dudrick13 has found no evidence of embolization. Corwin8 reported two instances of pneumothorax but no embolization in 98 subclavian catheterizations. In a series of 94 patients, Davidson l l had one pneumothorax and three hematomas and was unable to insert the catheter in six patients. Although peripheral catheterization is often associated with phlebitis and septicemia, Wilmore and Dudrick37 reported negative cultures of 15 subclavian catheters indwelling for an average of 19.7 days. Phlebitis or infection did not occur and did not necessitate removal of the subclavian catheters in his series. The catheters were removed electively with cessation of parenteral therapy. The reasons for the success of the subclavian vein approach are: (1) the subclavian vein is large and the catheter which courses through it does not cause irritation of the vein wall; (2) the rapid flow through the subclavian vein prevents clotting and bacterial growth; (3) the catheter courses through a relatively long tract of subcutaneous tissue and muscle, thus affording a greater inhibition of bacterial growth; (4) the necessary aseptic technique mininrizes initial contanrination; and (5) the placement of the catheter tip in the superior vena cava results in rapid dilution of the hypertonic solutions, thus preventing chenrical phlebitis.
TECHNIQUE OF PERCUTANEOUS SUBCLAVIAN CATHETERIZATION The patient is placed in the Trendelenburg position to promote maximum filling of the subclavian veins and to avoid air embolization
108
ALEXANDER DOOLAS
Figure 1. The subclavian vein lies between the clavicle and the first rib. The needle is inserted into the skin just below the midpoint of the clavicle. It is advanced under the clavicle, toward the suprasternal notch, and parallel to the frontal plane of the chest.
as the catheter is inserted. A folded towel placed between the scapulas allows extension of the shoulders so that the needle can assume a course parallel to the chest wall. The entire upper chest and shoulder area on the side to be catheterized is shaved and scrubbed with soap and water, defatted with ether, and painted with tincture of iodine or Zephiran or Betadine, and then is draped with sterile towels. After donning sterile gloves and mask, the surgeon makes a wheal with 1 per cent Xylocaine just lateral to the midpoint of the clavicle and 1 cm. below it. A 2 inch No. 14 needle is fitted onto a 3 ml. syringe. The needle is inserted through the wheal, advanced under the clavicle and parallel to the frontal plane of the chest wall toward the suprasternal notch (Fig. 1). A slight negative pressure is applied by slightly withdrawing the plunger. In muscular or fat patients the entire needle may have to be inserted below the skin before the vein is entered. Entrance into the vein is made obvious by a rush of venous blood into the syringe, after which the needle is advanced slightly further to assure complete insertion of the bevel. The syringe is removed and an 8 inch radiopaque No. 16 polyethylene catheter is inserted to its entire length. The needle is withdrawn so that 1 or 2 cm. of the catheter appear above the skin and the bevel is bent with a hemostat. The catheter is affixed to the skin with silk, and the intravenous tubing is inserted in the catheter. Gentamicin ointment is applied to the puncture site, and the needle and its connection with the intravenous tubing are covered with an occlusive dressing.
CARE OF THE CATHETER Blood, plasma, "riders," and other intravenous solutions should be avoided, since they lead to contamination. The occlusive dressing and
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
109
intravenous tubing are changed every 3 days. At this time the skin is defatted, painted with tincture of iodine or Zephiran or Betadine, gentamicin ointment is reapplied, and the area is redressed. In patients developing a fever of unknown origin, removal and culture of the catheter should be considered.
PREPARATIONS OF SOLUTIONS In Dudrick's manufacturing pharmacy the solutions are prepared in bulk with strict bacteriologic and pyrogenic control. Such elaborate facilities, however, are not commonly available or strictly necessary. There are two simple and relatively safe methods of mixing solutions: METHOD 1. Our pharmacy at Presbyterian-St. Luke's Hospital prepares the solution according to this method. Into a 2000 ml. Travenol vacuum plasma collection unit, which serves as the receiving container, 1000 ml. of 5 per cent dextrose/5 per cent amino acid and 500 ml. of 50 per cent dextrose in water are emptied through intravenous tubing inserted into the appropriate apertures of the containers. The resulting 1500 ml. solution contains 6 gm. of nitrogen and 1200 nonprotein calories, a nitrogen to calorie ratio of 1 :200. The quantity of amino acid solution may be increased, if needed, to 1500 ml. in each unit, thus supplying 8.5 gm. of nitrogen and 1300 calories with a nitrogen to calorie ratio of 1:150. Electrolytes and vitamins are simply added to the container. One thousand units of heparin may be added to each bottle to inhibit clotting of blood which may back up into the catheter. METHOD 2. An alternative method of preparation is as follows. Two hundred and fifty milliliters of amino acid solution are discarded from each of three 1000 ml. bottles of 5 per cent dextrose/5 per cent amino acid. To each bottle is added 350 ml. of 50 per cent dextrose in water. (This is possible because the 1000 ml. containers have a capacity of 1200 ml.) These three bottles supply 3300 ml. of fluid, 13.5 gm. of nitrogen, and 2560 calories, with a nitrogen to calorie ratio of 1: 190. The pouring of fluids must be conducted carefully in a clean room and preferably under a laminar flow hood to prevent airborne contamination. All other electrolytes, vitamins, etc., are added to each bottle. Dudrick13 has shown occasional positive cultures in solutions prepared by both techniques, but this seems to be of no clinical significance. In both methods room air enters the containers, thus forming an interface of room air and fluid as in all other intravenous fluid bottles.
MANAGEMENT OF NUTRITIONAL AND ELECTROLYTE BALANCE Patients who do not have severe liver or renal disease, and who have adequate tissue perfusion, may be started on approximately 3000 ml. of solution, supplying approximately 12 gm. of nitrogen, and 2400 calories. The usual requirements of K+ for the above quantities is 100 to 120
110
ALEXANDER DOOLAS
mEq. Sodium chloride may be added from a 5 per cent NaCl solution. Usually 100 to 200 ml. of this solution, supplying 75 to 150 mEq. of NaCl daily, is sufficient. Albumin may be infused initially to help raise the colloid osmotic pressure and reduce edema. Other minerals such as calcium, phosphorus, and iron may be added as needed. Magnesium is required daily in amounts of 5 to 10 mEq. Trace elements are not necessary for 3 or 4 weeks of total parenteral therapy. These can be supplied by administering 1 unit of fresh frozen plasma weekly. The following daily vitamin requirements must be supplied: Vitamin A Vitamin D Vitamin E Vitamin C Thiamine Riboflavin Pyridoxine Niacin Pantothenic acid
5000 U SP Units 500 USP Units 2.5 International Units 1000 mg. 50 mg. 10 mg. 5 mg. 100 mg. 25 mg.
Vitamin B 12 , folic acid, and vitamin K may be supplied periodically. As a rule insulin is not required. If the blood sugar remains above 200 mg. per 100 ml. or if there is a 2 per cent urinary loss, then insulin may be given. The recommended dose is 10 to 20 units of regular insulin subcutaneously every 6 hours for each 1000 calories. A longer lasting insulin may be used when the patient's requirements have stabilized. Electrolyte and blood sugar determinations are done daily, and adjustments are made. The patient is weighed daily and examined for edema and cardiorespiratory impairment. An initial weight loss is usually due to diuresis and is an encouraging finding. If facilities for urinary nitrogen quantitation are available, periodic checks should be made to evaluate the adequacy of the nutrients. The administration of fluids may be accelerated or more amino acid solution may be added to the vacuum collecting unit to achieve a proper balance. Some patients may require 0.45 gm. of nitrogen per kg. and 60 calories per kg. daily. Patients who have liver or renal failure cannot tolerate great quantities of proteins. It is recommended that parenteral nutrition be limited initially to 25 to 50 gm. of amino acids and 1500 calories, and increased slowly as the patient's condition allows. Patients with poor peripheral perfusion may develop severe acidosis and are poor candidates for parenteral hyperalimentation. Reactions to the amino acid solutions are infrequent. These are tachycardia, urticaria, pyrexia, and nausea. Decreasing the infusion rate or emplOying a different type of amino acid preparation may result in relief.
RESULTS Sixty subclavian catheters were inserted. There were three instances of pneumothorax which occurred in the first 15 cases at the time the
PLANNING INTRAVENOUS ALIMENTATION OF SURGICAL PATIENTS
111
author was unfamiliar with the technique. Twenty-nine patients were started on hyperalimentation, and twenty-three were maintained on it for more than 9 days. The average duration of parenteral hyperalimentation before elective removal of the catheter was 29 days. The longest duration was 126 days. Eleven catheters which remained in the vein for an average of 20 days were cultured. Four of these had positive cultures, but all of these patients had severe pre-existing infection and in three there was a preexisting bacteremia The other patient from whom yeast was cultured had carcinomatosis and wound infection, and was on cancer chemotherapy. The sterile catheters were in the vein on the average of 38 days with the longest in place 126 days. Nineteen of 23 patients gained significant weight and four lost from 1 to 6 pounds. Healing of fistulas and wounds occurred when these were present, with an accompanying sense of well being and loss of edema. The fluid orders and the management of their administration was conducted by the house staff, but the solutions were mixed by the pharmacy. As a preliminary study, we felt satisfied that the approach is feasible and safe for routine clinicaL use by house staff. ACKNOWLEDGMENT
I am indebted to Mr. Louis Gdalman, Director of the Pharmacies at Presbyterian-St. Luke's Hospital, and his staff for devising the methodology and preparing the nutrient solutions.
REFERENCES 1. Abbott, W. E., and Albertsen, K.: The effect of starvation, infection and injury on the metabolic process and body composition. Ann. N.Y. Acad. Sci., 110:941, 1963. 2. Brunschwig, A., Clark, D. E., and Corbin, N.: Postoperative nitrogen loss and studies on parenteral nitrogen nutrition by means of casein digest. Ann. Surg., 115:1091, 1942. 3. Brunschwig, A., and Corbin, N.: Clinical study of relative efficiency for nitrogen metabolism of casein digest administered intravenously and protein ingested by mouth. Surgery, 14:898, 1943. 4. Calloway, D. H., and Spector, H.: Nitrogen balance as related to caloric and protein intake in active young men. Amer. J. Clin. Nutrition, 2:405, 1954. 5. Cannon, P. R.: The importance of proteins in resistance to infection. J.A.M.A., 128:360, 1945. 6. Clark, A. H.: Effect of diet on the healing of wounds. Bull. Johns Hopkins Hosp., 30:117, 1919. 7. Cooper, D. R., lob, V., and Coller, F. A.: Response to parenteral glucose of normal kidney and kidney of postoperative patients. Ann. Surg., 129: 1, 1949. 8. Corwin, J. H., and Moseley, T.: Subclavian vein puncture and central vp.nous pressure technique and application. Amer. Surgeon, 32:413, 1966. 9. Cuthbertson, D. P.: The disturbance of metabolism produced by bony and non-bony injury with notes on certain abnormal conditions of bone. Biochem. J., 24:1244, 1930. 10. Cuthbertson, D. P.: Further observations on the disturbance of metabolism caused by injury with particular reference to the dietary requirements of fracture cases. Brit. J. Surg., 23:505, 1936. 11. Davidson, J. T., Ben Hur, N., and Nathen, H.: Subclavian puncture. Lancet, 2:1139,1963. 12. Davis, H. H.: The routine use of protein digest intravenously following major surgical procedures. Surg. Gynec. Obstet., 81 :31, 1945. 13. Dudrick, S. J., personal communications. 14. Dudrick, S. J., Rhoads, J. E., and Vars, H. M.: Growth of puppies receiving all nutritional requirements by vein. Fortschr. parenteralen Ernahrung, 2: 16, 1967.
112
ALEXANDER DOOLAS
15. Dudrick, S. J., Wilmore, D. W., Vars, N. M., and Rhoads, J. E.: Long term parenteral nutrition with growth development and positive nitrogen balance. Surgery, 64:134, 1968. 16. Dudrick, S. J., Vars, H. M., and Rhoads, J. E.: Long term intravenous hyperalimentation. Fed. Proc., 27:486,1968. 17. Dudrick, S. J., and Wilmore, D. W.: Long term parenteral feeding. Hospital Practice, Oct. 1968, p. 65. 18. Dudrick, S. J., Wilmore, D. W., Vars, H. M., and Rhoads, J. E.: Can intravenous feedings as the sole means of nutrition support growth in the child and restore weight loss in the adult? Ann. Surg., 169:974, 1969. 19. Elman, R.: Amino acid mixtures as parenteral protein food. Amer. J. Med., 5:760, 1948. 20. Elman, R.: Intravenous i'liection of amino acids in regeneration of serum proteins following severe experimental hemorrhage. Proc. Soc. Exper. BioI., 36:867, 1937. 21. Elman, R., and Weiner, D.O.: Intravenous alimentation. J.A.M.A., 112:796, 1939. 22. Hayes, M. A, and Brandt, R. L.: Carbohydrate metabolism in the immediate postoperative period. Surgery, 32:819, 1952. 23. Holden, W. D., Krieger, H., Levey, S., and Abbott, W. E.: The effect of nutrition on nitrogen metabolism in the surgical patient. Ann. Surg., 146:563, 1957. 24. Howard, J. E., Winternit, J., Parson, W., Bigham, R. S., and Eisenberg, H.: Studies on fracture convalescence-The influence of-diet on post traumatic nitrogen deficit exhibited by fracture patients. Bull. Johns Hopkins Hosp., 75:209, 1944. 25. Koop, C. E., Riegel, C., Grigger, R. P., and Barnes, M. T.: A study of protein hydrolysates, ossein gelatin and glucose in parenteral nutrition. Surg. Gynec. Obstet., 84:1065,1947. 26. Lawson, J. L.: Parenteral nutrition in surgery. Brit. J. Surg., 52:795, 1965. 27. McNair, R. D., O'Donnell, D., and Quigley, W.: Protein nutrition in surgical patients. Time factor in protein sparing action of dextrose in parenteral feeding. Arch. Surg., 68: 76, 1954. 28. McCray, P. M., Borden, R. P., and Ravdin, 1. S.: Nutritional edema: Its effect on the gastric emptying time before and after gastric operations. Surgery, 1 :53, 1937. 29. Moore, F. D.: Metabolic Care of the Surgical Patient. Philadelphia, W. B. Saunders Co., 1959, p. 460. 30. Mueller, A. J., Fickas, D., and Cox, W. M., Jr.: Minimum maintenance requirements of an enzymatic casein hydrolysate. Bull. Johns Hopkins Hosp., 72: 110, 1943. 31. Ravdin, 1. S.: Factors involved in the retardation of gastric emptying after gastric operations. Pennsylvania M. T., 41 :695, 1937-1938. 32. Ravdin, 1. S., McNamee, H. G., Kamholz, J. H., and Rhoads, J. E.: Effect of hypoproteinemia on susceptibility to shock resulting from hemorrhage. Arch. Surg., 48:491, 1944. 33. Riegel, C., Koop, E..C., Drew, J., Stevens, L. W., and Rhoads, J. E.: The nutritional requirements for nitrogen balance in surgical patients during the early postoperative period. J. Clin. Invest., 26:18,1947. 34. Studley, H. 0.: Percentage of weight loss a basic indicator of surgical risk in patients with chronic peptic ulcer. J.AM.A., 106:458,1936. 35. Thompson, W. D., Ravdin, 1. S., and Frank, 1. L.: Effect of hypoproteinemia on wound disruption. Arch. Surg., 36:500, 1938. 36. Werner, S. C.: The use of a mixture of pure amino acids in surgical nutrition. Ann. Surg., 126:169,1947. 37. Wilmore, D. W., and Dudrick, S. J.: Cannula Sepsis. JAM.A., 277:433, 1967. 1725 W. Harrison Street Chicago, Illinois 60612