GYNECOLOGIC
ONCOLOGY
Essential
4,66-69 (1976)
Fatty Acid Deficiency Hyperalimentation
with Long-Term
D. R. MELDRUM, G. A. DHOPESHWARKAR, S. LIN, AND M. L. SMITH Department
of Obstetrics and Gynecology, Department of Biochemistry, for the Health Sciences, Los Angeles, California 90024
UCLA Center
Received October 3, 1975 Content of essential fatty acids was determined in the plasma lipid fractions of patients with malignancies of the female reproductive tract. A marked deficiency was identified in two such patients while on prolonged total parenteral nutrition with hypertonic glucose and casein hydrolysate, compared to a control group of ambulatory and postoperative patients. The progressive deficiency observed in one patient was completely reversed by infusions of fat emulsion over a 3-week period. These results indicate a need for inclusion of essential fatty acids with prolonged total parenteral nutrition.
The need for a safe and effective method of total parenteral nutrition (TPN) has expanded recently in gynecology with an increasingly aggressive approach to the treatment of malignancies of the female reproductive tract. Bowel fistulas, obstruction, and radiation enteritis account for serious morbidity and mortality resulting from attempts at curative treatment of large or recurrent lesions. The increasing use of radical or even restricted surgery in combination with previous irradiation is particularly hazardous. Operative management of the bowel obstruction associated with radiation enteritis or recurrent tumor may require bypass of large segments of absorptive surface area leading to difficult postoperative problems with nutrition. The recent use of hypertonic solutions of glucose and amino acids by central venous infusion has been an important contribution to providing the calories and nutrients necessary during these periods of extensive tissue repair [1,2]. These methods, however, are associated with serious complications related to infection and the high osmotic load required. Furthermore, a major nutrient, lipid, is not provided. Since the mammalian organism is able to synthesize fats from glucose and may have considerable stores, a deficiency of lipids for energy and tissue formation is an unlikely problem. Certain long-chain polyunsaturated fats (essential fatty acids), however, must be obtained in the diet and may not be stored in adequate supply to cover long periods without oral intake. As important components of membrane phospholipids, a need for these essential fatty acids has been suggested in tissue repair. Fat emulsions are currently in use in other countries and recently their use has been approved in the United States. A 500 cc unit of Intralipid (Cutter Laboratories) provides 550 cal(50 g of fat; glycerin, 100Cal) with a high content of essential fatty acids. It can be infused through a peripheral vein and therefore may be combined with amino acids and a less hypertonic glucose solution providing the 66 Copyright @ 1976 by Academic press, Inc. All rights of repmduction in any form reserved.
FAT
DEFICIENCY
AND
HYPERALIMENTATION
67
necessary calories without some of the major complications of hyperalimentation. For a review of the metabolic alterations which may be associated with the use of intravenous fat emulsions, refer to a recent Symposium on Parenteral Nutrition [31. In addition to these evident advantages, there may be instances where significant EFA deficiency is induced by long-term parenteral nutrition. Oncology patients are particularly predisposed to such a deficiency since rapid synthesis of tumor tissue [4] and radiation therapy [5] have been shown to accelerate the development of deficiency states in laboratory animals. The following study was done to attempt to identify EFA deficiency in oncology patients undergoing long-term hyperalimentation and to determine whether such a deficiency could be corrected easily by the addition of Intralipid. MATERIALS AND METHODS Fifteen patients with malignancies of the female reproductive tract were selected as a control group from both outpatient and inpatient populations. Two patients requiring long-term infusion of hypertonic glucose and amino acids were studied. One of these patients, described in the accompanying case report, was studied each month for 3 months, and since the study results were then available, was treated with Intralipid. The second patient had only a single sample after 6 weeks of hyperalimentation. Blood samples were taken and immediately placed on ice in a heparinized tube, centrifuged at 4°C and the plasma was stored at -20°C until the lipid analyses could be carried out. Extraction was carried out with chloroform:methanol (2:l). Cholesterol esters were separated from the total lipids by thin-layer chromatography on silica gel G plates developed in 10% ether and 1% acetic acid in pentane. Methylation of cholesterol esters was accomplished by refluxing for 5-6 hr in 10% benzene in methanol containing 1% sulfuric acid. The resulting fatty acid methyl esters (together with free cholesterol) were extracted with ethyl ether; finally, the methyl esters were separated from cholesterol by chromatography on a mini Sio, column. Ethyl ether (5%) in pentane eluted the fatty acid methyl esters which were then analyzed by gas-liquid chromatography using a Beckman model Gc-M instrument fitted with a Win. x 6-ft column (packed with 10% DEGS on chromosorb W) maintained at 185°C. GLC peaks were triangulated to obtain areas and identified by retention times of corresponding known standard samples. RESULTS The mean and 2 SD of the percentage content of linoleic acid in cholesterol esters is shown in Fig. 1. The corresponding values for the two study patients are clearly below the range of normal with a progressive exhaustion of polyunsaturated fat in patient L.L. In this patient an abnormal fatty acid specific for essential fatty acid deficiency (20:309) could be identified. Treatment with 9 units of Intralipid over a 3-week period restored the abnormal blood lipid profile to normal. Arachidonic acid followed identical changes to those of linoleic acid. During Intralipid therapy, body weight was maintained in spite of discontinuation of hypertonic glucose due to systemic moniliasis and the use of only a peripheral venous line.
MELDRUM
ET AL.
60
I
0
I 4
I 8
I 12
I
/NT-,
I
I
I
Sunits
WEEKS ON HYPERALIMENTATION FIG. 1. The normal range of linoleic acid content within circulating cholesterol esters in a control population of gynecologic oncology patients is depicted. Values obtained in two patients on hyperalimentation are presented for comparison.
CASE REPORT
Patient L.L., 49 yr old, GO, presented January, 1974 with irregular bleeding, Class IV cervical cytology. Biopsy revealed epidermoid carcinoma. Metastatic work-up was negative. Clinically staged IIB. Underwent staging laparotomy confirming preoperative staging, at which time BSO was done and periaortic and pelvic nodes were sampled. External cobalt and two radium applications were administered with a total dose of 7500rad to pt. A and 6000rad to pt. B. May, 1974 she was admitted with a small bowel obstruction which was radiologically identified to be at the distal jejunum. After failure of response to long tube drainage, lysis of adhesions and gastrostomy was carried out June 1974, at which time massive irradiation damageto the bowel was noted. Hyperalimentation with 20% dextrose and 5% casein hydrolysate was begun post-op. Because of inability to reestablish GI function and radiologic demonstration of recurrent obstruction, reoperation was carried out with excision of all but 4 ft of the small bowel. Plasma sampleswere obtained after approximately 1, 2, and 3 months on hyperalimentation. When the lipid analyses were completed and a marked EFA deficiency was identified a further sample was taken, followed by infusion of 9 units of Intralipid over a period of 3 weeks. The final sample was taken 3 days after completion of therapy.
FAT
DEFICIENCY
AND
HYPERALIiiENTATION
69
DISCUSSION Essential fatty acid deficiency has been identified in certain predisposed groups of patients when prolonged intravenous therapy is required. Newborn infants have very limited stores of polyunsaturated fat and there are documented cases of deficiency after relatively short periods of intravenous therapy [6]. Other predisposing factors are periods of rapid growth, presence of tumor, or radiation therapy, the common factor being an increased requirement for tissue membrane synthesis during growth or repair. The postoperative period is also one of increased requirement, yet intake may be restricted for long periods. In one case of documented deficiency [7], wound healing did not occur until the deficiency was corrected by intravenous fat emulsion. Postoperative oncology patients thus have multiple factors predisposing to EFA deficiency. Although stores may be sufftcient during short periods of increased need and inadequate intake, the results of this study suggest that a fat emulsion with high EFA content should be part of any prolonged period of total parenteral nutrition. The additional calories supplied may enable the use of a combination of sugar, amino acids, and fat by peripheral infusion. SUMMARY: A progressive essential fatty deficiency was demonstrated in gynecological oncology patients requiring long-term hyperalimentation, in contrast to the lipid pattern of a control group. A relatively short period of therapy with intravenous fat emulsion was sufficient to normalize the lipid pattern of a patient with severe deficiency. It is recommended that fat emulsion be considered as part of any regimen of prolonged total parenteral nutrition. The additional calories supplied may facilitate development of a peripheral regimen of hyperalimentation. REFERENCES 1. Dudrick, S. J., Wilmore, D. W., and Vars, H. M. Long-term parenteral nutrition with growth in puppies and positive nitrogen balance in patients, Surg. Forum 18, 356357 (1967). 2. Dudrick, S. J., Wilmore, D. W., Vars, H. M., and Rhoads, J. E. Long-term total parenteral nutrition with growth, development and positive nitrogen balance, Surgery 64, 134-142 (1%8). 3. Meng, H. C., and Law, D. H. Proceedings of an International Symposium on Parenteral Nutrition, Charles C. Thomas, Springfield, Ill., pp. 291-459 (1970). 4. Decker, A. B., and Mead, J. F. Unpublished personal communication. 5. Cheng, A. L. S., Ryan, M., Altin Slater, R. B., and Devel, H. J. Jr. The effect of fat level of the diet on general nutrition, J. Nutrition 52, 637-643 (1954). 6. Paulsrud, J. R., Pensler, L., Witten, C. F., Stewart, S., and Holman, R. T. Essential fatty acid deficiency in infants induced by fat-free intravenous feeding, Amer. J. Clin. Nutrition 25, 897-904 (1972). 7. Cauldwell, M. D., Jennson, H. T., and Othersen, H. B. Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation, J. Ped. 81, 894-898 (1972).
ONCOLOGY
Essential
4,66-69 (1976)
Fatty Acid Deficiency Hyperalimentation
with Long-Term
D. R. MELDRUM, G. A. DHOPESHWARKAR, S. LIN, AND M. L. SMITH Department
of Obstetrics and Gynecology, Department of Biochemistry, for the Health Sciences, Los Angeles, California 90024
UCLA Center
Received October 3, 1975 Content of essential fatty acids was determined in the plasma lipid fractions of patients with malignancies of the female reproductive tract. A marked deficiency was identified in two such patients while on prolonged total parenteral nutrition with hypertonic glucose and casein hydrolysate, compared to a control group of ambulatory and postoperative patients. The progressive deficiency observed in one patient was completely reversed by infusions of fat emulsion over a 3-week period. These results indicate a need for inclusion of essential fatty acids with prolonged total parenteral nutrition.
The need for a safe and effective method of total parenteral nutrition (TPN) has expanded recently in gynecology with an increasingly aggressive approach to the treatment of malignancies of the female reproductive tract. Bowel fistulas, obstruction, and radiation enteritis account for serious morbidity and mortality resulting from attempts at curative treatment of large or recurrent lesions. The increasing use of radical or even restricted surgery in combination with previous irradiation is particularly hazardous. Operative management of the bowel obstruction associated with radiation enteritis or recurrent tumor may require bypass of large segments of absorptive surface area leading to difficult postoperative problems with nutrition. The recent use of hypertonic solutions of glucose and amino acids by central venous infusion has been an important contribution to providing the calories and nutrients necessary during these periods of extensive tissue repair [1,2]. These methods, however, are associated with serious complications related to infection and the high osmotic load required. Furthermore, a major nutrient, lipid, is not provided. Since the mammalian organism is able to synthesize fats from glucose and may have considerable stores, a deficiency of lipids for energy and tissue formation is an unlikely problem. Certain long-chain polyunsaturated fats (essential fatty acids), however, must be obtained in the diet and may not be stored in adequate supply to cover long periods without oral intake. As important components of membrane phospholipids, a need for these essential fatty acids has been suggested in tissue repair. Fat emulsions are currently in use in other countries and recently their use has been approved in the United States. A 500 cc unit of Intralipid (Cutter Laboratories) provides 550 cal(50 g of fat; glycerin, 100Cal) with a high content of essential fatty acids. It can be infused through a peripheral vein and therefore may be combined with amino acids and a less hypertonic glucose solution providing the 66 Copyright @ 1976 by Academic press, Inc. All rights of repmduction in any form reserved.
FAT
DEFICIENCY
AND
HYPERALIMENTATION
67
necessary calories without some of the major complications of hyperalimentation. For a review of the metabolic alterations which may be associated with the use of intravenous fat emulsions, refer to a recent Symposium on Parenteral Nutrition [31. In addition to these evident advantages, there may be instances where significant EFA deficiency is induced by long-term parenteral nutrition. Oncology patients are particularly predisposed to such a deficiency since rapid synthesis of tumor tissue [4] and radiation therapy [5] have been shown to accelerate the development of deficiency states in laboratory animals. The following study was done to attempt to identify EFA deficiency in oncology patients undergoing long-term hyperalimentation and to determine whether such a deficiency could be corrected easily by the addition of Intralipid. MATERIALS AND METHODS Fifteen patients with malignancies of the female reproductive tract were selected as a control group from both outpatient and inpatient populations. Two patients requiring long-term infusion of hypertonic glucose and amino acids were studied. One of these patients, described in the accompanying case report, was studied each month for 3 months, and since the study results were then available, was treated with Intralipid. The second patient had only a single sample after 6 weeks of hyperalimentation. Blood samples were taken and immediately placed on ice in a heparinized tube, centrifuged at 4°C and the plasma was stored at -20°C until the lipid analyses could be carried out. Extraction was carried out with chloroform:methanol (2:l). Cholesterol esters were separated from the total lipids by thin-layer chromatography on silica gel G plates developed in 10% ether and 1% acetic acid in pentane. Methylation of cholesterol esters was accomplished by refluxing for 5-6 hr in 10% benzene in methanol containing 1% sulfuric acid. The resulting fatty acid methyl esters (together with free cholesterol) were extracted with ethyl ether; finally, the methyl esters were separated from cholesterol by chromatography on a mini Sio, column. Ethyl ether (5%) in pentane eluted the fatty acid methyl esters which were then analyzed by gas-liquid chromatography using a Beckman model Gc-M instrument fitted with a Win. x 6-ft column (packed with 10% DEGS on chromosorb W) maintained at 185°C. GLC peaks were triangulated to obtain areas and identified by retention times of corresponding known standard samples. RESULTS The mean and 2 SD of the percentage content of linoleic acid in cholesterol esters is shown in Fig. 1. The corresponding values for the two study patients are clearly below the range of normal with a progressive exhaustion of polyunsaturated fat in patient L.L. In this patient an abnormal fatty acid specific for essential fatty acid deficiency (20:309) could be identified. Treatment with 9 units of Intralipid over a 3-week period restored the abnormal blood lipid profile to normal. Arachidonic acid followed identical changes to those of linoleic acid. During Intralipid therapy, body weight was maintained in spite of discontinuation of hypertonic glucose due to systemic moniliasis and the use of only a peripheral venous line.
MELDRUM
ET AL.
60
I
0
I 4
I 8
I 12
I
/NT-,
I
I
I
Sunits
WEEKS ON HYPERALIMENTATION FIG. 1. The normal range of linoleic acid content within circulating cholesterol esters in a control population of gynecologic oncology patients is depicted. Values obtained in two patients on hyperalimentation are presented for comparison.
CASE REPORT
Patient L.L., 49 yr old, GO, presented January, 1974 with irregular bleeding, Class IV cervical cytology. Biopsy revealed epidermoid carcinoma. Metastatic work-up was negative. Clinically staged IIB. Underwent staging laparotomy confirming preoperative staging, at which time BSO was done and periaortic and pelvic nodes were sampled. External cobalt and two radium applications were administered with a total dose of 7500rad to pt. A and 6000rad to pt. B. May, 1974 she was admitted with a small bowel obstruction which was radiologically identified to be at the distal jejunum. After failure of response to long tube drainage, lysis of adhesions and gastrostomy was carried out June 1974, at which time massive irradiation damageto the bowel was noted. Hyperalimentation with 20% dextrose and 5% casein hydrolysate was begun post-op. Because of inability to reestablish GI function and radiologic demonstration of recurrent obstruction, reoperation was carried out with excision of all but 4 ft of the small bowel. Plasma sampleswere obtained after approximately 1, 2, and 3 months on hyperalimentation. When the lipid analyses were completed and a marked EFA deficiency was identified a further sample was taken, followed by infusion of 9 units of Intralipid over a period of 3 weeks. The final sample was taken 3 days after completion of therapy.
FAT
DEFICIENCY
AND
HYPERALIiiENTATION
69
DISCUSSION Essential fatty acid deficiency has been identified in certain predisposed groups of patients when prolonged intravenous therapy is required. Newborn infants have very limited stores of polyunsaturated fat and there are documented cases of deficiency after relatively short periods of intravenous therapy [6]. Other predisposing factors are periods of rapid growth, presence of tumor, or radiation therapy, the common factor being an increased requirement for tissue membrane synthesis during growth or repair. The postoperative period is also one of increased requirement, yet intake may be restricted for long periods. In one case of documented deficiency [7], wound healing did not occur until the deficiency was corrected by intravenous fat emulsion. Postoperative oncology patients thus have multiple factors predisposing to EFA deficiency. Although stores may be sufftcient during short periods of increased need and inadequate intake, the results of this study suggest that a fat emulsion with high EFA content should be part of any prolonged period of total parenteral nutrition. The additional calories supplied may enable the use of a combination of sugar, amino acids, and fat by peripheral infusion. SUMMARY: A progressive essential fatty deficiency was demonstrated in gynecological oncology patients requiring long-term hyperalimentation, in contrast to the lipid pattern of a control group. A relatively short period of therapy with intravenous fat emulsion was sufficient to normalize the lipid pattern of a patient with severe deficiency. It is recommended that fat emulsion be considered as part of any regimen of prolonged total parenteral nutrition. The additional calories supplied may facilitate development of a peripheral regimen of hyperalimentation. REFERENCES 1. Dudrick, S. J., Wilmore, D. W., and Vars, H. M. Long-term parenteral nutrition with growth in puppies and positive nitrogen balance in patients, Surg. Forum 18, 356357 (1967). 2. Dudrick, S. J., Wilmore, D. W., Vars, H. M., and Rhoads, J. E. Long-term total parenteral nutrition with growth, development and positive nitrogen balance, Surgery 64, 134-142 (1%8). 3. Meng, H. C., and Law, D. H. Proceedings of an International Symposium on Parenteral Nutrition, Charles C. Thomas, Springfield, Ill., pp. 291-459 (1970). 4. Decker, A. B., and Mead, J. F. Unpublished personal communication. 5. Cheng, A. L. S., Ryan, M., Altin Slater, R. B., and Devel, H. J. Jr. The effect of fat level of the diet on general nutrition, J. Nutrition 52, 637-643 (1954). 6. Paulsrud, J. R., Pensler, L., Witten, C. F., Stewart, S., and Holman, R. T. Essential fatty acid deficiency in infants induced by fat-free intravenous feeding, Amer. J. Clin. Nutrition 25, 897-904 (1972). 7. Cauldwell, M. D., Jennson, H. T., and Othersen, H. B. Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation, J. Ped. 81, 894-898 (1972).
