Acute Folate Deficiency Associated with Intravenous Nutrition with Aminoacid-Sor bitol-Ethanol: Prophylaxis with Intravenous Folic Acid C. A. J . WARDROP, M. H. LEWIS,G. B. TENNANT, R. H. P. WILLIAMS A N D L. E. HUGHES
Departments of Haernatology and Surgery, Welsh National School of Medicine, University Hospital of W a l e s , Card$ (Received 27 M a y 1977; accepted for publication 6 July 1977) SUMMARY. Preoperative folate levels were initially normal in 3 0 patients with gastrointestinal tract disease but fell within 48 h by 60-95% in 20 patients who received intravenous nutrition for 6-12 d with aminoacid-sorbitol-ethanol (ASE). This depression persisted in patients not given folate supplements. Folate levels in 10 control patients not given ASE showed only minimal decline. Haematological changes were reduced to a minimum in 10patients given 0.5 mg i.v. folic acid daily whilst eight unsupplemented patients showed evidence of megaloblastic haemopoiesis. Three of these eight patients developed thrombocytopenia and/or leukopcnia which was fatal in one patient. We have reported (Wardrop et al, 1975a) an acute decline in folate levels in patients given i.v. nutrition with aminoacid-sorbitol-ethanol (ASE). Megaloblastic haemopoiesis can develop with life-threatening thrombocytopenia and leucopenia, but these changes respond to folate therapy in 3 3 d. We report here an attempt to prevent this complication of parenteral feeding by giving supplementary folic acid to patients on i.v. nutrition with ASE. O u r aim was to find a dose adequate to maintain normal serum folate concentrations before and after operation, and to prevent the blood and marrow changes associated with ASE treatment. Control subjects were also studied to observe any change in folate levels, in hospital, of clinically similar patients not given parenteral feeding. PATIENTS A N D METHODS Thirty patients with gastrointestinal tract abnormalities were studied, 20 of whom received aminoacid-sorbitol-ethanol (‘Aminoplex 5 ’ ; Geistlich Sons, Chester, England). Each patient receivcd 2-3 litres ASE daily, containing 50 g ethanol per litre, for 6-12 d before operation. Ethical approval for the trial was obtained from the Ethical Committee of the University Hospital of Wales. The 30 patients were part of a randomized, controlled trial designed to study indications for preoperative parenteral nutrition in improving the immune responses and postoperative course of patients with gastrointestinal malignancy. Only I 3 patients Correspondence: Dr C. A. J. Wardrop, Department of Haematology, Welsh National School of Medicine, Heath Park, Cardiff CF4 4XW. 52 I
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showed evidence of frank malnutrition judged by a history of weight loss exceeding 10lb and/or a subnormal serum albumin concentration of less than 34 g/l. These 13 patients were evenly distributed between the three treatment groups described below. In no case had alcohol intake before admission exceeded moderate social drinking, e.g. 2-3 pints of beer or 2-30 ml whisky daily. The distributions of diagnoses and operations were also similar in the three treatment groups. The final diagnoses were: cancer of oesophagus or stomach (15 patients), benign peptic ulcer with pyloric stenosis (four), biliary stones (one), chronic pancreatitis (one), rectal cancer (nine). Ten patients, Group ‘A’, received i.v. nutrition without folate supplements. As a prophylaxis against acute folate deficiency, the 10 Group ‘B’ patients were given 0.5 mg folic acid i.v. per day during parenteral nutrition, begining 18-24 h after the start of ASE; folate supplements continued for 7 d after operation. Intravenous folate was used to avoid any possible malabsorption or loss by vomiting. Group ‘C’, the 10 control patients, received neither i.v. nutrition nor folate supplements. All patients received daily oral supplements of vitamins A, B, C and D as well as oral high calorie and protein diets to the limit of their tolerance. Haematological investigations included blood examination (Coulter ‘ S ’ ) reticulocyte and platelet counts (Auto-technicon platelet counter) and blood-film examination on admission, with estimation of fasting serum iron and TIBC, vitamin B,, and serum and red cell folate concentrations as previously reported (Wardrop et al, 1975a). The baseline folate concentrations were taken as the means of two pre-treatment assays on blood samples separated by an interval of 12-24 h. Fasting blood examinations and red cell and serum folate assays were repeated after I, 2, 4 and 6 d of i.v. nutrition and I,3 and 5 d after the operation and withdrawal of ASE. Blood samples were obtained before the daily injection of 0.5 mg folic acid in patients given prophylaxis. Bone marrow aspirates were obtained at operation. Marrow aspiration was repeated in one patient who developed a leucopenia postoperatively.
RESULTS Serum and Red Cell Folate Concenrrations (Table I) Serum and red cell folate levels were initially normal in all 30 patients without significant differences between the three groups. Within 24 h of starting i.v. nutrition serum folate levels fell significantly (P
Departments of Haernatology and Surgery, Welsh National School of Medicine, University Hospital of W a l e s , Card$ (Received 27 M a y 1977; accepted for publication 6 July 1977) SUMMARY. Preoperative folate levels were initially normal in 3 0 patients with gastrointestinal tract disease but fell within 48 h by 60-95% in 20 patients who received intravenous nutrition for 6-12 d with aminoacid-sorbitol-ethanol (ASE). This depression persisted in patients not given folate supplements. Folate levels in 10 control patients not given ASE showed only minimal decline. Haematological changes were reduced to a minimum in 10patients given 0.5 mg i.v. folic acid daily whilst eight unsupplemented patients showed evidence of megaloblastic haemopoiesis. Three of these eight patients developed thrombocytopenia and/or leukopcnia which was fatal in one patient. We have reported (Wardrop et al, 1975a) an acute decline in folate levels in patients given i.v. nutrition with aminoacid-sorbitol-ethanol (ASE). Megaloblastic haemopoiesis can develop with life-threatening thrombocytopenia and leucopenia, but these changes respond to folate therapy in 3 3 d. We report here an attempt to prevent this complication of parenteral feeding by giving supplementary folic acid to patients on i.v. nutrition with ASE. O u r aim was to find a dose adequate to maintain normal serum folate concentrations before and after operation, and to prevent the blood and marrow changes associated with ASE treatment. Control subjects were also studied to observe any change in folate levels, in hospital, of clinically similar patients not given parenteral feeding. PATIENTS A N D METHODS Thirty patients with gastrointestinal tract abnormalities were studied, 20 of whom received aminoacid-sorbitol-ethanol (‘Aminoplex 5 ’ ; Geistlich Sons, Chester, England). Each patient receivcd 2-3 litres ASE daily, containing 50 g ethanol per litre, for 6-12 d before operation. Ethical approval for the trial was obtained from the Ethical Committee of the University Hospital of Wales. The 30 patients were part of a randomized, controlled trial designed to study indications for preoperative parenteral nutrition in improving the immune responses and postoperative course of patients with gastrointestinal malignancy. Only I 3 patients Correspondence: Dr C. A. J. Wardrop, Department of Haematology, Welsh National School of Medicine, Heath Park, Cardiff CF4 4XW. 52 I
522
C.A . J . Wardrop et al
showed evidence of frank malnutrition judged by a history of weight loss exceeding 10lb and/or a subnormal serum albumin concentration of less than 34 g/l. These 13 patients were evenly distributed between the three treatment groups described below. In no case had alcohol intake before admission exceeded moderate social drinking, e.g. 2-3 pints of beer or 2-30 ml whisky daily. The distributions of diagnoses and operations were also similar in the three treatment groups. The final diagnoses were: cancer of oesophagus or stomach (15 patients), benign peptic ulcer with pyloric stenosis (four), biliary stones (one), chronic pancreatitis (one), rectal cancer (nine). Ten patients, Group ‘A’, received i.v. nutrition without folate supplements. As a prophylaxis against acute folate deficiency, the 10 Group ‘B’ patients were given 0.5 mg folic acid i.v. per day during parenteral nutrition, begining 18-24 h after the start of ASE; folate supplements continued for 7 d after operation. Intravenous folate was used to avoid any possible malabsorption or loss by vomiting. Group ‘C’, the 10 control patients, received neither i.v. nutrition nor folate supplements. All patients received daily oral supplements of vitamins A, B, C and D as well as oral high calorie and protein diets to the limit of their tolerance. Haematological investigations included blood examination (Coulter ‘ S ’ ) reticulocyte and platelet counts (Auto-technicon platelet counter) and blood-film examination on admission, with estimation of fasting serum iron and TIBC, vitamin B,, and serum and red cell folate concentrations as previously reported (Wardrop et al, 1975a). The baseline folate concentrations were taken as the means of two pre-treatment assays on blood samples separated by an interval of 12-24 h. Fasting blood examinations and red cell and serum folate assays were repeated after I, 2, 4 and 6 d of i.v. nutrition and I,3 and 5 d after the operation and withdrawal of ASE. Blood samples were obtained before the daily injection of 0.5 mg folic acid in patients given prophylaxis. Bone marrow aspirates were obtained at operation. Marrow aspiration was repeated in one patient who developed a leucopenia postoperatively.
RESULTS Serum and Red Cell Folate Concenrrations (Table I) Serum and red cell folate levels were initially normal in all 30 patients without significant differences between the three groups. Within 24 h of starting i.v. nutrition serum folate levels fell significantly (P
