A P P L I E D N U T R I T I O N A L I N V E S T I G A T I O N Nutrition Vol. 12, No, 6, 1996

Effect of Iron-Supplemented Total Parenteral Nutrition in Patients With

Iron Deficiency Anemia

D A V I D L. B U R N S , MD, E D W A R D A. M A S C I O L I , MD, A N D B R U C E R. B I S T R I A N , MD, P H D

From the Nutrition Support Service, Department of Medicine, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts, USA

Date accepted: 1 Sep tember 1995

ABSTRACT

Iron deficiency anemia is common among hospitalized patients, and blood losses from diagnostic phlebotomy increase the likelihood of a negative iron balance. The role for iron supplementation of total parenteral nutrition (TPN) in these patients is unclear. Twenty-three patients with iron deficiency anemia were identified. Twelve patients were randomized to receive TPN without iron (group 1 ) and 11 received TPN supplemented with 10 mg of iron as iron dextran daily (group 2). Both groups were matched for age, serum iron studies, red cell indices, and hemogram. After a 7-d period, the mean serum iron in group 2 increased from 10 to 26 #g/dL, with an increased transferrin saturation from 7.3 to 15.3% (each, p < 0.05). No changes in total iron binding capacity, ferritin, reticulocyte count, hemoglobin, hematocrit, or mean corpuscular volume were observed in the two groups. The incidence of infectious complications was not different between both groups. We conclude that iron supplementation of TPN appears safe and is effective in increasing serum iron levels. The use of iron-supplemented short-term TPN needs to be further studied given no change in red cell indices, hemoglobin, hematocrit, or transfusion requirement. Nutrition 1996; 12:411-415

Key words: iron dextran, parenteral iron, total parenteral nutrition, iron deficiency anemia

INTRODUCTION

Iron deficiency is the most common etiology for anemia, with an estimated 500 million cases worldwide. * Chronic gas- trointestinal blood loss is the most prevalent underlying cause of iron deficiency; however, in hospitalized patients, recurrent diagnostic phlebotomy may play an even greater role. Many investigators have demonstrated the efficacy and relative safety of parenteral iron replacement therapy with iron dextran for iron deficiency, z-4 However, parenteral iron administration is associated with various side effects, including the possibility of an increased risk of infection. Total parenteral nutrition (TPN) serves as a vehicle for administration of essential nutrients, including vitamins and trace elements, although iron is not a component of commercially available trace element prepara- tions. Currently, low-dose iron dextran supplementation ( 1 - 2 mg) in TPN to meet the usual daily requirement is commonly used to meet obligate body iron losses. Several groups have also studied therapeutic iron supplementation of TPN in rela- tively high doses in patients with acute gastrointestinal or surgi-

cal blood loss or patients with anticipated phlebotomy to restore or sustain red cell mass. 5'6 We report a randomized prospective study of patients with iron deficient anemia receiving short- term TPN supplemented with modest therapeutic doses of iron as iron dextran.

MATERIALS AND METHODS

All patients evaluated by the hospital nutrition support ser- vice (NSS) for initiation of TPN had nutritional assessments that included the following laboratory measurements: serum albumin, 24-h urinary creatinine, complete blood count with red blood cell indices and serum iron (Fe), total iron binding capacity (TIBC), ferritin (Ferr), and reticulocyte counts (Re- tic). Those patients with Fe-to-TIBC ratio (or transferrin satu- ration ITS]) of 10% or less were identified as iron deficient 7 and were randomized to receive no iron supplementation or 10 mg of iron as iron dextran in their daily TPN. Patients with a history of reaction or allergy to iron dextran were excluded from the study. Before initiation of iron supplements, verbal consent was obtained from enrolled patients as per the condition

Correspondence to: Bruce R. Bistrian, MD, PhD, Deaconess Hospital, 194 Pilgrim Rd., Boston, MA 02215, USA.

Nutrition 12:411-415, 1996 ©Elsevier Science Inc. 1996 Printed in the USA. All rights reserved. ELSEVIER

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412 EFFECT OF IRON-SUPPLEMENTED TOTAL PARENTERAL NUTRITION

of the institution review board study approval. Data were used if the patients completed 7 d of TPN with or without iron.

Study patients had minimal oral intake and received no oral iron supplements. All patients received TPN solutions con- taining macronutrients of dextrose and amino acids with a goal of providing 25 kcal/kg of body weight and 1.5 g/kg of amino acids per estimated ideal body weight. Three-in-one admixtures containing lipid were avoided because of concerns of emulsion stability in TPN containing iron as a trivalent cation. 8 All TPN solutions contained multivitamins and trace elements. Group 2, the iron-supplemented group, received 10 mg of iron as iron dextran (Infed, Schein Pharmaceuticals, Port Washington, NY) in their TPN daily.

Patients were transfused with blood or packed red cells by their primary care team, usually to maintain a hemoglobin con- centration of 10 g/dL or greater. Laboratory studies were or- dered by the primary care team and the NSS. Most of the phlebotomy was performed by the NSS nursing staff. Blood was drawn from the patient's central venous catheter and pre- ceded by an 8- to 10-mL blood discard to clear the catheter of fluid. Records of all phlebotomy were kept and aggregate daily phlebotomy determined, as was all transfusion of blood prod- ucts including confirmation by the hospital blood bank.

Laboratory data were obtained on day 0 and repeated on days 8-10. Studies included hemoglobin (Hgb) , hematocrit (Hct), mean corpuscular volume (MCV), serum Fe, TIBC, Ferr, and Retic. Serum Fe and TIBC were determined on a Cobas-Fara II autoanalyzer (Roche, Fairfield, N J), Ferr was measured on a ES300 autoanalyzer (Behringer-Manheim, Indian- apolis, IN). The hemogram with red cell indices was done on a STAK-S (Coulter, Highlea, FL) and Retic counts by the New Methylene Blue Stain method (Phillipsburg, NJ) and manually counted.

The development of nosocomial infection while receiving TPN was evaluated according to Centers for Disease Control and Prevention guidelines. 9 The first criterion was that no evi- dence of infection was present at the time of hospital admission (or initiation of TPN). Second, for the diagnosis of infection, two of the three following criteria had to be present: tempera- ture of greater than 38°C; isolation of a pathogenic organism; or local pain, swelling, erythema, purulent drainage, or radiologic evidence of infection (i.e., an infiltrate on chest x ray). Infec- tion was graded as absent or present.

Creatinine height index (CHI) was determined by 24-h uri- nary creatinine divided by the expected urinary creatinine and expressed as a percentage. The predicted 24-h creatinine excre- tion is 18 mg/kg of ideal body weight for females and 23 rag/ kg for males. The transfusion requirement was based on the total number of units of packed red blood cells transfused over the study period multiplied by 280 mL/U, which represents the average volume prepared by our blood bank. Comparison of the two study groups before initiation of TPN was done using a two-tailed Student's t test. Pre-TPN and post-TPN labo- ratory data were also compared using a two-tailed Student's t test with statistical significance set at p < 0.05. All values are reported as means ___ SEM.

RESULTS

There were 23 patients who participated in the study, all of whom continued to completion. Eleven patients (group 2) received 10 mg of iron dextran in their daily TPN and 12 patients (group 1) did not get iron supplementation. Patient characteristics are shown in Table I and background and nutri- tional data for both groups are shown in Table II. Mean age was 51.4 and 52.5 year, percent ideal body weight was 103.3 and 102.2%, CHI was 84.5 and 72.9%, and the total lymphocyte

count (TLC) was 1210 and 15t5 cells/mm 3 (normal >1000 cells/mm3), respectively, for groups 1 and 2. No value was statistically significantly different. The mean pre-TPN serum albumin was 3.2 and 2.3 g/dL, respectively, for groups 1 and 2, which was statistically significant (p < 0.05) and might reflect a greater severity of illness in group 2.

All patients were maintained on 22-25 kcal/kg of actual weight and 1.5 g/kg of amino acids per corrected lean body mass. The patients in group 2 received a mean of 69.1 mg of iron dextran over the study period. The cost increment to the hospital for 10 mg of iron dextran was approximately $2.00 per bag of TPN. Two patients in each group had operative procedures during the study period. None of the women patients had their menses during the study. Repeat laboratory data was obtained on day 9.

Pre-TPN serum Fe studies, Hgb, Hct, Retic, and red blood cell indices are shown in Table III. For groups 1 and 2, respec- tively, the serum Fe was 10 and 10 #g /dL (normal 40-160 /zg/dL), TIBC 171 and 148 #g /dL (normal 250-440 #g/dL) , TS 5.9 and 7.1% (normal >25%), Ferr was 238 and 265 ng/ mL (normal 10-150 ng/mL). All study patients had low serum Fe and TIBC values and a TS of less than 10%. Pre-TPN hemograms were as follows: Hgb was 9.7 and 9.9 g/dL (normal 12-15 g /dL) , Hct was 28.5 and 29.7% (normal 36-44%) , MCV was 84 and 87/zm 3 (normal 82-98 #m3), and Retic was 1.9 and 2.1% (normal 0.5-1.5%). Iron studies, hemograms, and red blood cell indices were statistically the same at day 0.

There were no reactions or side effects noted in patients who received iron supplementation. Post-TPN laboratory data for both groups are shown in Table III. In group 1, the post- TPN serum Fe was 16 #g/dL, TIBC was 178 #g/dL, and TS was 9.3%, demonstrating no change. In group 2, the mean serum Fe increased from 10 to 26 #g/dL, which was a statisti- cally significant change (p < 0.05). This increase in serum Fe was reflected in an increased TS from 7.3 to 15.3%, also sig- nificant (p < 0.05). No other changes were observed in the TIBC, Ferr, Retic, Hgb, Hct, or MCV between the two groups.

Patients in group 1 had a mean daily phlebotomy of 37.5 mL of blood versus 49.3 mL in group 2; this was not significantly different. Patients had a transfusion requirement of 21.5 and 44.3 mL daily, respectively, for both groups, which was most likely secondary to blood loss from phlebotomy, although losses from surgery may have played a role.

Infectious complications were comparable for both groups. Group 1 had four documented infections and group 2 had three. Types of infection included central line sepsis, urinary tract infection, and surgical wound infection.

DISCUSSION

Iron deficiency anemia is a common finding among hospital- ized patients, and recurrent phlebotomy may result in large blood losses, further contributing to depletion of iron stores. Normally, the daily requirement of iron is approximately 1 mg of absorbed iron to offset obligate losses from skin, desquama- tion of gastrointestinal mucosal cells, and microscopic bleeding from the gut and genitourinary tract. Several groups have quan- titated the impact of recurrent phlebotomy in hospitalized pa- tients on the development of anemia and have demonstrated blood losses of 40-60 mL/d. ~°-12 Possible mechanisms to re- duce phlebotomy losses include the use of pediatric blood col- lection tubes and more judicious ordering of diagnostic studies. One milliliter of blood with an Hgb concentration of 15 g/dL contains 0.5 mg of iron. ~3 Thus, daily iron losses of 20-30 mg can be expected in routinely phlebotomized patients.

TPN is not routinely supplemented with iron. Some authors advocate the addition of 1 -2 mg of iron dextran in TPN to

EFFECT OF IRON-SUPPLEMENTED TOTAL PARENTERAL NUTRITION

TABLE I.

413

PATIENT CHARACTERISTICS

Patient Age (yr) Sex Diagnosis

Group 1 1 76 F 2 32 M 3 70 M 4 84 F 5 37 F 6 41 M 7 76 M 8 31 M 9 30 F

10 46 M 11 48 F 12 44 F

Group 2 13 48 M 14 66 M 15 41 F 16 72 F

17 66 M 18 41 F 19 45 M 20 61 M 21 28 M 22 37 F 23 73 M

Pancreatic cancer, large bowel obstruction Sclerosing cholangitis, s/p liver transplant Cardiogenic shock Ovarian cancer, small bowel obstruction Pancreatitis Cholangiocarcinoma s/p Aorto-bifemoral bypass Ulcerative colitis, sip proctocolectomy Pancreatic pseudocyst Pancreatic adenocarcinoma, sip Whipple procedure Carcinoma of the esophagus, sip esophagogastrectomy Ulcerative colitis

Diverticulitis, s/p sigmoid colectomy Duodenal adenocarcinoma, s/p gastrojejunostomy s/p Aorto-bifemoral bypass sip Coronary artery bypass and mitral valve

replacement Ulcerative colitis, sip total colectomy Rectal squamous cell carcinoma, sip ileal diversion s/p Revision of gastric bypass Pancreatic adenocarcinoma, s/p Whipple procedure Ulcerative colitis Pancreatic pseudocyst Prostate carcinoma, sip radical prostatectomy

14 meet daily requirements. However, chronic long-term addition of 2 m g / d of iron dextran as with home TPN can result in iron overload, and such patients should be monitored (Burns DB, Driscoll DF, Bistrian BR, unpublished data). The safety and efficacy of parenteral iron for the treatment of iron deficiency has been well documented. However, its role as a supplement in TPN for the therapy of iron deficiency anemia is unclear and has not been investigated prospectively in a controlled fashion.

Figueredo and Kaminski15 studied nine patients with iron deficiency anemia and added 100 mg of iron dextran to 10 consecutive bottles of TPN, demonstrating an increased serum Fe, Hgb, and Retic. However, the definition of iron deficiency and the presence of a control group were not specified. Gilbert et al.~6 added iron dextran to the TPN of 17 patients with low serum transferrin levels, providing 200-400 mg of iron, and showed an increased serum transferrin and a decreased Hgb

and Hct. Because these effects were directly opposite to those anticipated, essentially this study questioned the efficacy of iron-supplemented TPN.

Norton and colleagues 6 prospectively evaluated cancer pa- tients with anticipated phlebotomy who were anemic but not further documented to be iron deficient. Patients received 0, 25, 87.5, or 175 mg of iron dextran in TPN over a 1-wk period. The patients treated with 87.5 and 175 mg had increased serum Fe levels after 3 wk of therapy, and Hgb, Retic, and transfusion requirement were unchanged compared with controls. There were no documented increased episodes of infection in the iron- treated group. The authors concluded that 87.5 mg of iron per week would increase serum Fe to the normal range without side effects. 6

Measurement of serum Fe, TIBC, and Ferr can be used to identify and estimate the likelihood and magnitude of iron deficiency, although, classically, bone marrow biopsy remains

TABLE II.

PATIENT DEMOGRAPHIC AND NUTRITIONAL DATA

Serum Albumin TLC Group Age (yr) % IBW* CHI (g/dL) (cells/mm 3)

1 51.4 ± 5.8 103.3 ± 3.5 84.5 ___ 21.4 3.2 ± 0.6 1210 ___ 155 2 52.5 ± 4.7 102.2 ± 3.5 72.9 _ 6.9 2.3 ± 0.2 1515 ___ 230

Values are means ± SEM. *Ideal Body Weight.

414 EFFECT OF IRON-SUPPLEMENTED TOTAL PARENTERAL NUTRITION

TABLE III.

LABORATORY DATA

Pre-TPN Post-TPN

Iron (#g/dL) Group 1 10 _+ 2 16 ± 4 Group 2 10 _+ 1 26 ± 6 Normal 40-160 (t9 < 0.05)

TIBC (#g/dL) Group 1 171 _+ 14 178 _ 17 Group 2 148 ± 18 165 +_ 15 Normal 250-440

TIBC ratio (%) Group l 5.9 + 0.7 9.3 - 1.6 Group 2 7.1 ± 0.8 15.3 ± 3.1 Normal >25 (p < 0.05)

Ferr (ng/mL) Group l 238 _ 71 458 +_ 153 Group 2 265 -z-_ 74 424 ___ 189 Normal 10-150

Retic (%) Group 1 1.9 --- 0.2 2.0 ± 0.4 Group 2 2.1 _ 0.5 2.7 Z 0.4 Normal 0.5 - 1.5

ngb (g/dL) Group 1 9.7 _ 0.4 10.1 ± 0.4 Group 2 9.9 _+ 0.4 9.4 __- 0.4 Normal 12 - 15

Hct (%) Group 1 28.5 + 1.2 30.9 __. 1.3 Group 2 29.7 _ 0.4 28.3 ± 1.0 Normal 36-44

MCV (#m 3) Group 1 84 ± 3 85 ± 2 Group 2 87 + 3 86 ± 3 Normal 82-98

the gold standard for evaluation of iron stores. Serum Ferr concentration is directly proportional to body iron stores and can reflect development of deficiency. However, Ferr is also an acute-phase reactant and dramatically increases with in- flammation, diminishing its value as a marker of iron defi- ciency. Lipschitz et al. 17 observed a mean Ferr of 4 ng /mL in patients with uncomplicated iron deficiency anemia, as defined by a TS of 16% or less. Cook 7 concurred that of the various laboratory studies that can be used to evaluate deficiency, the single best criterion is a TS of <16%. Both serum Fe and transferrin fall with inflammation, but TS should remain an indicator of iron status. Therefore, the criteria used in the pres- ent study were based on a TS of less than 10% in an attempt to eliminate patients with anemia of chronic disease (ACD) . Patients in each group had elevated serum Ferr values, sug- gesting acute inflanmmtion. Therefore, we cannot completely rule out a component of ACD. However, most patients receiv- ing acute TPN have some degree of illness, inflammation, or injury.

Patient randomization was successful for age, percent ideal body weight, CHI, TLC, iron studies, Hgb, Hct, and red blood cell indices. The exception was pre-TPN serum albumin con- centration, which was significantly lower in the iron-treated group (p < 0.05). This difference may represent greater under-

lying protein calorie malnutrition (PCM) , acuity of illness, or catabolic stress in group 2, which in turn might have contributed to the increased daily phlebotomy (49.3 versus 37.5 mL) . Sub- sequently, this was mirrored in a larger daily transfusion re- quirement of 44.3 versus 21.5 mL in groups 2 and 1, respec- tively. However, these differences in phlebotomy and transfu- sion needs were not statistically different.

Serum transferrin has a half-life of 7 - 1 0 d and is elevated in iron deficiency anemia and depressed in the setting of PCM. Thus, a patient with iron deficiency anemia and coexisting mal- nutrition will have a lower serum TIBC than a patient with uncomplicated iron deficiency. TM Each study group had serum TIBC of 171 and 148 #g /dL, respectively, for groups 1 and 2 ( lower limit of normal, 250 # g / d L ) . Given the depressed CHI, serum albumin, and TIBC, each group had mild to moder- ate PCM.

Adverse reactions to iron dextran are variable and can range from mild or transient to life-threatening anaphylactoid reac- tions. Other groups that have studied TPN supplementation with iron have used TPN containing lipid or have not specified whether lipid was a component of the TPN. 6A5'16 All commer- cially available lipid preparations are stabilized with an anionic egg yolk phospholipid emulsifier. Ferric iron as it exists in iron dextran is a trivalent cation and can neutralize the negative anionic surface charge of lipid particles, causing emulsion breakdown with cracking or creaming of the admixture. 8 This clinically can result in fat embolism with pulmonary complica- tions, adult respiratory distress syndrome, and possibly death. Given concerns of systemic side effects and issues of iron stability in TPN, we elected to provide 10 mg of iron dextran daily only in lipid-free two-in-one TPN admixtures. Study pa- tients did not receive iron test doses, because side effects are rare in doses of 10 m g / d and the slow rate of delivery of 0.42 mg/h. None of the studied patients experienced any adverse reactions.

A theoretic side effect of iron administration is an increased risk of infection or exacerbation of chronic infection. Some authors have suggested that in potentially infected patients, TPN should not be supplemented with large quantities of iron due to concerns about infectious complications. 19-2~ Our study and previous studies cited involving parenteral iron dextran, however, have not demonstrated an increased infectious com- plication rate.

Provision of 10 mg of iron daily over a 1-wk period resulted in increased serum Fe levels from 10 to 26 # g / d L (p < 0.05) and increased TS from 7.3 to 15.3% (p < 0.05). These findings are consistent with previous studies by Norton 6 and Fiqueredo.15 The ability to increase se rum Fe levels in our study group suggests that iron deficiency may have played a greater role than ACD, because the iron was not sequestered in tissue stores.

No changes were evident in the TIBC, Ferr, Retic, Hgb, Hct, MCV, or transfusion requirement. This is likely secondary to the following reasons. First, patients were only given an aggregate dose of 70 mg of iron over a 1-wk period with continued iron losses that would make the net balance smaller. This is a small amount relative to the total body iron stores of 3 - 4 g. Second, follow-up laboratory data were obtained on day 9, which may have been too early for reassessment of the red cell indices and hemogram. Under maximal stimulation, as much as 100-125 mg of iron can be used by the bone marrow daily for hemoglobin synthesis. 22 Dudrick and colleagues 5 gave up to 500 mg of iron dextran/L of TPN and a maximum total dose of 7000 mg over 5 d to patients with acute massive blood loss or chronic anemia. They noted an increase in Hgb of 5.6 g / d L over 23 d in the acute blood loss cohort and 6.8 g / d L over 121 d in the chronic anemia group. Our study patients

EFFECT OF I R O N - S U P P L E M E N T E D TOTAL P A R E N T E R A L NUTRITION 415

were more similar to the chronic anemia group and did not sustain an acute blood loss; thus, they may require longer fol- low-up to document any changes in the hemogram or transfu- sion needs.

CONCLUSION

Hospitalized patients are in negative iron balance secondary to phlebotomy losses, and those with documented iron defi- ciency may require iron supplementat ion to maintain Hgb and red blood cell production. W e conclude that supplementat ion

of TPN is safe and has been demonstrated to increase serum Fe concentration. It did not result in any untoward side effects or increase in infectious complications. However, the role of iron as a additive to short-term TPN needs to be further clarified given the lack of benefit in Hgb, Hct, or transfusion require- ment.

ACKNOWLEDGEMENTS

We thank Drs. E.A. Pomfret, J.J. Pomposell i , and L.M. Gramlich for their participation in recruit ing patients for this study.

REFERENCES

1. Finch CA, Huebers H. Medical progress. Perspectives in iron me- tabolism. N Engl J Med 1982;306:1520

2. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. J Am Med Assoc 1980;243:1726

3. Auerbach M, Witt D, Toler W, et al. Clinical use of the total dose intravenous infusion of iron dextran. J Lab Clin Med 1988; 111:566

4. Porter KA, Blackburn GL, Bistrian BR. Safety of iron dextran in total parenteral nutrition: a case study. J Am Coil Nutr 1988; 120:721

5. Dudrick SJ, O'Donnell JJ, Raleigh DP, et al. Rapid restoration of red blood cell mass in severely anemic surgical patients who refuse transfusion. Arch Surg 1985; 120:721

6. Norton JA, Peters ML, Wesley R, et al. Iron supplementation of total parenteral nutrition: a prospective study. JPEN 1983;7:457

7. Cook JD. Clinical evaluation of iron deficiency. Sem Hematol 1982; 19:6

8. Driscoll DF. Clinical issues regarding the use of total nutrient ad- mixtures. DICP, Ann Pharmacother 1990;24:296

9. Garner JS, Jarvis WR, Emori TG, et al. CDC definitions for nosoco- mial infections, 1988. Am J Infect Control 1988; 16:128

10. Eyster E, Bernene J. Nosocomial anemia. J Am Med Assoc 1973;223:73

11. Smoller BR, Kruskall MS, Horowitz GL. Reducing adult phlebot- omy blood loss with the use of pediatric-sized blood collection tubes. Am J Clin Pathol 1989;91:701

12. Foulke GE, Harlow DJ. Effective measures for reducing blood loss from diagnostic laboratory tests in intensive care unit patients. Crit Care Med 1989; 17:1143

13. Fairbanks VF. Iron in medicine and nutrition. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea and Febiger, 1994:192

14. Jeejeebhoy KN. Nutrient requirements and deficiencies in GI dis- eases. In: Sleisenger MH, Fortran JS, eds. Gastrointestinal disease: pathophysiology, diagnosis and management. Vol. 2, 5th ed. Phila- delphia: WB Saunders, 1993:2027

15. Figueredo JV, Kaminski MV. Iron dextran in intravenous hyperali- mentation solutions in the treatment of iron deficiency anemia. JPEN 1979;3:509

16. Gilbert L, Dean RE, Karaganis A. Iron-dextran administration via TPN solution in malnourished patients with low serum transferrin levels. JPEN 1979;3:509

17. Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of ferritin as an index of iron stores. N Engl J Med 1974;290:1213

18. McMahon MM, Bistrian BR. The physiology of nutritional assess- ment and therapy in protein-calorie malnutrition. Disease-a-Month 1990; 36:377

19. Murray MJ, Murray AB, Murray MB, et al. The adverse effect of iron repletion on the course of certain infections. Br Med J 1978;2:1113

20. Weinberg ED. Nutritional immunity. J Am Med Assoc 1975;231:39

21. Bothe A, Benotti P, Bistrian B, et al. Use of iron with total paren- teral nutrition. N Engl J Med 1975;239:1153

22. Cook JD, Skikne BS. Iron deficiency: definition and diagnosis. J Intern Med 1979;226:349