Intravenous Iron.Dextran in the Treatment of Iron Deficient Anemia Cage S. Johnson, MD Los Angeles, California
Administration of oral ferrous salts is the preferred method of treatment for anemia due to iron deficiency. However, in certain clinical situations, the response to oral therapy may be suboptimal. Parenteral iron therapy is effective in these instances and may produce a faster response than the oral route. Of 30 patients treated by total dose intravenous infusion of irondextran, a prompt reticulocytosis occurred in all patients except one case associated with systemic lupus erythematosus. Hematologic improvement in this case followed remission of the systemic lupus erythematosus. Hematologic response was complete in 18 patients in five to nine weeks, but could not be evaluated in 11 cases because of recurrent bleeding. There were two adverse reactions: generalized pruritus after injection in one patient, and superficial thrombophlebitis at the injection site of another. The response to therapy in iron deficient anemia is dependent on bone marrow capacity, the severity of the anemia, and the availability of iron. Response was fastest in those who had been severely anemic for prolonged periods of time. Total dose infusion with iron-dextran is a safe and effective treatment for iron deficient anemia in selected cases. Initial response appears to be faster than that on oral therapy with the exception of those with a mild degree of anemia. Introduction The therapeutic objectives in the management of iron deficient anemia are twofold. First and most important is identification and correction of the underlying cause. Since iron deficient anemia is always the consequence of negative iron balance, usually from excessive blood loss, correction of the lesion responsible for iron loss is the most important consideration in the overall health needs of the patient. The second goal is correction of the anemia and replacement of iron stores. Proper management of both of these goals will reduce the frequency of recurrent From the Los Angeles County-University of Southern California Medical Center, Los Angeles, California. Supported in part by Grant No. HL15162 from the National Institutes of Health. Presented at the 82nd Annual Meeting of the National Medical Association, Los Angeles, California, July 31-August 4, 1977. Requests for reprints should be addressed to Dr. Cage S. Johnson, RMR 304, University of Southern California, 2025 Zonal Avenue, Los Angeles, CA 90033.
anemia. Oral administration of ferrous salts is a well tolerated and effective therapy for this anemia. On the usual daily dose of three tablets, which contain 150 to 200 mg of elemental iron, the hemoglobin level should return to normal in eight weeks.I However, repletion of iron stores necessitates continuing therapy for 6 to 12 months thereaf-
ter.2'3 Therapeutic failure on oral iron should prompt a reassessment of the clinical situation to affirm that iron deficiency is truly the cause of the anemia and that one of the other hypochromic anemias (the anemias associated with chronic disease, thalassemia minor, or the sideroblastic anemias) is not present. True failure to re6pond to oral iron is unusual. Active infection or chronic inflammatory disease such as rheumatoid arthritis or systemic lupus erythematosus may blunt the response because of faulty iron utilization. Gastric resection or malabsorption syndromes may prevent adequate iron
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
absorption. In disorders such as hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), blood may be lost in greater quantities than oral iron can replace. Prolonged release formulations result in release of iron in the lower gastrointestinal tract, whereas iron absorption is maximal in the upper tract; the use of these compounds may lead to less effective absorption.4 However, therapeutic failures are most often the result of misdiagnosis, inadequate therapy, or noncompliance. Patient compliance is a major obstacle to the satisfactory treatment of iron deficiency. Studies of this problem4,5 clearly indicate that true intestinal intolerance occurs in less than ten percent of individuals and that psychologic factors are mainly responsible for noncompliance. Lowering the dose effectively deals with intolerance but results in submaximal response. Because of these problems, attempts to find a suitable parenteral preparation for iron therapy have been ongoing since the late 19th century. Early preparations were unsatisfactory because these agents were unstable and caused a high frequency of toxic reactions due to release of free ionized iron into the plasma. Furthermore, the dose that could be administered was limited, requiring multiple injections to complete a course of therapy. In addition, there was high loss of the dose in the urine and this limited efficacy. With the introduction of iron-dextran in the 1950s, many of these problems were overcome.4
Pharmacology Iron-dextran4f6i7 is a complex of a high molecular weight dextran fraction with Fe(OH)3. The commercial preparation is a dark brown solution containing 50 mg of elemental iron per ml. The complex is highly stable in blood, has a very low toxicity (the LD50 is greater than 1000 mg/kg in mice), and can be administered by either intramuscular or intravenous routes. After intramuscular injection, 1101
Table 1. Calculation of Iron Dose A. Iron deficit (mg) = Hb deficit (gm) x 3.4 mg iron per gm Hb + iron stores B. Hb deficit (gm) = rbc deficit (dl) x the normal MCHC (gm/dl) .. normal Hb - observed Hb normal Hb C. RBC deficit (dl) = x normal rbc volume D. Arbitrary normal values 1. rbc volume = 0.35 dl per kg body weight 2. MCHC = 33 gm/dl 3. Iron stores = 15 mg per kg 4. Normal Hb = 15 gm/di E. Substituting B and C into A yields the equation Hb - Qbserved Hb x Iron deficit = normal normal rbc volume x normal MCHC normal Hb F. Substituting D into E yields
x
3.4 mg iron per gm Hb + iron stores
Iron deficit =1515 x 0.35 x kg x 33 x 3.4 + 15 x kg G. Condensation of the equation in F yields Iron deficit in mg = 2.6 x kg x (15 - Hb) + 15 x kg Hb = Hemoglobin rbc = red blood cell
50 percent of the dose is absorbed in 72 hours and the remainder over a variable period; some of the dose may remain at the ipjection site permanently. Skin staining due to residual iron and melanin deposition may occur. When given by vein, the complex circulates intact and little free iron is released which explains the low frequency of toxic reactions. In either case, the serum iron reaches very high levels. The serum is colored brown by the complex, which may interfere with bilirubin and calcium determinations, but not with other laboratory tests. The complex is slowly cleared from the plasma over three to four weeks and ultimately utilized for hemoglobin synthesis. Local and systemic reactions to iron-dextran occur after either parenteral route, but are generally mild and usually respond to supportive measures.6 Anaphylaxis has been responsible for six deaths 4,8-10 after both intramuscular and intravenous use, but the risk seems small in view of the many millions of doses given in the past 25 years. Sarcoma occurs at intramuscular injection sites in animals, and has been increasingly reported in humans."1 Intravenous iron-dextran has the advantages of avoiding discomfort, skin staining, and erratic absorption from intramuscular sites, and it can be used in patients with thrombocytopenia, coagulation disorders, and in those on anticoagulant therapy where intramuscular injections are contraindicated. With the introduction 1102
of total dose infusion by ]3asu for the treatment of iron deficient anemia in the late stages of pregnancy,7"2 it became possible to deliver the total dose of iron calculated to replenish both hemoglobin levels and iron stores at one sitting. With this method, Basu was able to obviate the risks of transfusion in his patients and, further, noted a rapid response. The ability of parenteral iron therapy to produce a faster response than oral iron has been confirmed by some studies, 13"14 but denied by others.'a"6 This unsettled controversy and a rapid response in a patient who refused transfusion for religious reasons prompted a reassessment of the response to intravenous iron-dextran.
Materials and Methods Hospitalized patients at the Los Angeles County-University of Southern California Medical Center, with the diagnosis of iron deficie,nt anemia manifested by typical hypochromic microcytic anemia and confirmed by low serum iron, elevated iron binding capacity, an'd saturation less than 12 percent or by absent bone marrow iron stores, were considered for intravenous iron-dextran if they met one of the following criteria: 1. Therapeutic failure on adequate doses of oral iron due to continuing heavy blood loss 2. Recent acute blood loss with stable cardiovascular function that might require transfusion with any further bleeding
3. Refusal of transfusion due to religious preferences 4. Chronic gastrointestinal disease that might be aggravated by oral iron 5. Severe thrombocytopenia since constipation may follow oral therapy with straining at defecation. The consequent increase in cerebrospinal fluid pressure may increase the risk of intracranial bleeding 6. Repeated noncompliance 7. Malabsorption syndromes The iron dose for each patient was calculated (Table 1) by estimation of the red blood cell mass deficit and conversion of that deficit into grams of hemoglobin and then into milligrams of iron using the value of 3.4 mg of iron per gram of hemoglobin which is derived from the molecular weights of iron and hemoglobin. The normal values used in this calculation were arbitrarily selected from the range of values in standard hem,atologic texts. This calculation gives higher doses than that supplied by the manufacturer because of the higher iron store factor used, but either is acceptable. The dose of iron-dextran calculated for each patient was rounded off to the nearest 0.1 gm for ease of administration and given by intravenous infusion according to a modification of the method of Wallerstein.f An intravenous line was placed to provide vascular access in case of an anaphylactic reaction. A test dose of 0.5 ml (25 mg) of the complex was diluted with 9.5 ml of normal saline and injected through the intravenous tubing over two minutes. The patients
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
were observed for 15 nlinutes after the test dose, and, if no reaction occurred, the remainder of the dose was diluted in 200 ml of normal saline and infused at a rate no faster than 50 mg of iron per minute. The entire procedure was completed within 75 minutes in all cases. Vital signs were monitored at 15minute intervals throughout the procedure. Hemoglobin and reticulocyte counts17 were measured immediately before the infusion and daily thereafter until reticulocyte counts doubled over base line. The values were repeated at approximately seven, 15, and 30 days after infusion and at monthly intervals until response was complete. Thirty patients aged 19 to 72 were treated by this method. There were six males and 24 females. The dose of iron-dextran varied from 800 to 2,500 mg of iron. The diagnoses in these patients are given in Table 2.
Results The infusion of iron-dextran was completed in all patients without incident. There were only two adverse reactions; one patient developed generalized pruritus without rash 24 hours after the infusion, and one patient developed superficial thrombophlebitis at the intravenous site. Both responded to supportive therapy. In 29 (97 percent) of the patients the response to intravenous iron was immediate as seen by doubling of the reticulocyte count over base line within 48 hours of the infusion followed by a rise in the hemoglobin level of 0.5 to 2.4 gm/100 ml by day 7. One patient with active inflammatory disease and iron deficiency had a delayed response to iron-dextran.
Case Reports Case 1 W.C., a 23-year-old woman with systemic lupus erythematosus and active arthritis, carditis, and cerebritis, but no nephritis, had been hospitalized on four occasions for control of her disease in the year preceding the diagnosis of iron deficiency. No source of excessive blood loss was identified. However, each hospitalization had been lengthy, and diagnostic phlebotomy was estimated at 2,400 ml during this period. Hemoglobin values had been 9 to 10 gmI100
Table 2. Diagnoses on Patients in the Series
Diagnoses
Number of Cases
Peptic ulcer disease Duodenal ulcer-5* Marginal ulcer-3 Gastric ulcer-2 Menometrorrhagia** Carcinoma colon Regional enteritis Ulcerative colitis Hiatal hernia Gastric polyposis Osler-Rendu-Weber disease Scleroderma with malabsorption Gingivitis, severe Nosocomial phlebotomy Total
10
5 5 2 1 1 1 1 1 1 1 30
*Jehovah's Witness-2 cases **Autoimmune thrombocytopenia-3 cases
ml and approximately 900 mg of iron had been lost through phlebotomy. At the time of treatment, hemoglobin was 7.0 gm/100 ml, hematocrit 24 percent, and reticulocyte count 0.6 percent. The bone marrow revealed erythroid hyperplasia and absent iron stores. She received 1,000 mg of iron by infusion, and the hematologic values were essentially unchanged at day 30. Six months later she had entered a remission on steroid therapy, and the hemoglobin was 13 gm/100 ml. Comment: in this case the dynamics of the anemia of chronic inflammatory disease appeared to be dominant. Despite hypochromic anemia and iron deficiency, the iron was apparently sequestered by the reticuloendothelial system after metabolism of the irondextran complex and was not made available for hemoglobin synthesis until six months later with remission of the active inflammatory process. Massive bleeding requiring transfusion therapy occurred shortly after iron-dextran infusion in eleven cases so that response could not be evaluated. The remaining 18 patients were divided into four groups based on pretreatment hemoglobin levels. Those with hemoglobins less than 7.0 gm/100 ml were placed in groupA, those with hemoglobins 7.0 to 8.5 gm/100 ml in group B, group C for hemoglobins 8.5 to 10.0 gm/100 ml, and group D for hemoglobins greater than 10 gm/100 ml. The results of therapy are summarized in Table 3 and plotted in Figure 1.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
The response to therapy in patients with severe anemia (group A) was extremely rapid despite continued bleeding in two cases. The mean hemoglobin (Figure 1) rose from 5.3 gm/100 ml to 11.0 gm/100 ml in 32 days, an average rise of 0.18 gm/100 ml/day. The hemoglobin rose at the highest rate during the first 15 days after therapy, and the highest reticulocyte count was seen in this group. Response was complete in these patients within five to seven weeks after infusion. Initial responses were spectacular in most instances, as seen in the following examples.
Case 2 D.D., a 19-year-old woman with menometrorrhagia and autoimmune thrombocytopenia, had a hemoglobin of 5.7 gm/100 ml and a platelet count of 3000 Al. After iron-dextran infusion of 2,100 mg of iron, the hemoglobin was 7.8 gm/100 ml on day 7 and 11.1 gm/100 ml on day 15.
Case 3 O.E., a 33-year-old woman with a long history of menometrorrhagia, was at 36 weeks gestation. Her hemoglobin was 4.5 gm/100 ml, and it rose to 6.8 gm/100 ml at day 7 and 10.0 gm/100 ml at day 15 after infusion of 1,500 mg of iron.
Case 4 S.F., a 33-year-old woman with duodenal ulcer, refused transfusion be1103
Table 3. Results of Intravenous Infusion of Iron-Dextran
A B C D
Number of Patients
Pre-treatment Hemoglobin mean
7 6 3 2
5.3 7.4 9.2 10.9
(gm/100 ml) range 4.5 7.08.9 10.5 -
6.1 7.8 9.3 11.3
Mean Rate of Rise in Hemoglobin (gm/100 ml/day) Day 0-7 8-15 16-30 0-30 0.33 0.19 0.15 ND
0.26 0.15 ND 0.08
0.08 0.08 0.08 0.08
0.18 0.12 0.10 0.08
Peak Reticulocyte Count*
Response Completed (Weeks)
7 % 6 % 4 %
7 9 9 8
3.5%
ND-Not done
*--Corrected for anemia17 cause of religious reasons. Her hemoglobin was 4.5 gm/100 ml before treatment with 2,500 mg of iron and it rose to 6.0 gm/100 ml at day 7 and 9.1 at day 15. The response to therapy in patients with less severe anemia (group B) was not as rapid as that in group A despite a similar mean reticulocyte count at the peak of response (Table 3), and response was not complete until nine weeks in this group. The mean hemoglobin rose from 7.4 gm/100 ml to 11.7 gm/100 ml in 35 days, an average rise of 0.12 gm/100 ml/day. One case from this group illustrates the efficiency of intravenous therapy in continued heavy blood loss.
Case 5 G.G., a 41-year-old man with chronic bleeding from duodenal ulcer disease, refused surgery and had a hemoglobin between 6 and 8 gm/100 ml despite ten doses of 200 mg of iron-dextran given intramuscularly at weekly intervals. After infusion of 2,000 mg of iron-dextran, the hemoglobin rose from 7.2 gm/100 ml to 8.5 at day 15, and 12 at day 35. Patients with milder degrees of anemia (groups C and D) had lower reticulocyte responses and response rates. In group C the mean hemoglobin rose from 9.2 gm/100 ml to 12.3 gm/100 ml in 32 days, an average rise of 0.1 gm/100 ml/day. In group D the mean hemoglobin rose from 10.9 gm/100 mg/ day to 13.3 gm/100 in 29 days, an average rise of 0.08 gm/100 ml/day. In groups A, B, and C the rate of response was higher in the first 15 days and declined during the second 15 days, whereas the response in group D was linear throughout. As hemoglobin levels reached 9.5 to 10 gm/100 ml in those with more severe anemia, the response rate paralleled that in Group D. 1104
One case from group C illustrates the importance of repeated searches for the source of blood loss.
Case 6 A.V., a 77-year-old man with persistent stool blood loss, had a hemoglobin of 9.3 gm/100 ml. Intravenous iron-dextran was recommended so that melena would not be masked by oral iron, and he was treated with an 1,800 mg infusion. The hemoglobin rose to 12.5 gm/100 ml at day 30. Radiological examination of upper and lower gastrointestinal tracts was normal. Stools remained positive for occult blood, and barium meals were repeated two and four months later and were again unrevealing. On the fourth try, barium enema revealed a small cecal mass which was found to be an adenocarcinoma at surgery.
Discussion The response to iron replacement depends upon the capacity of the bone marrow to produce cells, the degree of erythropoietin stimulation, and the amount of iron available for hemoglobin synthesis. The erythroid mass in iron deficient anemia is increased18 as is the erythropoietin level,13 and these are related to the severity and duration of the anemia. Thus the major variable in regulating response is the amount of iron supplied to developing erythroblasts in the marrow.'3 When the marrow is saturated with iron, hemolglobin synthesis will proceed at its maximum, but if the marrow is only partially supplied with iron, hemoglobin synthesis will be proportionately less than maximum. The fastest response will be seen with that therapy which supplies sufficient iron to allow the
marrow to proceed at or near its maximum capacity. Cope and associates15 compared the response after treatment with approximately equivalent amounts of oral, intramuscular, and intravenous iron and concluded that these methods of therapy were equally effective and that the response after parenteral therapy was often, but not consistently, faster than the response after oral therapy. McCurdy16 compared oral with intramuscular iron in a small group of patients and concluded that there was no significant difference in response rate. This study has been widely accepted as evidence against a faster response after parenteral therapy.4 In this study, the packed cell volume (PCV) was measured to quantitate the response to therapy. This value is a less than optimal way to evaluate hypochromic anemia.19 In addition, three of the patients treated parenterally had thalassemia trait, a disorder which is intrinsically hypochromic and in which a PCV rise may not accurately reflect response to iron replacement. Pritchard20'21 studied this problem in hospitalized women with iron deficient anemia due to benign gynecological disease and measured red cell mass to quantitate response. During the period of study, uterine bleeding was controlled with estrogen therapy, and those with thalassemia trait were excluded from the study group. In these elegant studies, Pritchard found that intramuscular iron was only slightly more rapid than oral (P=.02) whereas intravenous therapy was significantly more rapid than oral (P
Administration of oral ferrous salts is the preferred method of treatment for anemia due to iron deficiency. However, in certain clinical situations, the response to oral therapy may be suboptimal. Parenteral iron therapy is effective in these instances and may produce a faster response than the oral route. Of 30 patients treated by total dose intravenous infusion of irondextran, a prompt reticulocytosis occurred in all patients except one case associated with systemic lupus erythematosus. Hematologic improvement in this case followed remission of the systemic lupus erythematosus. Hematologic response was complete in 18 patients in five to nine weeks, but could not be evaluated in 11 cases because of recurrent bleeding. There were two adverse reactions: generalized pruritus after injection in one patient, and superficial thrombophlebitis at the injection site of another. The response to therapy in iron deficient anemia is dependent on bone marrow capacity, the severity of the anemia, and the availability of iron. Response was fastest in those who had been severely anemic for prolonged periods of time. Total dose infusion with iron-dextran is a safe and effective treatment for iron deficient anemia in selected cases. Initial response appears to be faster than that on oral therapy with the exception of those with a mild degree of anemia. Introduction The therapeutic objectives in the management of iron deficient anemia are twofold. First and most important is identification and correction of the underlying cause. Since iron deficient anemia is always the consequence of negative iron balance, usually from excessive blood loss, correction of the lesion responsible for iron loss is the most important consideration in the overall health needs of the patient. The second goal is correction of the anemia and replacement of iron stores. Proper management of both of these goals will reduce the frequency of recurrent From the Los Angeles County-University of Southern California Medical Center, Los Angeles, California. Supported in part by Grant No. HL15162 from the National Institutes of Health. Presented at the 82nd Annual Meeting of the National Medical Association, Los Angeles, California, July 31-August 4, 1977. Requests for reprints should be addressed to Dr. Cage S. Johnson, RMR 304, University of Southern California, 2025 Zonal Avenue, Los Angeles, CA 90033.
anemia. Oral administration of ferrous salts is a well tolerated and effective therapy for this anemia. On the usual daily dose of three tablets, which contain 150 to 200 mg of elemental iron, the hemoglobin level should return to normal in eight weeks.I However, repletion of iron stores necessitates continuing therapy for 6 to 12 months thereaf-
ter.2'3 Therapeutic failure on oral iron should prompt a reassessment of the clinical situation to affirm that iron deficiency is truly the cause of the anemia and that one of the other hypochromic anemias (the anemias associated with chronic disease, thalassemia minor, or the sideroblastic anemias) is not present. True failure to re6pond to oral iron is unusual. Active infection or chronic inflammatory disease such as rheumatoid arthritis or systemic lupus erythematosus may blunt the response because of faulty iron utilization. Gastric resection or malabsorption syndromes may prevent adequate iron
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
absorption. In disorders such as hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), blood may be lost in greater quantities than oral iron can replace. Prolonged release formulations result in release of iron in the lower gastrointestinal tract, whereas iron absorption is maximal in the upper tract; the use of these compounds may lead to less effective absorption.4 However, therapeutic failures are most often the result of misdiagnosis, inadequate therapy, or noncompliance. Patient compliance is a major obstacle to the satisfactory treatment of iron deficiency. Studies of this problem4,5 clearly indicate that true intestinal intolerance occurs in less than ten percent of individuals and that psychologic factors are mainly responsible for noncompliance. Lowering the dose effectively deals with intolerance but results in submaximal response. Because of these problems, attempts to find a suitable parenteral preparation for iron therapy have been ongoing since the late 19th century. Early preparations were unsatisfactory because these agents were unstable and caused a high frequency of toxic reactions due to release of free ionized iron into the plasma. Furthermore, the dose that could be administered was limited, requiring multiple injections to complete a course of therapy. In addition, there was high loss of the dose in the urine and this limited efficacy. With the introduction of iron-dextran in the 1950s, many of these problems were overcome.4
Pharmacology Iron-dextran4f6i7 is a complex of a high molecular weight dextran fraction with Fe(OH)3. The commercial preparation is a dark brown solution containing 50 mg of elemental iron per ml. The complex is highly stable in blood, has a very low toxicity (the LD50 is greater than 1000 mg/kg in mice), and can be administered by either intramuscular or intravenous routes. After intramuscular injection, 1101
Table 1. Calculation of Iron Dose A. Iron deficit (mg) = Hb deficit (gm) x 3.4 mg iron per gm Hb + iron stores B. Hb deficit (gm) = rbc deficit (dl) x the normal MCHC (gm/dl) .. normal Hb - observed Hb normal Hb C. RBC deficit (dl) = x normal rbc volume D. Arbitrary normal values 1. rbc volume = 0.35 dl per kg body weight 2. MCHC = 33 gm/dl 3. Iron stores = 15 mg per kg 4. Normal Hb = 15 gm/di E. Substituting B and C into A yields the equation Hb - Qbserved Hb x Iron deficit = normal normal rbc volume x normal MCHC normal Hb F. Substituting D into E yields
x
3.4 mg iron per gm Hb + iron stores
Iron deficit =1515 x 0.35 x kg x 33 x 3.4 + 15 x kg G. Condensation of the equation in F yields Iron deficit in mg = 2.6 x kg x (15 - Hb) + 15 x kg Hb = Hemoglobin rbc = red blood cell
50 percent of the dose is absorbed in 72 hours and the remainder over a variable period; some of the dose may remain at the ipjection site permanently. Skin staining due to residual iron and melanin deposition may occur. When given by vein, the complex circulates intact and little free iron is released which explains the low frequency of toxic reactions. In either case, the serum iron reaches very high levels. The serum is colored brown by the complex, which may interfere with bilirubin and calcium determinations, but not with other laboratory tests. The complex is slowly cleared from the plasma over three to four weeks and ultimately utilized for hemoglobin synthesis. Local and systemic reactions to iron-dextran occur after either parenteral route, but are generally mild and usually respond to supportive measures.6 Anaphylaxis has been responsible for six deaths 4,8-10 after both intramuscular and intravenous use, but the risk seems small in view of the many millions of doses given in the past 25 years. Sarcoma occurs at intramuscular injection sites in animals, and has been increasingly reported in humans."1 Intravenous iron-dextran has the advantages of avoiding discomfort, skin staining, and erratic absorption from intramuscular sites, and it can be used in patients with thrombocytopenia, coagulation disorders, and in those on anticoagulant therapy where intramuscular injections are contraindicated. With the introduction 1102
of total dose infusion by ]3asu for the treatment of iron deficient anemia in the late stages of pregnancy,7"2 it became possible to deliver the total dose of iron calculated to replenish both hemoglobin levels and iron stores at one sitting. With this method, Basu was able to obviate the risks of transfusion in his patients and, further, noted a rapid response. The ability of parenteral iron therapy to produce a faster response than oral iron has been confirmed by some studies, 13"14 but denied by others.'a"6 This unsettled controversy and a rapid response in a patient who refused transfusion for religious reasons prompted a reassessment of the response to intravenous iron-dextran.
Materials and Methods Hospitalized patients at the Los Angeles County-University of Southern California Medical Center, with the diagnosis of iron deficie,nt anemia manifested by typical hypochromic microcytic anemia and confirmed by low serum iron, elevated iron binding capacity, an'd saturation less than 12 percent or by absent bone marrow iron stores, were considered for intravenous iron-dextran if they met one of the following criteria: 1. Therapeutic failure on adequate doses of oral iron due to continuing heavy blood loss 2. Recent acute blood loss with stable cardiovascular function that might require transfusion with any further bleeding
3. Refusal of transfusion due to religious preferences 4. Chronic gastrointestinal disease that might be aggravated by oral iron 5. Severe thrombocytopenia since constipation may follow oral therapy with straining at defecation. The consequent increase in cerebrospinal fluid pressure may increase the risk of intracranial bleeding 6. Repeated noncompliance 7. Malabsorption syndromes The iron dose for each patient was calculated (Table 1) by estimation of the red blood cell mass deficit and conversion of that deficit into grams of hemoglobin and then into milligrams of iron using the value of 3.4 mg of iron per gram of hemoglobin which is derived from the molecular weights of iron and hemoglobin. The normal values used in this calculation were arbitrarily selected from the range of values in standard hem,atologic texts. This calculation gives higher doses than that supplied by the manufacturer because of the higher iron store factor used, but either is acceptable. The dose of iron-dextran calculated for each patient was rounded off to the nearest 0.1 gm for ease of administration and given by intravenous infusion according to a modification of the method of Wallerstein.f An intravenous line was placed to provide vascular access in case of an anaphylactic reaction. A test dose of 0.5 ml (25 mg) of the complex was diluted with 9.5 ml of normal saline and injected through the intravenous tubing over two minutes. The patients
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
were observed for 15 nlinutes after the test dose, and, if no reaction occurred, the remainder of the dose was diluted in 200 ml of normal saline and infused at a rate no faster than 50 mg of iron per minute. The entire procedure was completed within 75 minutes in all cases. Vital signs were monitored at 15minute intervals throughout the procedure. Hemoglobin and reticulocyte counts17 were measured immediately before the infusion and daily thereafter until reticulocyte counts doubled over base line. The values were repeated at approximately seven, 15, and 30 days after infusion and at monthly intervals until response was complete. Thirty patients aged 19 to 72 were treated by this method. There were six males and 24 females. The dose of iron-dextran varied from 800 to 2,500 mg of iron. The diagnoses in these patients are given in Table 2.
Results The infusion of iron-dextran was completed in all patients without incident. There were only two adverse reactions; one patient developed generalized pruritus without rash 24 hours after the infusion, and one patient developed superficial thrombophlebitis at the intravenous site. Both responded to supportive therapy. In 29 (97 percent) of the patients the response to intravenous iron was immediate as seen by doubling of the reticulocyte count over base line within 48 hours of the infusion followed by a rise in the hemoglobin level of 0.5 to 2.4 gm/100 ml by day 7. One patient with active inflammatory disease and iron deficiency had a delayed response to iron-dextran.
Case Reports Case 1 W.C., a 23-year-old woman with systemic lupus erythematosus and active arthritis, carditis, and cerebritis, but no nephritis, had been hospitalized on four occasions for control of her disease in the year preceding the diagnosis of iron deficiency. No source of excessive blood loss was identified. However, each hospitalization had been lengthy, and diagnostic phlebotomy was estimated at 2,400 ml during this period. Hemoglobin values had been 9 to 10 gmI100
Table 2. Diagnoses on Patients in the Series
Diagnoses
Number of Cases
Peptic ulcer disease Duodenal ulcer-5* Marginal ulcer-3 Gastric ulcer-2 Menometrorrhagia** Carcinoma colon Regional enteritis Ulcerative colitis Hiatal hernia Gastric polyposis Osler-Rendu-Weber disease Scleroderma with malabsorption Gingivitis, severe Nosocomial phlebotomy Total
10
5 5 2 1 1 1 1 1 1 1 30
*Jehovah's Witness-2 cases **Autoimmune thrombocytopenia-3 cases
ml and approximately 900 mg of iron had been lost through phlebotomy. At the time of treatment, hemoglobin was 7.0 gm/100 ml, hematocrit 24 percent, and reticulocyte count 0.6 percent. The bone marrow revealed erythroid hyperplasia and absent iron stores. She received 1,000 mg of iron by infusion, and the hematologic values were essentially unchanged at day 30. Six months later she had entered a remission on steroid therapy, and the hemoglobin was 13 gm/100 ml. Comment: in this case the dynamics of the anemia of chronic inflammatory disease appeared to be dominant. Despite hypochromic anemia and iron deficiency, the iron was apparently sequestered by the reticuloendothelial system after metabolism of the irondextran complex and was not made available for hemoglobin synthesis until six months later with remission of the active inflammatory process. Massive bleeding requiring transfusion therapy occurred shortly after iron-dextran infusion in eleven cases so that response could not be evaluated. The remaining 18 patients were divided into four groups based on pretreatment hemoglobin levels. Those with hemoglobins less than 7.0 gm/100 ml were placed in groupA, those with hemoglobins 7.0 to 8.5 gm/100 ml in group B, group C for hemoglobins 8.5 to 10.0 gm/100 ml, and group D for hemoglobins greater than 10 gm/100 ml. The results of therapy are summarized in Table 3 and plotted in Figure 1.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 71, NO. 11, 1979
The response to therapy in patients with severe anemia (group A) was extremely rapid despite continued bleeding in two cases. The mean hemoglobin (Figure 1) rose from 5.3 gm/100 ml to 11.0 gm/100 ml in 32 days, an average rise of 0.18 gm/100 ml/day. The hemoglobin rose at the highest rate during the first 15 days after therapy, and the highest reticulocyte count was seen in this group. Response was complete in these patients within five to seven weeks after infusion. Initial responses were spectacular in most instances, as seen in the following examples.
Case 2 D.D., a 19-year-old woman with menometrorrhagia and autoimmune thrombocytopenia, had a hemoglobin of 5.7 gm/100 ml and a platelet count of 3000 Al. After iron-dextran infusion of 2,100 mg of iron, the hemoglobin was 7.8 gm/100 ml on day 7 and 11.1 gm/100 ml on day 15.
Case 3 O.E., a 33-year-old woman with a long history of menometrorrhagia, was at 36 weeks gestation. Her hemoglobin was 4.5 gm/100 ml, and it rose to 6.8 gm/100 ml at day 7 and 10.0 gm/100 ml at day 15 after infusion of 1,500 mg of iron.
Case 4 S.F., a 33-year-old woman with duodenal ulcer, refused transfusion be1103
Table 3. Results of Intravenous Infusion of Iron-Dextran
A B C D
Number of Patients
Pre-treatment Hemoglobin mean
7 6 3 2
5.3 7.4 9.2 10.9
(gm/100 ml) range 4.5 7.08.9 10.5 -
6.1 7.8 9.3 11.3
Mean Rate of Rise in Hemoglobin (gm/100 ml/day) Day 0-7 8-15 16-30 0-30 0.33 0.19 0.15 ND
0.26 0.15 ND 0.08
0.08 0.08 0.08 0.08
0.18 0.12 0.10 0.08
Peak Reticulocyte Count*
Response Completed (Weeks)
7 % 6 % 4 %
7 9 9 8
3.5%
ND-Not done
*--Corrected for anemia17 cause of religious reasons. Her hemoglobin was 4.5 gm/100 ml before treatment with 2,500 mg of iron and it rose to 6.0 gm/100 ml at day 7 and 9.1 at day 15. The response to therapy in patients with less severe anemia (group B) was not as rapid as that in group A despite a similar mean reticulocyte count at the peak of response (Table 3), and response was not complete until nine weeks in this group. The mean hemoglobin rose from 7.4 gm/100 ml to 11.7 gm/100 ml in 35 days, an average rise of 0.12 gm/100 ml/day. One case from this group illustrates the efficiency of intravenous therapy in continued heavy blood loss.
Case 5 G.G., a 41-year-old man with chronic bleeding from duodenal ulcer disease, refused surgery and had a hemoglobin between 6 and 8 gm/100 ml despite ten doses of 200 mg of iron-dextran given intramuscularly at weekly intervals. After infusion of 2,000 mg of iron-dextran, the hemoglobin rose from 7.2 gm/100 ml to 8.5 at day 15, and 12 at day 35. Patients with milder degrees of anemia (groups C and D) had lower reticulocyte responses and response rates. In group C the mean hemoglobin rose from 9.2 gm/100 ml to 12.3 gm/100 ml in 32 days, an average rise of 0.1 gm/100 ml/day. In group D the mean hemoglobin rose from 10.9 gm/100 mg/ day to 13.3 gm/100 in 29 days, an average rise of 0.08 gm/100 ml/day. In groups A, B, and C the rate of response was higher in the first 15 days and declined during the second 15 days, whereas the response in group D was linear throughout. As hemoglobin levels reached 9.5 to 10 gm/100 ml in those with more severe anemia, the response rate paralleled that in Group D. 1104
One case from group C illustrates the importance of repeated searches for the source of blood loss.
Case 6 A.V., a 77-year-old man with persistent stool blood loss, had a hemoglobin of 9.3 gm/100 ml. Intravenous iron-dextran was recommended so that melena would not be masked by oral iron, and he was treated with an 1,800 mg infusion. The hemoglobin rose to 12.5 gm/100 ml at day 30. Radiological examination of upper and lower gastrointestinal tracts was normal. Stools remained positive for occult blood, and barium meals were repeated two and four months later and were again unrevealing. On the fourth try, barium enema revealed a small cecal mass which was found to be an adenocarcinoma at surgery.
Discussion The response to iron replacement depends upon the capacity of the bone marrow to produce cells, the degree of erythropoietin stimulation, and the amount of iron available for hemoglobin synthesis. The erythroid mass in iron deficient anemia is increased18 as is the erythropoietin level,13 and these are related to the severity and duration of the anemia. Thus the major variable in regulating response is the amount of iron supplied to developing erythroblasts in the marrow.'3 When the marrow is saturated with iron, hemolglobin synthesis will proceed at its maximum, but if the marrow is only partially supplied with iron, hemoglobin synthesis will be proportionately less than maximum. The fastest response will be seen with that therapy which supplies sufficient iron to allow the
marrow to proceed at or near its maximum capacity. Cope and associates15 compared the response after treatment with approximately equivalent amounts of oral, intramuscular, and intravenous iron and concluded that these methods of therapy were equally effective and that the response after parenteral therapy was often, but not consistently, faster than the response after oral therapy. McCurdy16 compared oral with intramuscular iron in a small group of patients and concluded that there was no significant difference in response rate. This study has been widely accepted as evidence against a faster response after parenteral therapy.4 In this study, the packed cell volume (PCV) was measured to quantitate the response to therapy. This value is a less than optimal way to evaluate hypochromic anemia.19 In addition, three of the patients treated parenterally had thalassemia trait, a disorder which is intrinsically hypochromic and in which a PCV rise may not accurately reflect response to iron replacement. Pritchard20'21 studied this problem in hospitalized women with iron deficient anemia due to benign gynecological disease and measured red cell mass to quantitate response. During the period of study, uterine bleeding was controlled with estrogen therapy, and those with thalassemia trait were excluded from the study group. In these elegant studies, Pritchard found that intramuscular iron was only slightly more rapid than oral (P=.02) whereas intravenous therapy was significantly more rapid than oral (P
