Intravenous Iron Dextran in Clinical Medicine
`
`Roger D. Hamstra, MD; Matthew H. Block, PhD, MD; Alan L. Schocket, MD
`
`Four hundred seventy-one adult patients and ten adult prisoner
`injections of
`volunteers received 2,099 intravenous (IV)
`iron dextran
`(Imferon), usually 250 to 500 mg at less than 100 mg/min. Intravenous iron
`supplies enough iron to permit RBC formation greater than 50 mL/day and
`repletion of tissue iron. Tissue iron did not always supply iron at an optimal
`rate. Hemoglobin production was higher after IV than oral or intramuscular
`iron if the hemoglobin level was less than 9 g/dL. Three life-threatening
`immediate anaphylactoid and eight severe delayed reactions were observed.
`There were no deaths. Delayed reactions were more frequent in women and
`collagen-vascular diseases and less frequent in pregnancy. Because anaphy-
`lactoid reactions are serious and unpredictable, IV iron dextran should be
`used only when iron deficiency anemia cannot be treated adequately with
`oral iron.
`(JAMA 243:1726-1731, 1980)
`
`PARENTERAL iron therapy is a
`therapeutic option in the treatment of
`iron deficiency anemia. Both dextri-
`ferron and iron dextran have been
`given intravenously (IV) with accept¬
`able patient tolerance and hemoglo¬
`In the United States,
`bin response.
`because of fear of adverse reactions,
`extensive experience in the use of IV
`iron has not been reported. This
`report relates our experience with IV
`iron dextran therapy from January
`1962 to January 1970. During this
`period, 293 patients from a general
`hospital population (Colorado Gener¬
`al Hospital, Denver), 178 patients
`from a thoracic surgical service (Na¬
`tional Jewish Hospital, Denver), plus
`ten prisoner volunteers were treated
`with IV iron dextran (Table 1).' The
`patients and prisoner volunteers were
`given a total of 2,099 injections (Table
`2). The latter were intensively studied
`response to phleboto¬
`during their
`my." No patient was admitted to the
`study after January 1970, and the
`study was terminated in January
`1975.
`
`From the Divisions of Hematology (Drs Hamstra
`Immunology (Dr Schock-
`and Block) and Clinical
`et), University of Colorado Health Science Center,
`Denver.
`Reprints not available.
`
`PATIENTS AND METHODS
`iron deficiency was
`The diagnosis of
`established by assessment of
`(1) blood
`(2) mean corpuscular hemoglobin
`loss;
`concentration, mean corpuscular volume,
`and RBC morphology; and (3) measure¬
`ment of plasma and bone marrow iron
`levels. Blood loss in patients was substan¬
`tiated by a history of hematemesis, hema-
`turia, melena, menorrhagia, and frequent
`stool examination for occult blood by the
`guaiac reaction, and in prisoners by phle¬
`botomy and almost daily testing of stools
`for occult blood, also by the guaiac meth¬
`od.
`
`Patient Population
`Forty-two percent of the patients were
`on the medical service, with 68% being
`inpatients (Table 1). Four percent of the
`patients had obstetrical or gynecological
`problems, the majority prepartum or post-
`partum. Forty-one percent of the patients
`
`Table 1.
`
`Source of Patients
`
`—
`
`Medicine
`General surgery
`Autotransfusion
`Obstetrics
`Gynecology
`Pediatrics
`Other
`Prisoners
`Total
`
`In-
`patients
`130
`25
`178
`27
`12
`1
`3
`10
`386
`
`Out¬
`patients
`64
`1
`0
`19
`9
`1
`1
`0
`95
`
`the majority
`were subjected to surgery,
`having cardiac surgery with autotransfu¬
`sion' at National Jewish Hospital. Based
`on prior experience at Colorado General
`Hospital, all patients at National Jewish
`Hospital with even a suspicious personal
`family history of a drug reaction,
`or
`allergic rash, or rheumatoid arthritis were
`excluded from the IV iron dextran auto-
`transfusion program. The small number of
`general surgical patients is partly attrib¬
`utable to admission at Colorado General
`Hospital of patients bleeding from the
`gastrointestinal tract to the medical ser¬
`vice with subsequent transfer to the surgi¬
`cal service when workup was complete and
`the patient's condition was stable. In addi¬
`tion, there were ten prisoners who volun¬
`teered for studies in which erythropoietic
`response to chronic1 and acute' blood loss
`was measured while iron stores, but not
`necessarily iron availability, were main¬
`tained with IV iron dextran.
`
`Injection Schedules
`inpa-
`At Colorado General Hospital,
`tients were usually injected daily and
`outpatients once or twice weekly. Auto-
`transfused patients at National Jewish
`Hospital were injected immediately after
`each phlebotomy one to four times in the
`ten days preceding surgery.' Prisoners in
`the chronic blood loss experiment were
`injected one to five times weekly.
`Each injection usually contained 250 or
`500 mg because the drug was supplied in
`ampules containing these amounts and
`because variations of 100 mg per injection
`did not influence reaction rate or erythro¬
`poietic response (Table 2). The initial
`injection varied from 2.5 to 500 mg; if well
`
`Table 2.—Intravenous Iron
`Dextran Injections
`
`Iron Content
`per Injection, mg
`<100
`100-249
`250
`251-499
`500
`501-999
`1,000
`>1,000
`Total
`
`No. of
`Injections
`28
`176
`1,046
`34
`775
`11
`16
`13
`2,099
`
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`
`Pharmacosmos, Exh. 1008, p. 1
`
`

`

`Table 3.—Intravenous Iron
`Dextran Therapy
`
`Total Amount of
`Iron Given, mg
`2.5-499
`500-999
`1,000-1,499
`1,500-1,999
`2,000-2,499
`2,500-2,999
`3,000-3,499
`3,500-3,999
`4,000-4,999
`5,000-9,999
`10,000-15,000
`> 15,000
`Total
`
`No. of
`Patients
`78
`158
`50
`61
`63
`27
`15
`4
`10
`7
`6
`2
`481
`
`tolerated, subsequent injections contained
`250 to 500 mg. Twenty-three patients,
`however, received their entire dose (1.0 to
`2.5 g) in one injection. Ten of the 23 were
`given the iron dextran diluted in 5%
`dextrose (5% v/v) at 100 to 400 mL/hr (250
`to 1,000 mg/hr). The other 13 received the
`undiluted drug at
`1
`to 5 mL/min. The
`autotransfused patients were given 250 mg
`of iron dextran, usually diluted in 250 mL
`of 5% dextrose in water or
`in normal
`to 30-minute period
`saline over a 20-
`immediately after each phlebotomy.1
`Prisoners subjected to chronic phleboto¬
`my were given 1.25 mg of iron for each
`milliliter of RBCs phlebotomized; the iron
`dextran was injected within three to five
`minutes through the phlebotomy tube im¬
`mediately after each phlebotomy.2 Pris¬
`oners subjected to a single erythropheresis
`received 1.5 mg of undiluted iron dextran
`per milliliter of RBCs that had undergone
`erythropheresis in one bolus by syringe
`within 20 minutes.1 One prisoner
`inad¬
`vertently was injected with 20 mL of
`undiluted iron dextran in the left brachial
`artery.
`The total amount of iron injected varied
`from 2.5 mg to 29 g (Table 3). Patients
`usually received 1.5 to 3.0 g to correct
`anemia, including 1.0 g to replenish tissue
`stores of iron. The largest amounts were
`given to treat chronic uncorrectable blood
`loss, one patient receiving 29 g of
`iron.
`Autotransfused patients received 250 mg
`for each of one to five 500-mL units of
`blood phlebotomized.1 The prisoners sub¬
`jected to chronic phlebotomy received up
`to a total of 12.8 g, and those subjected to a
`single erythropheresis received up to 3.0 g
`or iron.
`
`Evaluation
`of Erythropoietic Response
`Evaluation of erythropoietic response to
`iron therapy requires measurement of the
`amount and duration of RBC loss and
`calculation of the rate of RBC production.
`To avoid inaccuracy in measurement of
`amount and duration of blood loss and
`possibly in calculation of rate of erythro-
`poiesis from increments of grams per
`deciliters per day, we report the rate of
`
`Table 4. —Rate of RBC Synthesis
`in Response to Phlebotomy and
`Intravenous Iron Dextran
`
`Increment
`RBCs,
`Above
`mL/Day Normal
`
`19*
`
`68-93
`
`3.6-4.9X
`
`Normal adult
`(70-kg man)
`Chronic phlebotomy
`in prisonerst
`Acute phlebotomy
`in prisonerst
`•Wintrobe.'
`tCorrected to that of 70-kg man."
`
`48-67
`
`2.5-3.5X
`
`RBC production only in prisoners (Table
`investigations on long-term
`4).
`In our
`phlebotomies in prisoners, stools were
`checked two to five times per week for
`occult blood loss by the guaiac technique
`and blood loss from phlebotomies was
`measured.2 Under the conditions of this
`experiment,
`the rate of RBC production
`was equal to the amount of RBCs removed
`by phlebotomy once the prisoners were
`proved by blood volume studies to be in a
`steady state.2 The rate of response to a
`single phlebotomy of one half
`to two
`thirds of the RBC volume was estimated
`from the increment in RBC volume.3 Actu¬
`ally, measurement of RBC production by
`increment in grams per deciliter per day
`yielded results similar to those we and
`others obtained by the more difficult mea¬
`surement of increments in RBC volume.
`
`Evaluation of Reactions
`Reactions to IV iron were evaluated
`personally through daily visits to patients
`hospitalized at the University of Colorado
`Medical Center. All patients treated at
`National Jewish Hospital were inpatients
`on a chest surgical service and were seen
`daily. Outpatients were seen at least week¬
`ly and close telephone contact was main¬
`tained, the patients having our office and
`home telephone numbers.
`Reactions were classified as localized or
`systemic (Table 5). Localized reactions
`were manifested by pain in the vein
`injected and by flushing, warmth, and a
`metallic taste associated with injection
`rates greater than 100 mg/min. Symptoms
`lasted less than one minute and were
`alleviated by slowing or stopping the
`injections for less than one minute. These
`injections were completed without further
`difficulty, and symptoms did not interfere
`with ordinary activity.
`Systemic reactions were subclassified as
`immediate or delayed (Table 5). Immedi¬
`ate reactions occurred within five minutes
`of injection;
`they were further classified
`as (1) life-threatening anaphylactoid reac¬
`tions characterized by hypotension, syn¬
`cope, purpura, wheezing, dyspnea, respira¬
`tory arrest, and cyanosis, lasting up to one
`hour and occurring only after the first
`
`Table 5.
`
`Reactions to Intravenous
`Iron Dextran
`
`—
`
`No reaction
`Reaction
`Localized to vein or
`caused by too rapid in¬
`jection into vein
`Systemic
`Immediate
`Life-threatening
`Non-life-threatening
`Delayed
`Severe
`Moderate
`Mild
`
`No.(%) of
`Patients
`(N=481)
`356(74)
`125(26)
`
`72(15)
`53(11)
`15(3)
`3(0.6)
`12(2)
`38(8)
`6(1)
`16(3)
`16(3)
`No.(%)of
`Injections
`(N=2,099)
`1,824(87)
`275(13)
`
`No reaction
`Reaction
`Localized to vein or
`caused by too rapid in¬
`jection into vein
`Systemic
`Immediate
`Life-threatening
`Non-life-threatening
`Delayed
`Severe
`Moderate*
`Mild
`
`185(9)
`90(4)
`16(0.7)
`3(0.1)
`13(0.6)
`74 (4)
`8(0.4)
`44(2)
`22(1.0)
`•Ten reactions in one patient with rheumatoid
`arthritis, 13 reactions in one patient with rheuma¬
`toid arthritis, and eight reactions in one patient
`with lupus erythematosus.
`
`injection; and (2) non-life-threatening re¬
`actions characterized by mild,
`transient
`hypotension, malaise, itching, and urticar¬
`ia, lasting less than five minutes and not
`otherwise interfering with normal activi¬
`ty.
`Delayed
`systemic
`reactions
`started
`within four to 48 hours of injection and
`lasted three to seven days. They were char¬
`acterized by lymphadenopathy, myalgia,
`arthralgia, fever, and headache occurring
`singly or
`in combination. The delayed
`reactions were subclassified as mild (no¬
`ticeable, but not interfering with normal
`activity), moderate (limitation of ordinary
`activity, but not requiring bed rest), and
`severe (disabling and requiring bed rest).
`systemic
`All
`reactions classified as
`severe are described in detail in Table 6.
`
`Prisoners' Rights
`The rights of
`the prisoners were re¬
`spected in conformance with the Helsinki
`the World Health Orga¬
`Declaration of
`nization and the Nuremberg Code. Ap¬
`proval was also obtained from the gover¬
`nor, attorney general, and director of
`institutions of the State of Colorado, the
`warden and psychiatrist of the Colorado
`State Penitentiary, and the next of kin of
`each volunteer.
`
`RESULTS
`Rate of RBC Production
`The rates of RBC production in
`
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`Pharmacosmos, Exh. 1008, p. 2
`
`

`

`Table 6.—Severe Reactions to Iron Dextran Administration
`
`Diagnoses
`
`Dose of Iron
`Dextran, mg
`
`Reaction
`_._ Subsequent Iron
`Type
`Dextran Therapy
`Onset
`Duration
`
`Respiratory arrest, hypo-
`tension, purpura
`Hypotension, cyanosis,
`dyspnea
`Syncope, wheezing, hives
`(blood pressure not re-
`corded)
`
`Arthralgia
`Arthralgia
`Myalgia, arthralgia, ery-
`thema nodosum, fever
`Myalgia, arthralgia, fever,
`headache
`
`1 min
`
`1 min
`
`1 min
`
`8 hr
`48 hr
`48 hr
`
`24 hr
`
`48 hr
`
`...
`
`48 hr
`
`4 hr
`
`.
`
`.
`
`.
`
`1 hr
`
`1 hr
`
`3 days
`3 days
`5 days
`
`3 days
`
`4 days
`
`5 days
`
`4 days
`
`None
`
`None
`
`12 injections, 10-
`250 mg each,
`without reaction
`
`None
`None
`None
`
`Undiluted, 4 injec-
`tions, 500 mg
`each without
`reaction
`None
`
`500 mg weekly for
`5 wk
`None
`
`12 hr (wheezing)
`5 days (arthralgia)
`
`None
`
`8/29/M/54
`
`9/45/M/72
`
`10/24/F/52
`
`11/46/F/47
`
`Iron deficiency, bleeding pep- 500 undiluted for
`6 consecutive days
`tic ulcer
`Blood loss research (prisoner 500 undiluted weekly
`volunteer), varicose veins
`for 11 wk
`Iron deficiency, menorrhagia
`1,200 in 5% dextrose
`in water
`2,500 in 500 mL of
`dextrose in water
`
`Iron deficiency, gastrointesti-
`nal bleeding
`
`Myalgia, arthralgia, fever,
`adenopathy
`Thrombophlebitis, pulmo-
`nary embolus
`Myalgia, arthralgia, sore
`neck, fever
`Arthralgia, adenopathy,
`wheezing, fever
`
`Table 7.—Correlation of Incidence of Patient Reactions* With Other Factors
`
`No Reaction
`
`Reaction
`
`294
`82
`
`218
`158
`
`15
`418
`
`46
`
`110
`210
`
`43
`390
`
`1,129
`902
`
`78
`26
`
`78
`27
`
`10
`38
`
`19
`39
`
`2
`46
`
`41
`27
`
`>.05t
`
`x2 (1 df)
`
`0.3104
`
`9.2776
`
`23.0484
`
`4.2517
`
`<.05
`
`5.0933
`
`1.0814
`
`0.4152
`
`<.054:
`
`>.05t
`
`>.05t
`
`Age, yr
`<55
`>55
`Sex
`
`F M
`
`Collagen vascular disease
`Present
`Absent
`Pregnancy
`Present
`Absent
`<Age 45
`All ages
`Cancer
`Present
`Absent
`Dose,§ mg
`<251
`>251
`
`"Refers only to severe and moderate delayed reactions.
`tNot significant.
`^Correlation of pregnant to nonpregnant women of all ages.
`§Number of injections producing a reaction correlated with dose.
`
`6). Some patients had more than one
`reaction (Table 5). The incidence of
`severe reactions was associated with
`doses of more than 250 mg (especially
`in patients weighing less than 50 kg),
`and these were particularly common
`in patients with rheumatoid arthritis
`and other inflammatory disease (Ta¬
`bles 5 and 6). Table 7 correlates the
`number of patients who had reactions
`with age, sex, collagen vascular dis¬
`ease, pregnancy, cancer, and dose.
`Only one reaction, a potentially lethal
`anaphylactoid reaction in patient 1
`(Table 6), occurred in the 178 patients
`
`subjected to autotransfusion at Na¬
`tional Jewish Hospital, where all
`patients with a possible personal or
`family history of a drug reaction,
`allergic rash, or rheumatoid arthritis
`were excluded. Furthermore, at this
`hospital, each injection of
`IV iron
`dextran was given over a 20-
`to
`30-minute period in 250 mL of 5%
`dextrose or normal saline.
`Two hundred seventy-five (13%) of
`the injections caused a reaction, but
`only three (0.1%) were immediate
`life-threatening and 52 (2.7%) were
`delayed severe or moderate (Table 5).
`
`normal men" and in prisoners sub¬
`jected to a single phlebotomy of one
`half to two thirds of the circulating
`RBC mass3 are listed in Table 4. The
`rate of RBC production in the pris¬
`oners subjected to repeated phle¬
`botomies varied inversely with the
`hemoglobin level induced by the phle¬
`botomies.2 Maximum production was
`3.5 to 4.9 times normal at a hemoglo¬
`bin level of about 8 g/dL. The average
`rate of erythropoiesis was 2.5 to 3.5
`in prisoners subjected
`times normal
`to one massive phlebotomy, reducing
`hemoglobin concentration to 6 to 9
`g/dL. The RBC volume rose more
`rapidly four to seven days after phle¬
`botomy, when the prisoners were
`most anemic. A lower
`rate was
`achieved 9 to 25 days after phleboto¬
`my, when the hemoglobin concentra¬
`tion was closest to normal. When a
`hemoglobin level of about 8 g/dL was
`subsequently maintained for 20 days
`by repeated phlebotomy,
`these pris¬
`oners maintained the same rate of
`RBC production1 as those bled for 9 to
`23 weeks.2
`
`Reactions
`Three hundred fifty-six (74%) of
`the patients did not have a reaction.
`One hundred twenty-five (26%) expe¬
`rienced a reaction, but only 25 (5%)
`had reactions that limited or inhib¬
`ited ordinary activity. Three (0.6%) of
`these 25 patients had life-threatening
`anaphylactoid reactions (Tables 5 and
`
`Case/Age, yr
`Sex/Weight, kg
`Potentially lethal
`1/37/M/63
`
`2/38/F/45
`
`3/55/F/49
`
`2.5 in 5% glucose/
`Mitral stenosis due to rheu-
`Ringer's
`malic fever, autotransfusion
`Iron deficiency, ulcerative co- 200 undiluted
`litis
`Rheumatoid arthritis, iron defi- 10 undiluted
`ciency, previous gastrecto-
`my
`Not potentially lethal
`4/65/F/50
`Rheumatoid arthritis
`Lupus erythematosus
`5/60/F/54
`Iron deficiency (etiology un-
`6/39/F/47
`known)
`Blood loss research (prisoner 1,500 undiluted
`volunteer)
`
`200 undiluted
`500 undiluted
`500 undiluted
`
`7/27/M/59
`
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`Pharmacosmos, Exh. 1008, p. 3
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`

`

`One patient with rheumatoid arthri¬
`tis and one with lupus erythematosus
`accounted for two of the eight (0.3% )
`severe, not potentially lethal
`reac¬
`tions (Table 6); neither was retreated
`with iron dextran. Thirty-one of the
`44 moderate delayed reactions oc¬
`curred in two patients with rheuma¬
`toid arthritis and in one patient with
`lupus erythematosus (Table 5). These
`three patients requested that treat¬
`ment with IV iron dextran be contin¬
`ued because the benefit from treat¬
`ment of
`the anemia exceeded the
`transient discomfort from the reac¬
`tions. Doses of 50 mg did not cause a
`reaction in these three patients; doses
`of 100 mg caused arthralgia and
`myalgia that was not disabling; doses
`of 250 mg caused disabling pain for a
`day or two. When the first injection
`did not cause a reaction, subsequent
`injections of the same size and at the
`same or lower rate did not cause a
`reaction, provided the plasma had
`been cleared of iron dextran from the
`previous injection.
`Iron dextran is
`cleared with a half-life of about three
`days,5 making weekly intervals ac¬
`ceptable.
`Severe and moderate delayed reac¬
`tion (Tables 5 and 6), such as fever,
`arthralgia, myalgia, and adenopathy,
`did not necessarily preclude further
`injections. Indeed, we have observed
`that an injection early in the course
`caused an appreciably greater reac¬
`tion than the same-size injection giv¬
`en later in the course of treatment.
`We gave an iron dextran injection to
`one patient (No. 3) in whom hives had
`developed after a previous injection
`(Table 6). Another patient, not
`in¬
`cluded in Table 6, who had hives and
`itching with oral and intramuscular
`iron dextran, was subsequently suc¬
`cessfully treated IV with a series
`injections of
`of
`iron dextran, each
`preceded by injections of 50 mg
`of diphenhydramine hydrochloride
`(Benadryl) two or three minutes prior
`to each injection of iron dextran.
`A 47-year-old woman with rheumatic
`heart disease had well-established iron
`deficiency due to peptic ulcer disease and
`could not
`tolerate oral
`iron because of
`gastrointestinal distress, hives, pruritus,
`and tachycardia. After premedication with
`50 mg of diphenhydramine hydrochloride,
`25 mg of iron dextran was given IV. Full
`resuscitative resources were immediately
`at hand. Vital signs did not change, and
`only two hives were noted within 20 min¬
`the succeeding week, daily
`utes. Over
`infusions of IV iron dextran were given,
`
`the dose gradually increasing to 250 mg
`per injection, each dose preceded by 50 mg
`of diphenhydramine hydrochloride. The
`patient was discharged after a total of
`1,250 mg of iron had been given, and she
`responded with an increase in hemoglobin
`level from 6.5 to 12.5 g/dL in three weeks.
`A single inadvertent
`intra-arteri-
`injection of 1,000 mg of undiluted
`al
`iron dextran over a 20-minute period
`caused marked redness, warmth, and
`tingling in the hand and arm distal to
`the brachial artery injection site dur¬
`ing the infusion. These were gone 20
`minutes after the injection, and there
`was no delayed reaction.
`COMMENT
`therapy for
`iron deficiency
`Ideal
`recognition
`anemia
`includes
`and
`its etiology and rapid
`treatment of
`restoration to normal of hemoglobin
`value and tissue iron in a safe, pain¬
`less, cheap, and convenient manner.
`Rate of RBC Production and
`Delivery of Iron to Erythroblasts
`for Hemoglobin Synthesis
`A rate of RBC production of ten to
`times normal,
`requiring daily
`12
`delivery of 200 to 240 mg of iron to
`erythroblasts,
`is theoretically feasi¬
`ble. Less than half this rate, requiring
`daily delivery of about 100 mg of iron
`to erythroblasts, was achieved in the
`long-term experiments on prisoners
`(Table 4), probably due to the lack of
`intense enough erythropoietic
`an
`stimulus, because hemoglobin concen¬
`tration was not maintained below 8
`g/dL.2 In prisoners subjected to a
`single large erythropheresis, an aver¬
`age rate of 3.0 times normal was
`achieved (Table 4).
`In patients whose hemoglobin con¬
`centration is 9 g/dL or higher,
`the
`maximal rate of hemoglobin synthe¬
`sis likely to be achieved is only two to
`2.5 times normal,2"
`requiring daily
`delivery of only 40 to 50 mg of iron to
`erythroblasts. If the hemoglobin con¬
`centration is lower than 9.0 g/dL, this
`rate reaches four to five times nor¬
`mal, requiring daily delivery of about
`100 mg of iron to erythroblasts. These
`calculations of RBC and hemoglobin
`synthetic rates assume that there are
`no conditions (fever, malnutrition,
`infection, malignancy, chronic in¬
`flammatory disease,
`renal
`insuffi¬
`ciency) depressing the erythropoietic
`response to the anemia. It is therefore
`probable that daily delivery of more
`than 100 mg of iron to erythroblasts
`
`is necessary only as long as hemoglo¬
`than 9
`bin concentration is
`less
`g/dL.
`Normally, about 95% of the 19 to 21
`mg of iron delivered daily to erythro¬
`blasts is derived from destruction of
`RBCs, and the remainder from tissue
`iron stores. In contrast, in the patient
`with chronic iron deficiency, there is
`a progressive decrease in the rate of
`delivery of iron to erythroblasts due
`to the chronic blood loss because
`progressively fewer RBCs
`survive
`long enough to die of
`senescent
`hemolysis2 and tissue iron stores are
`depleted prior to recognition of ane¬
`mia.' Therefore, with increasing se¬
`verity and duration of iron deficiency
`these two major sources of
`anemia,
`iron yield progressively less iron for
`hemoglobin synthesis, and medical
`iron becomes an increasingly impor¬
`tant source of iron needed for hemo¬
`globin synthesis.67
`In the average patient, a maximum
`of 50 mg of
`iron may be absorbed
`daily following the ingestion of fer¬
`rous sulfate.8 The amount of
`iron
`absorbed from a single dose of oral
`iron varies with the dosage of iron.
`The highest single dose given was 100
`mg, 38 mg of which was absorbed.
`Higher doses and the depressant
`effect of a single dose on absorption
`of subsequent doses were not investi¬
`gated. Hillman and Henderson,6 how¬
`ever, were able to induce four male
`volunteers to consume 300 mg of
`ferrous gluconate every two hours
`while awake (eight
`to nine doses
`daily), an amount most patients can¬
`volunteers
`These
`not
`consume.
`achieved a 2.9 to 4.0-fold increase in
`rate of RBC production,
`requiring
`absorption of 60 to 80 mg of
`iron,
`depending on availability of iron from
`tissue stores and hemolysis of senes¬
`to hemoglobinate the
`cent RBCs,
`RBCs formed. Actually, absorption is
`often less than 40 mg daily because of
`the following factors:
`failure to
`(1)
`ingest iron due to unreliability or lack
`of cooperation and, especially
`in
`patients with gastrointestinal inflam¬
`matory disease, pain and diarrhea (as
`much as 40% of oral
`iron prescribed
`by physicians is not
`ingested);
`(2)
`interference with absorption of iron
`by consumption of antacids, clay,
`high grain diet, and antibiotics like
`tetracycline910;
`inflammatory dis¬
`(3)
`ease of the gastrointestinal tract such
`as regional enteritis; (4) rapid transit
`time, as in ulcerative colitis or any
`
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`

`

`other cause of diarrhea; and (5) by
`surgically
`abnormalities.
`induced
`Consequently, when the patient's he¬
`moglobin concentration is 9.0 g/dL or
`higher, oral iron will ensure hemoglo¬
`bin and RBC synthesis at a maximal
`rate provided that none of the factors
`limiting iron absorption are opera¬
`tive. When the patient with iron
`deficiency anemia has a hemoglobin
`concentration below 9 g/dL, except
`under optimal conditions of
`iron
`absorption and by highly motivated
`iron alone will not
`volunteers, oral
`but parenteral
`iron will maintain
`hemoglobin and RBC synthesis at a
`rate. The clinical signifi¬
`maximal
`cance of
`rate of RBC
`this greater
`formation following IV rather than
`oral iron therapy lasting only as long
`as the hemoglobin concentration is
`less than 9 g/dL is questionable.
`Restoration and Utilization
`of Tissue Iron
`According to Bentley and Jacobs,"
`normal serum ferritin levels, an indi¬
`tissue iron, were
`rect measure of
`observed two months after a normal
`hemoglobin level was attained and
`four months after initiation of oral
`iron therapy. The definition of nor¬
`malcy used probably included some
`individuals having a deficit or even
`absence of tissue iron.12 In contrast to
`reple¬
`findings,
`Bentley and Jacobs'
`tion of tissue stores may require as
`long as six months of continuous oral
`iron therapy.13
`for erythro-
`Tissue iron is useful
`poiesis only if it is transferrable at an
`rate to erythroblasts when
`optimal
`iron is not available from senescent
`RBCs or therapeutic iron; the amount
`of tissue iron merely defines the total
`amount that is eventually available
`for hemoglobin synthesis. Tissue iron
`is not optimally available in hemo-
`chromatosis after multiple phle¬
`botomies, in pernicious anemia after
`treatment with cyanocobalamin,
`in
`prisoners given a single dose of IV
`iron dextran as recently as six weeks
`prior to erythropheresis of one half to
`two thirds of their RBC volume,3 and
`in patients and volunteers with a
`recurrence of iron deficiency anemia
`previously treated with IV or oral
`iron.13 Gradual conversion of ferritin
`to less readily mobilizable hemosider-
`in parallels increase in duration and
`amount of
`tissue iron.7 Therefore,
`more clinically significant
`informa¬
`tion concerning availability of
`iron
`
`for hemoglobin synthesis is obtained
`from plasma iron concentration than
`from the amount of tissue iron.
`In contrast to Pritchard and Ma¬
`son,14 Haskins et al15 and Mundow'6
`iron therapy is
`determined that oral
`inadequate to provide enough tissue
`iron to treat recurrent blood loss.17
`These observations may be summa¬
`(1)
`tissue iron is
`rized as follows:
`more likely to be replenished by IV
`than oral medication if more IV iron
`is given than required to reconstitute
`the hemoglobin mass; (2) the longer
`IV iron is stored in tissue (starting
`about six weeks after injection), the
`less readily available this iron is for
`hemoglobin synthesis; (3) the greater
`the availability of medicinal iron, the
`less important is the availability of
`tissue iron in the treatment of iron
`the more intense the
`(4)
`deficiency;
`erythropoietic stimulus (varying with
`the severity of the anemia), the great¬
`er is the potential rate of RBC forma¬
`tion and the higher is the rate of
`delivery of iron required to hemoglo-
`binate the RBC being formed; and (5)
`normal men (whose tissues contain
`about 600 mg of readily mobilizable
`iron as ferritin and 600 mg of slowly
`mobilizable iron as hemosiderin, and
`who can absorb a maximum of about
`5 mg of food iron daily) are unable to
`compensate for iron lost by one phle¬
`botomy a week (225 mg of iron) for
`longer than about five weeks. Because
`of less tissue iron, most women are
`unable to compensate for longer than
`about two weeks.
`
`Reactions to Iron Dextran
`The 72 localized reactions (Table 5)
`were due to too rapid injection of IV
`iron dextran and were preventable by
`decreasing the rate of injection; none
`occurred in the National Jewish Hos¬
`patients. Reactions
`pital
`severe
`enough to interfere with normal
`activity,
`that
`is,
`those classified as
`life-threatening immediate, or mod¬
`erate or severe delayed reactions,
`occurred in 25 patients (Table 5).
`Although the moderate or severe
`delayed reactions result in disability,
`the immediate severe anaphylactoid
`reactions, which are potentially lethal
`and unpredictable (Tables 5 and 6),
`are the major problem. The mecha¬
`nism causing these potentially lethal
`reactions is unknown; clinically, they
`anaphylactoid
`reactions
`resemble
`seen after administration of radio-
`contrast materials and so are proba-
`
`bly caused by release of mediators
`such as histamine from mast cells.
`The release may be related to specific
`cells, direct
`IgE bound to mast
`complement activation, or direct ef¬
`fect on mast cells. These severe,
`reactions
`should
`be
`immediate
`treated as an anaphylactic reaction
`antihistamines,
`epinephrine,
`with
`corticosteroids, methyl
`xanthines,
`and supportive measures. They were
`rare in this study, occurring in only
`three of 2,099 injections and three of
`the 481 subjects.
`The severe delayed reactions (Table
`6) were usually associated with large
`doses of iron dextran given to rela¬
`tively small patients. The symptom
`complex resembles a serum sickness
`reaction. Another explanation is that
`since iron dextran can circulate unal¬
`tered for several days,17 daily injec¬
`tions may cause progressive increase
`in plasma concentrations, accounting
`for the appearance of reactions after
`a few days of daily injections of
`relatively large doses. Decreasing the
`dose to 250 mg or less per injection
`and increasing the interval between
`injections has resulted in a decrease
`in incidence and severity of this type
`of reaction.
`Reactions observed after IV iron
`dextran resemble those observed af¬
`ter intramuscular iron dextran. We
`have seen identical reactions to IV
`and intramuscular
`iron dextran as
`well as to IV dextriferron.
`Serious toxic reactions to oral iron
`are very rare. Gastrointestinal
`intol¬
`erance itself is not particularly dan¬
`gerous, but it is a common cause of
`failure to ingest the prescribed iron, a
`reported to the
`decision often not
`physician and in one series occurring
`in 32% of patients.18 Oral
`iron tends
`to aggravate gastrointestinal distress
`in patients with inflammatory bowel
`disease. A serious and even lethal
`problem is ingestion of iron by chil¬
`dren, one of the most common causes
`of childhood death by poisoning. The
`higher incidence of reactions with IV
`than with oral iron must be weighed
`the advantages of IV iron
`against
`dextran over oral and intramuscular
`iron (Table 8).
`Indications for IV Iron Dextran
`The indications for use of IV iron
`dextran (Table 9) are based on com¬
`parison of the advantages and disad¬
`vantages of IV vs intramuscular and
`oral iron listed in Table 8.
`
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`
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`
`

`

`Advantages and
`Table 8.
`Disadvantages of Intravenous
`Iron Dextran
`
`—
`
`Advantages
`Intravenous vs intramuscular iron
`More rapid hemoglobin production
`when severely anemic (hemoglo¬
`bin level, <9 g/dL)
`More rapid hemoglobin production
`when continuously bleeding
`Less pain and irritation
`Intravenous vs oral
`iron
`More rapid hemoglobin production
`when severely anemic (hemoglo¬
`bin level, <9 g/dL)
`More rapid hemoglobin production
`when continuously bleeding
`Saturation of tissue stores
`Elimination of dangerous drug from
`the home
`Avoidance of gastrointestinal intoler¬
`ance
`Circumvention of malabsorption
`Assurance of adequate treatment of
`the unreliable and/or uncoopera¬
`tive patient
`Disadvantages
`Intravenous vs intramuscular iron
`Technically more difficult to adminis¬
`ter, especially in babies and in
`adults with poor veins
`Burning along vein and flushing if in¬
`jected too rapidly
`iron
`Intravenous vs oral
`Frequency, unpredictable occur¬
`rence and potentially lethal nature
`of anaphylactoid (anaphylactic?)
`reactions
`Less convenience
`Allergic reactions
`
`Indication for Intravenous
`Table 9.
`Iron Dextran Treatment of
`Iron Deficiency Anemia
`
`—
`
`Commonly Recognized Indications
`Oral
`iron intolerance
`Chronic uncorrected bleeding
`Malabsorption
`Unreliable or uncooperative patient
`inflammatory disease
`Gastrointestinal
`(ulcer, colitis, enteritis)
`Coagulation disorders (hemophilia,
`thrombocytopenia)
`Recently Recognized Indications
`Renal dialysis
`High intake of antacids, clay, grain
`diet
`Autotransfusion or repeated use of
`single donor
`Uncorrected operative blood loss
`Questionable Indications
`Depleted tissue stores (all patients
`with chronic iron deficiency)
`
`Table 9 lists the indications for IV
`iron dextran. Recently
`recognized
`indications deserve comment. Pa¬
`tients undergoing hemodialysis have
`a negative iron balance of 1 to 2 g of
`iron yearly. Usually, oral iron cannot
`be relied on to correct this negative
`iron balance," presumably because of
`interference with absorption by ant-
`acids.10 Reactions to IV iron dextran
`in this kind of p