R
`15
`. A48
`
`THE JOURNAL of the American Medical Association
`
`May 2, 1980
`SERIALS
`MAY 5 1980
`
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`Cv, uO~vL/~~021 Ol 101 OcC &O
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`H~ku l U L ~ Ll~kMkY
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`64o u l
`
`

`

`JAMA
`
`THE JouRNAL of the American Medical Association
`
`JAMA's mission Is education: To Inform
`Its readers of progress In clinical medicine,
`pertinent research, and landmark evolu(cid:173)
`tions In other areas as they form an inter(cid:173)
`lace with medicine. It is a forum for open
`and responsible discussion.
`
`May 2, 1980
`Vol 243, No. 17
`
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`Copyright @ 1980 by the
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`American Medical Association -
`
`MEDICAL NEWS , , , , , , , , , , , , ......... .. .. ............... .. ......................... 1697
`Fact or Fiction About Formaldehyde? .•. What Does Exercise Mean for
`the Menstrual Cycle? ••• Treatment Improved for Ragweed, Penlclllln
`Allergies
`
`FROM THE NIH ............. . ........ ......... ..................... .............. .. . 1705
`New Treatment for Myoclonus Patients .• . Cllnlcal Trials Provide New
`Information
`
`JAMA 75 YEARS AGO .. ...................................... ...... .. ............ 1722
`
`REFERENCE DIRECTORIES
`Prevlou1 U1tlng1: US Meeting,, April 4; Organization, of Medical lnterHI, April 18;
`Foreign Meeting,, March 14; State A11ocfatlon1 and Exam, and Ucen1ure, March
`28; AMA Olflclal1, April 11
`
`INSTRUCTIONS FOR AUTHORS ............................ April 11, 1980, p 1418
`
`LETTERS ............ . ....... ..... .. ................ . ...... . ........ .. ............... 1111
`A Neurochemlcal Mechanl1m for Exceptional Achievement In Gout N. Sher, MO,
`Brooklyn, NY . . . S.n1flfvlty of Hemoccult Slide TH IM. Fleisher, PhD, S. J. Wlnawer,
`MD, New York . . . Uthlum Carbonate Treatment of Mania A11oclated With
`Klinefelter'• Syndrome 0 . G. Cameron, MD, PhD, S. G. Landau, MD, Ann Arbor, Mich
`... Monograph• by Department of Drugi M. E. Kosman, PhD, Chicago ... Multilevel
`Care V. A. Portnoi, MD, J . Mulhearn, Washington, DC ... S.mllaterat Decubltu1
`BreHI Examination A. 0. Heymann, MD, New York . .. Patient.Partner Sat11factlon
`Level• With the Inflatable Penile Pro1the1l1 W. L. Furlow, MD, Rochester, Minn, 0. C.
`Renshaw, MD, Maywood, Ill ... Gentamlcln•Re1l1tant Staphylococcu1 aureu• K. M.
`Edwards, MO, D. L. Munro, RN, C. E. Hunt, MD, A. T. Davis, MD, Chicago
`
`ORIGINAL CONTRIBUTIONS
`
`Pulmonary Involvement In Rheumatoid Arthritis ..... . .............. . .......... .. 17 15
`Lt Col P. Cervantea-Perez, MO; Lt Col A. H. Toro-Perez, MO:
`MaJ P. Rodriguez-Jurado, MO, Mexico City
`
`Protein-Calorie Malnutrltlon in a Community Hospital ..... .. ...... . .... .. .... .. 172D
`M. 0 . Willard, MO; R. B. Giladorf. MO, PhD; R. A. Price, MO, Phoenix, Ariz
`
`Sudden Death and Hepatic Fatty Metamorphosis .. . .. .... ..... ... . .. ........... 1723
`B. Rendall, MO, Chapel Hill, NC
`
`Intravenous Iron Dextran In Clinical Medicine ...... . .... ..... ... . .. ..... . . .. . ... 1726
`R. 0 . Hamolra, MO; M. H. Block, PhD, MO; A. L. Schocket, MO, Denver
`
`SPECIAL COMMUNICATION
`
`Home or Hospital Bi rths? ............... . ... .. ......... . . . . . .. .... ... ........ . .... . . 1732
`G. 0 . Adomoon, MO, 0 . J. Gare, MO, Toronto
`
`BRIEF REPORTS
`
`The Myth of the Low Anion Gap .... .. .......... .. .... . ............................ 1737
`R. J. Goldsleln, MO, Tampa, Fla; N. S. Lichtenstein, MO: O. Souder, MO, Boston
`
`Chemotherapy for Advanced Male Breast Cancer ........ .... .......... .. ...... 1739
`H-Y. Yap, MB, MRCP; C. K. Tashima, MO; G. R. Blumenschein, MO;
`G. N. Horlobagyl, MO; N. Eckles, MO, Houston
`
`Persistence of Vacuolated RBCs After Splenectomy In Adults .. . .... .. . ...... 17 41
`B. A. Neilan, MD, J. F. Perry, Jr, MO, PhD, Minneapolis
`
`1691
`
`

`

`CONTENTS- Continued
`
`CLINICAL NOTES
`
`'Runner's Trots' ...... . ......................... . ..•................ . ... • ...•.... . .... 17 43
`R. N. Fogoros, MO, Pittsburgh
`
`Diabetes lnsipldus and Complicated Pregnancy .............. . ............•. . .. 1744
`J. W. Campbell, MD. Wheeling, WVa
`
`Anaphylactlc Cardiac Arrest in a Parturient .....••...........................• ... 1745
`A. Baraka, MO, S. Sfelr, MO, Beirut, Lebanon
`
`EDITORIALS
`
`My Name Is Leglonella ......... . .......... .. ...... ... ...... ......................... 1747
`
`Home Delivery Controversy .............. . •...•... . .... . ......... • ..... • ........ ... 1747
`
`The NCCLS and Medical Devices ....................••••• ... ....•................. 1748
`
`TOPICS IN RADIOLOGY
`
`Rectal Disease In a Patient With Delirium Tremens .. . ...... ... ..•.............. 1749
`J. H. Stanley, MO, Charleston, SC
`
`BOOKS .................................... ..... .... .. ................................ 1751
`Nephrology (Hamburge r. Crosnier. Grunfeld, eds) Reviewed by J. P. Hayslett, MD.
`New Haven. Conn ... Diagnosis and Therapy of Coronary Artery Disease (Cohn. ed)
`Reviewed tiy P . T. Kuo. MD. Piscataway. NJ . . . Pediatric Hematology•Oncology
`(Lenzkowsky) Reviewed by R. A. Saeler, MD. Chicago .
`. Care of the Mentally
`Retarded (Blac kwell) Reviewed by R. R. Parlour, MD. University, Ale . .. A Gulde to
`Physical Examination (Bates) Reviewed by H. S . Meyer, MD. Ch.icego ... Notice ...
`Books Received
`
`QUESTIONS AND ANSWERS ............................ . ....... ............... 1757
`Surgical Reduction of Remaining Breast After Mastectomy J. Horton. MB. CHB.
`R.H. McShane. MD. Albany. NY .. . Latent Syphilis Infection of 48 Years' Duration
`L. Nicholas. MD, Philadelphia ... Pregnancy and Malignant Melanoma Activation
`C. M . Proudfit. PhD, Chicago
`
`OBITUARIES ...................................... . ................................. 1759
`
`CLASSIFIED ADVERTISING ............ . . . .. .................................... 1764
`
`INDEX TO ADVERTISERS ........... .. .......... . ................................ 1778
`
`The Cover
`
`This week the cover story
`will be found on
`page 1707.
`
`AMA Offlcora
`President: Hoyt D. Gardner, MO• : President-Elect: Robert 8 . Hunter, MO•; Imme diate Pait Pre1ldent: Tom E.
`Nesbitt, MO; Secretary·-Treaaurer: H. Thomas Ballantine, Jr, MO; Speaker, Hou1e of Delegate ■: William Y. Rial,
`MD; Vice-Speaker, House of Delegates: Harrison L. Rogers. Jr, MO
`
`AMA Tru1tae■
`L owell H. Steen. MO (Chairman)• ; H. Thomas .saua~tine, Jr, MO; ~oaeph F. Boyle, Mo•: Daniel T. Cloud, MO;
`Charles Max Cole, MO; John J. Coury, Jr, MD ; WIiham S . Hotchkiss, MO; Frank J. Jirka, Jr, M D; W . J. (Jack)
`Lawis, MO; George H. Mills, MO• ; Hubert A. Ritter, MO; George A. Rowland, MO
`• Executive Committee
`
`EDITORIAL BOARD
`
`Byron J. Balley, MD
`Galveston, Tex
`
`Arthur E. Bauo, MD
`New Haven, Conn
`
`L eonard 8 . Berman, MO
`Orange. Calif
`
`Frederick C. Blodl, MO
`lowo City
`
`Kenneth M. Brlnkhoua, MD
`Chapel Hill. NC
`
`WIiiiam H. Croaby, MD
`Washington. DC
`
`Donald J. DalHalo, MD
`La Jolla. Calif
`
`George E. Ehrlich, MD
`Philadelphia
`
`Joaquin Ferri, MD
`Barcelona, Spain
`
`GIibert 8 . Forbea, MD
`Rochester, NY
`
`D a nlel X. Freedman, MD
`Chicago
`
`Emil J Frelrolch, MD
`Houston
`
`Harold G. Jacobson, MD
`Bronx. NY
`
`George D. Lundborg, MD
`Davis and Sacramento, Ca lif
`
`Frederick D. Malklnson, MD
`Chicago
`
`Marlin L. Nusynowltz, MO
`San Antonio, Tex
`
`Nlcholaa J. Plaacano, MD
`Lexington. Ky
`
`Jame• Ransom, PhD
`Los Altos. Calif
`
`Allred Soffer, MD
`Perk Ridge. Ill
`
`Raymond L. Teplltz, MD
`Duarte. Calil
`
`Maurice W. Van Allen, MD
`Iowa City
`
`Robert M. Veatch, PhD
`Wasttington, DC
`
`It
`
`I
`
`Executive Vlc•Pre1ldent: James H. Sammons, MD
`Group Vlc•Prealdent , Scientific PubllcaUona:
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`Director, Advertlalng Sale• and Pro motion Service•
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`
`1692
`
`JAMA, May 2, 1980-Vol 243. No. 17
`
`I
`
`

`

`Intra venous Iron Dex tr an 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
`volunteers received 2,099 intravenous (IV)
`injections of Iron dextran
`(lmferon), 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 wom~n and
`collagen-vascular diseases and less frequent In pregnancy. Because anaphy(cid:173)
`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)
`
`PATIENTS AND METHODS
`The diagnosis of iron deficiency was
`established by assessment of (1) blood
`loss; (2) mean corpuscular hemoglobin
`concentration, mean corpuscular volume,
`and RBC morphology; and (3) measure(cid:173)
`ment of plasma and bone marrow iron
`levels. Blood loss in patients was substan(cid:173)
`tiated by a history of hematemesis, hema(cid:173)
`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 t he guaiac meth(cid:173)
`od.
`
`Patient Population
`Forty-two percent of t he 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(cid:173)
`partum. Forty-one percent of the patients
`
`PARENTERAL iron therapy is a
`therapeutic option in the treatment of
`iron deficiency anemia. Both dextri(cid:173)
`ferron and iron dextran have been
`given intravenously (IV) with accept(cid:173)
`able patient tolerance and hemoglo(cid:173)
`bin response. In the United States,
`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 t his
`period, 293 patients from a general
`hospital population (Colorado Gener(cid:173)
`al Hospital, Denver), 178 patients
`from a thoracic surgical service (Na(cid:173)
`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
`during their response to phleboto(cid:173)
`my.'-' No patient was admitted to the
`study after Ja nuary 1970, and the
`study was terminated in J anua ry
`1975.
`
`From the Divisions of Hematology (Ors Hamstra
`and Block) and Clinical Immunology (Dr Schock(cid:173)
`et), University of Colorado Health Science Cent er,
`Denver.
`Reprint s not available.
`
`were subjected to surgery, the majority
`having cardiac surgery with autotransfu(cid:173)
`sion' at National Jewish Hospital. Based
`on prior experience at Colorado General
`Hospital, all patients at National Jewish
`Hospital with even a suspicious personal
`or fami ly history of a drug reaction,
`allergic rash, or rheumatoid arthritis were
`excluded from the IV iron dextran auto(cid:173)
`transfusion program. The small number of
`genera l surgical patients is partly attrib(cid:173)
`utable to admission at Colorado General
`Hospital of patients bleeding from the
`gastroi ntestinal tract to t he medical ser(cid:173)
`vice with subsequent transfer to t he surgi(cid:173)
`cal service when workup was complete and
`the patient's condition was stable. In addi(cid:173)
`tion, there were ten prisoners who volun(cid:173)
`teered fo r studies in which erythropoietic
`response to chronic' and acute' blood loss
`was measured while iron stores, but not
`necessarily iron availability, were main(cid:173)
`tained with IV iron dextran.
`
`Injection Schedules
`At Colorado General Hospital, inpa(cid:173)
`tients were usually injected daily and
`outpatients once or twice weekly. Auto(cid:173)
`transfused patients at National Jewish
`Hospital were injected immediately aftir
`each phlebotomy one to four times in tie
`ten days preceding surgery.' Prisoners in
`t he chronic blood loss experiment were
`injected one to five times weekly.
`Each injection usually contained 250 pr
`500 mg because the drug was supplied in
`ampules containing these amounts anl
`because variations of 100 mg per injectioo
`did not influence reaction rate or erythre>(cid:173)
`poietic response (Table 2). The initicl
`injection varied from 2.5 to 500 mg; if wel
`
`Table 1.-Source of Patients
`
`M
`edicine
`G
`eneral surgery
`A
`utotransfusion
`bstetrics
`0
`G
`ynecology
`p
`ediatrics
`ther
`0
`p
`risoners
`T otal
`
`In•
`patients
`130
`25
`178
`27
`12
`1
`3
`10
`386
`
`Out•
`patients
`64
`1
`a
`19
`9
`1
`1
`a
`95
`
`lntravenous Iron
`Ta b le 2.-
`Dextran Injections
`
`Iron Content
`per Injection, mg
`< too
`100-249
`250
`25 1-499
`500
`501-999
`1,000
`> 1,000
`Total
`
`No. of
`Injections
`28
`176
`1,046
`34
`775
`11
`16
`13
`2,099
`
`1726
`
`JAMA, May 2, 1980- Vol 243, No. 17
`
`Intrave no us Iron Dextran-Hamstra et al
`
`

`

`Table 3. - Intravenous Iron
`Dextran Therapy
`
`Total Amount ol
`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. ol
`Patients
`78
`158
`50
`61
`63
`27
`15
`4
`10
`7
`6
`2
`481
`
`Table 4.-Rate of RBC Synthe sis
`in Response to Phlebotomy and
`Intravenous Iron Dextran
`
`Increment
`Above
`RBCs,
`ml/ Day Normal
`
`Normal adutt
`(70•kg man)
`Chronic phlebotomy
`in prisoners t
`Acute phlebotomy
`in prisonerst
`
`19'
`
`...
`
`88·93 3.6-4.9X
`
`48-67
`
`2.5-3.5X
`
`•wintrobe.'
`tCorrected to that of 70-kg man.u
`
`tolerated, subsequent injections contained
`250 to 500 mg. Twenty-three patients,
`however, received their entire dose (LO 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
`saline over a 20-
`to 30-minute period
`immediately after each phlebotomy.'
`Prisoners subjected to chronic phleboto(cid:173)
`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(cid:173)
`mediately after each phlebotomy.' Pris(cid:173)
`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.' One prisoner inad(cid:173)
`vertently was injected with 20 mL of
`undiluted iron dextran in the left brachia(
`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 phlebotomjzed.' The prisoners sub(cid:173)
`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 Erythropoletic 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(cid:173)
`poiesis from increments of grams per
`deciliters per day, we report the rate of
`
`JAMA, May 2, 1980- Vol 243, No. 17
`
`RBC production only in prisoners (Table
`4). In our investigations on long-term
`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.' 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.' The rate of response to a
`single phlebotomy of one ha lf to two
`thirds of the RBC volume was estimated
`from the increment in RBC volume.' Actu(cid:173)
`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(cid:173)
`surement of increments in RBC volume.
`
`Evaluation of Reactions
`Reactions to JV 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(cid:173)
`ly and close telephone contact was main(cid:173)
`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(cid:173)
`ate reactions occurred within five minutes
`of injection; they were further classified
`as (1) life-threatening anaphylactoid reac(cid:173)
`tions characterized by hypotension, syn(cid:173)
`cope, purpura, wheezing, dyspnea, respira(cid:173)
`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 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. (%) ol
`Patients
`(N=4B1 )
`356(74)
`125(26)
`
`72(15)
`53(11)
`15(3)
`3(0.6)
`12(2)
`38(8)
`6( 1)
`16(3)
`16(3)
`No.(%) ol
`Injections
`(N= 2,099)
`1,824(87)
`275(13)
`
`185(9)
`90(4)
`16(0 7)
`3(0 1)
`13(0.6)
`74(4)
`8(04)
`44(2)
`22(1.0)
`
`•Ten reactions in one patient with rheumatoid
`arthritis, 13 reactions in one patient with rheuma(cid:173)
`toid arthritis, and eight reactions In one patient
`with lupus erythematosua
`
`injection; and (2) non-life-threatening re(cid:173)
`actions characterized by mild, transient
`hypotension, malaise, itching, and urticar(cid:173)
`ia, lasting less than five minutes and not
`otherwise interfering with normal activi(cid:173)
`ty.
`Delayed systemic
`reactions started
`within four to 48 hours of injection and
`lasted three to seven days. They were char(cid:173)
`acterized by lymphadenopathy, myalgia,
`arthralgia, fever, a nd headache occurring
`singly or in combination. The delayed
`reactions were subclassified as mild (no(cid:173)
`ticeable, but not interfering with normal
`activity), moderate (limitation of ordinary
`activity, but not requiring bed rest), and
`severe (disabling and requiring bed rest).
`All systemic reactions classified as
`severe are described in detail in Table 6.
`
`Prisoners' Rights
`The rights of the prisoners were re(cid:173)
`spected in conformance with the Helsinki
`Declaration of the World Health Orga(cid:173)
`nization and the Nuremberg Code. Ap(cid:173)
`proval was also obtained from the gover(cid:173)
`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 m
`
`Intravenous Iron Dextran-Hamstra et al 1727
`
`

`

`Table 6.-Severe Reactions to Iron Dextran Administration •
`
`I
`
`Reaction
`
`Type
`
`Onset
`
`Duration
`
`Subs•quent Iron
`Dextran Therapy
`
`...
`
`t 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
`
`t 2 hr (wheezing)
`5 days (arthralgia)
`
`None
`
`Diagnoses
`
`Dose of Iron
`Dextran, mg
`
`2.5 in 5% glucose/
`Ringer's
`200 undiluted
`
`10 undiluted
`
`Caoe/Age, yr/
`Sex/ Weight, kg
`Potentially lethal
`11371"'1 163 Mitra l stenosis due to rheu•
`matic fever, autotransfusion
`Iron deficiency, ulcerative co-
`litis
`Rheumatoid arthritis, iron deli-
`ciency, previous gastrecto-
`my
`Not potentially lethal
`4 165/f/50
`Rheumatoid arthritis
`5160/ F / 54
`Lupus erythematosus
`6139/ F / 47
`Iron deficiency (etiology un-
`known)
`Blood loss research (prisoner
`volunteer)
`
`2138/ F / 45
`
`3155/F/49
`
`7127 I M /59
`
`1 min
`
`Respiratory arrest, hypo-
`tension, purpura
`Hypotension, cyanosis,
`dyspnea
`Syncope, wheezing, hives 1 min
`(blood pressure not re-
`corded)
`
`1 min
`
`200 undiluted
`500 undiluted
`500 undiluted
`
`1.500 undiluted
`
`Arthralgia
`Arthralgia
`Myalgia, arthralgia, ery•
`theme nodosum, fever
`Myalgia, arthralgia, fever, 24 hr
`headache
`
`8 hr
`48 hr
`48 hr
`
`8129/M / 54
`
`9 145/ M / 72
`
`t0/24 / F / 52
`
`11 146/ F / 47
`
`Iron deficiency. bleeding pep·
`tic ulcer
`Blood loss research (priSoner
`volunteer). varicose veins
`Iron deficiency, menorrhagia
`
`Iron deficiency, gastrointesti•
`nal bleeding
`
`500 undiluted for
`Myalgia, arthralgia, fever, 48 hr
`6 consecutive days
`adenopathy
`500 undiluted weekly Thrombophlebitis, pulmo-
`for 11 wk
`nary embolus
`1,200 in 5% dextrose Myalgia, arthralgia, sore
`in water
`neck, fever
`2,500 in 500 ml of
`Arthralgia, adenopathy,
`dextrose in water
`wheezing, fever
`
`...
`
`48 hr
`
`4 hr
`
`normal men' and in prisoners sub-
`jected to a single phlebotomy of one
`half to two thirds of the circulating
`RBC mass' 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.' 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
`times normal in prisoners subjected
`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-
`t1on was closest to normal. When a
`hemoglobin level of about 8 g/dL was
`subsequently maintained for 20 days
`by repeated phlebotomy, these pris(cid:173)
`oners maintained the same rate of
`RBC production' as those bled for 9 to
`23 weeks.'
`
`Reactions
`Three hundred fifty-six (74 % ) of
`the patients did not have a reaction.
`One hundred twenty-five (26%) expe(cid:173)
`rienced a reaction, but only 25 (5%)
`had reactions that limited or inhib(cid:173)
`ited ordinary activity. Three (0.6%) of
`these 25 patients had life-threatening
`anaphylactoid reactions (Tables 5 and
`
`Table 7.-Correlation of Incidence of Patient Reactions · With Other Factors
`
`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
`
`No Reaction
`
`Reaction
`
`-x.' (1 df)
`
`p
`
`294
`82
`
`218
`158
`
`15
`418
`
`46
`
`110
`210
`
`43
`390
`
`1,129
`902
`
`78
`26
`
`78
`27
`
`10
`38
`
`1
`
`19
`39
`
`2
`46
`
`41
`27
`
`0.3104
`
`>.05t
`
`9.2776
`
`23.0484
`
`4.2517
`
`5.0933
`
`1.0814
`
`0.4152
`
`<.01
`
`<.01
`
`< .05
`
`< .05t
`
`> .051
`
`> .05t
`
`• 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(cid:173)
`bles 5 and 6). Table 7 correlates the
`number of patients who had reactions
`with age, sex, collagen vascular dis(cid:173)
`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(cid:173)
`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'l
`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 51
`
`1728
`
`JAMA, May 2, 1980-Vol 243, N o. 17
`
`Intravenous Iron Dextran- Hamstra et a
`
`

`

`One patient with rheumatoid arthri(cid:173)
`tis and one with lupus erythematosus
`accounted for two of the eight (0.3%)
`severe, not potentially lethal reac(cid:173)
`tions (Table 6); neither was retreated
`with iron dextran. Thirty-one of the
`44 moderate delayed reactions oc(cid:173)
`curred in two patients with rheuma(cid:173)
`toid arthritis and in one patient with
`lupus erythematosus (Table 5). These
`three patients requested that treat(cid:173)
`ment with IV iron dextran be contin(cid:173)
`ued because the benefit from treat(cid:173)
`ment of the anemia exceeded the
`transient discomfort from the reac(cid:173)
`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,' making weekly intervals a~(cid:173)
`ceptable.
`Severe and moderate delayed reac(cid:173)
`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(cid:173)
`tion than the same-size injection giv(cid:173)
`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(cid:173)
`cluded in Table 6, who had hives and
`itching with oral and intramuscular
`iron dextran, was subsequently suc(cid:173)
`cessfully treated IV with a series
`of injections 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 JV. Full
`resuscitative resources were immediately
`at hand. Vital signs did not change, and
`only two hives were noted within 20 min(cid:173)
`utes. Over the succ