VOL.        121,     No.         i

            EXTRAVASATION                                                       OF CALCIUM      GLUCONATE                                                                                                        AS A
                  CAUSE   OF                                                SOFT   TISSUE   CALCIFICATION
                                                                                IN INFANCY*
                            By       PAUL            E. BERGER,                   M.D.,t          KATHLEEN        P. HEIDELBERGER,                                                                M.D.,
                                                                      and      ANDREW               K. POZNANSKI,       M.D.t
                                                                                        ANN       ARBOR,           MICHIGAN

 QOFT                 tissue               calcification                 in the         neonate                    consisted                 of         an        infusion                of     calcium                gluconate
L)        or       young                infant          is       an     unusual               occur-               into        a vein              in        the         dorsum                 of the           hand           which
rence.     In our experience            at the C. S. Mott                                                          subsequently                         infiltrated                    into           the     subcutaneous
Children’s          Hospital,       the     most      common                                                       tissues.            Several               hours             later           a purplish               discolora-
                                                                                                                   tion        of        the         dorsum                    of         the         hand            was       noted
cause      of roentgenologically              demonstrable
                                                                                                                   which             was          treated                 by warm                     soaks           and       eleva-
soft tissue      calcification      in this age group          has
                                                                                                                   tion.         The              following                    day             swelling,               erythema,
been      extravasation          into     the    soft    tissues
                                                                                                                   and a large bleb appeared on the dorsum                                                                      of the
during              attempted                    intravenous                    administra-                        hand.  Four days later the bleb opened                                                                       spon-
tion of a solution            containing         calcium    glu-                                                   taneously                   and           drained,                  but        the         erythema               was
conate.                                                                                                            persistent.       At                      JO      days            of        age,         there     was            per-
    It is our purpose          to report     3 such cases of                                                       sistent     swelling                       and         hard            deposits              between               the
calcium      gluconate        extravasation.           We have                                                     second             and  third digits    were                                          palpated.    At                    3
also attempted           to reproduce         this finding     in                                                  weeks             of age a roentgenogram                                                 was obtained
laboratory        animals       and have       obtained     his-                                                   ( Fig. i) which      demonstrated                                                    extensive     linear
tologic     specimens        for correlation           with  our                                                   and platelike   calcification     with                                               definite  vascular
                                                                                                                   calcification             also noted                              extending   up the fore-
roentgenographic            findings.
                                                                                                                   arm. At                weeks   of age                            a 2 cm. eschar   that had
                                     REPORT            OF     CASES
                                                                                                                   formed              (Fig. 2) began                                to slough   and was re-
                                                                                                                   moved,              the underlying                             base          appearing                necrotic.
       CASE         I.     K.P.-               299     938.           A 3 pound          6 ounce                   At      6 weeks                the         base          showed                granulation                   tissue
Negro              male,             transferred     C. S. Mott  to     the                                        with    mild   contracture                                           from   scar     formation
Children’s      Hospital      at 24 hours        of age because                                                    causing    some limitation                                          of metacarpal-phalan-
of apneic       episodes      and probable            sepsis.    The                                               geal flexion                   of the                third          and fourth                     digits.    The
pregnancy       was complicated          by rupture        of mem-                                                 patient    was                 treated                 with          soaks  and                    mechanical
branes     I week       prior to delivery.         Delivery       was                                              debridement                     by fine mesh                            gauze.
by cesarean         section    at 33 weeks           of gestation                                                     The baby                     was discharged                             at         10    weeks           of age
because      of maternal        temperature          of 102.6#{176} F.                                             with          the         lesion                on       the           dorsum               of       the      hand
and transverse           lie. Cultures      of amniotic         fluid                                              granulating                     well.
subsequently         grew hemolytic         Streptococcus         and
E. co/i. Apgar         at I minute      was i and the baby                                                                CASE         II.     S.H.-I                    171        867.         A 7        pound             3 ounce
required                 intubation                  and         resuscitation.                 At       6         female   was delivered    at 43 weeks     of gestation
hours,             the       baby          developed                  apnea       and         brady-               by cesarean    section  because     of fetal  distress.
cardia.                                                                                                            Apgar   was 8 at 2 minute       and  10 at 5 minutes.
   On admission        the infant         was 32 to 33 weeks                                                       At      2     hours             of        age         the         baby             developed                 apnea
gestation.      There      was a Grade            2/6     systolic                                                 and       cyanosis         for approximately             2   minutes
murmur;      the remainder          of the examination           was                                               which        abated        on stimulation.          Six recurrent
otherwise      unremarkable.            The admission         chest                                                episodes       of apnea at 30 to 6o minute                 intervals
roentgenograms          were       interpreted      as possible                                                    ensued.       Clonic       movements        of the left arm and
mild respiratory          distress       syndrome      or pneu-                                                    leg were          noted,       associated      with     the apneic
monia.     The patient          was started       on penicillin                                                    episodes.
and kanamycin.                                                                                                          Laboratory          studies     showed     a C.S.F.      glucose
   At 2 days of age calcium              was 5.2 mg. per cent                                                      less    than     10   mg. per cent, serum              glucose       less
and phosphorus          5.5 mg. per cent.            Treatment                                                     than        10       mg.          per          cent,           and           a serum               calcium            of
   *   From        the     Department           of Radiology,t           and    Department           of Pathology,             The      University                of Michigan              Medical          Center,      Ann     Arbor,

 110                                             P. E.          Berger,               K. P. Heidelberger                          and           A.        K.          Poznanski                                                 MAY,              1974

                                                                                                                   the       right          side       of the               scalp           was         noted,           its        etiology
                                                                                                                   unknown.                     This           was              described                 as      a central                     area
                                                                                                                   of       black              necrosis                   surrounded                       by          a peripheral
                                                                                                                   area          of       erythema.                        Culture                 of     the          area           showed
                                                                                                                   no growth                        and              2     needle     aspirations                              demon-
                                                                                                                   strated   no                  fluid          or        pus.    The   clinical                          impression
                                                                                                                   was        cellulitis                  of        the          scalp         and             treatment                       with
                                                                                                                   soaks              was        begun.                   The          patient                 was        discharged
                                                                                                                   home               3     days           later                with          soaks               prescribed                       for
                                                                                                                   the        scalp              lesion.                  Return               visit              10      days                 later
                                                                                                                   showed                 an       indurated                       “bony”                 area          in      the            tern-
                                                                                                                   poral          region,              posterior                      and          superior              to         the         area
                                                                                                                   of       necrosis.                 The                necrotic                  area           was           debrided
                                                                                                                   and       cultures                 grew     Staphylococcus                                     aureus,                 coagu-
                                                                                                                   lase       positive.                   Treatment         consisted                                          of         soaks,
                                                                                                                   topical                neosporin,                      and          oral        cloxacillin,                      125         mg.
                                                                                                                   QID.               Ten        days               later          the        scalp             lesion              was          felt
                                                                                                                   to   be     improving                                    and          skull      roentgenograms
                                                                                                                   were    obtained                            to         rule         out     osteomyelitis                                   (Fig.
                                                                                                                   3). A calcified                        plaque   was                        noted               in the soft tis-
                                                                                                                   sues overlying                         the temporal                          bone               and the possi-
                                                                                                                   bility         of extravasation                                 of calcium                     gluconate                     was
                                                                                                                   suggested     as the etiology.                                              In retrospect                              it     was
                                                                                                                   noted     that an intravenous                                                 extravasation                                  had
                                                                                                                   infiltrated                   in    this              area          JO     days             before               the         area
                                                                                                                   of necrosis    and                      erythema      was                            noted.     At 6 weeks
                                                                                                                   of age the scalp                          was described                                as erythematous
                                                                                                                   with     a white                        necrotic     center                              surrounded      by
                                                                                                                   calcium.                 Examination                                     days          later         showed                    de-

Fic.     I. Case,.       Extensive       linear    and platelike                                      calcifi-
    cation    with Vascular         calcification        extending                                    up the
    forearm.       ‘I’hree    weeks     after     extravasation                                       of cal-
    cium gluconate.

9.1         mg.      per         cent.            Treatment                was         begun             with
intravenous                  and           oral         glucose.
       At      2   days          of age           the      total    serum             calcium             was
6.      mg.         per      cent.          The           patient          was        treated            with
4 cc. intravenous                       calcium       gluconate                     and          calcium
gluconate      was                  added       to the oral                   feedings.             Three
days          later     the      serum      calcium                       was          reported              as
2.7         mg.     per    cent.       This    was                   treated             with               cc.
intravenous                      calcium.                 The       following                   day        the
serum              calcium               was        8.3       mg.       per      cent           and        the
child         was        doing           well      and       continued                to do       well      on
oral          feedings             with            oral       calcium            supplementa-                      Fic.     2. Case  i. Eschar                                   on      dorsum      of hand         weeks
tion.         At      14     days           of      age       an    area         of     necrosis            on         following    extravasation                                         of calcium      gluconate.
 VOL.        121,      No.         i                                          Extravasation                                     of Calcium                    Gluconate                                                                                              III

creased    induration,                                 good granulation    tissue in                                                      travenous                      penicillin                and             methicillin.                     There            was
the necrotic     area,                              and no exudate.     At io weeks                                                      roentgenologic                              evidence                      of         amorphous                     calcific
of       age        the           head              lesion         continued                        to         improve                   density     in the region                                     of the right     tibial    condyle
with    only                minimal       cellulitis                          and           small             amounts                    which     was believed                                   to     be secondary          to calcium
of calcium                   still present.                                                                                              gluconate      infiltration.                                   In spite   of the roentgeno-
       At      6 months                      of age           there           was        complete                        heal-           logic            findings,                  the          patient                     was         continued         on
ing.        Only            a fibrotic                 scar        was            present                at        the        site       intravenous                           antibiotics                         for            3     weeks       without
ofprevious                       necrosis.                                                                                               further              complication.
                                                                                                                                                The erythema,                              swelling,                    and           mass          diminished
       CASE       V.B.-i
                       III.   263    169. One   month      old                                                                           and         at       the        time         of discharge                            only          a small            resid-
infant    female,     second   of twins, was born at 33                                                                                  ual lump                   remained                    in that                 area.
weeks gestation         with a birth weight of2 pounds
                                                                                                                                                                         REVIEW                   OF         LITERATURE
‘5 ounces.       The infant      did well initially,     then
developed       mottling,     tachypnea      and grunting                                                                                       In        1936                the         first         2      reports                    of        complica-
during      the second       week.     She began      having                                                                             tions             secondary                          to         intramuscular                                     admin-
apneic              episodes                   and           was         transferred                          to         C.         S.   istration   of calcium       gluconate   appeared     in
Mott           Children’s                     Hospital                 at     i    month                 of age.               On
                                                                                                                                         the medical    literature.      The case of Tumpeer
admission                    the             baby            was         severely               dehydrated
                                                                                                                                         and Denenholz’8          was that of an infant,    who
with           serum             pH          6.8,       and        blood             urea           nitrogen                        of
                                                                                                                                         on        the          third               day           of        life            developed                      tetany,
I.c         mg.       per        cent.          The          initial          serum            calcium                        was
4.8     mg. per                  cent.
                                                                                                                                         and            was          treated                  with                 I        cc. calcium    gluco-
      The  patient                       was          treated               for     dehydration                               and        nate             intravenously                                and                  9 cc. intramuscu-
acidosis,                  and           the           hypocalcemia                            was                 treated               larly.               An              additional                               io         cc.          of      calcium
with           intravenous                          calcium                 gluconate.                        The             cal-       gluconate                        was given                          into each                         buttock                on
cium           rose         to         7.7     mg.           per        cent.          Ten           days                after           the fourth                        and fifth                         days.  The                         infant               did
administration                         of calcium,                          a 2.5 cm.                by         2.5           cm.        well,            but on the twentieth                                                day the                buttocks
“lump”         was                 noted     over                  the        medial                condyle                      of      were             noted to be hard     and                                            indurated                  and           on
the         right           knee.             This           was         described                   as tender,                          roentgenograms               at 5 weeks       of age there          was
warm,               red,           circumscribed                              and            nonfluctuant.
                                                                                                                                         diffuse      spread       of radiopaque           material         “ap-
Consultants                       from          the      Departments                           of Infectious
                                                                                                                                         parently          along      the     fascial     planes       of the
Disease               and         Orthopedics                          clinically              felt           that            the
                                                                                                                                         thighs       and buttock,             from    the hips         to the
differential                  diagnosis                was one of cellulitis                                         versus
                                                                                                                                         knees.”        At the sixth             week,     the overlying
osteomyelitis                     and               the baby  was  started                                           on in-
                                                                                                                                         skin     sloughed          and a piece          of calcium           ex-
                                                                                                                                         truded       which       was analyzed           and proved             to
                                                                                                                                         be calcium           phosphate.          On follow-up           roent-
                                                                                                                                         genograms           there was progressive               resorption
                                                                                                                                         of    the      calcified        material,       so that           at 4
                                                                                                                                         months                     of        age         only              a slight                     amount                    per-
                                                                                                                                         isted.           Tumpeer                         and          Denenholz’8                               speculated
                                                                                                                                         that             the            normally                      soluble                        calcium               gluco-
                                                                                                                                         nate,            “may                 cause              coagulation                             of the             tissue
                                                                                                                                         when              injected                    into            patients                         with          the          dis-
                                                                                                                                         turbed                     calcium                     metabolism                                  of       tetany.”
                                                                                                                                         Coagulation        “within     the blood                                                           vessels”  was
                                                                                                                                         felt to account        for the necrosis                                                             and slough-
                                                                                                                                         ing typical      of gangrene.
                                                                                                                                             Van     Hofe    and    Jennings’9                                                           reported                    the
                                                                                                                                         case           of an             infant             who              had             received                 calcium
Fic.     3. Case ii. Large           amorphous        calcification                                                           (ar-
                                                                                                                                         gluconate                       on     the          third,                fifth,             and        sixth         days
    rows)      projecting      over    temporal     region,       shown                                                         on
    oblique       roentgenograms           to be in soft          tissues                                                        of      of      life         because                  of         twitching.                            Ten          cc.      of       10

     temporoparietal           area.    Four    weeks       following                                                          cx-       per   cent   calcium   gluconate                                                               solution     was
     travasation        of calcium gluconate.                                                                                            given   into the thigh   muscles                                                             on 2 occasions
 112                                                P. E.           Berger,           K.        P. Heidelberger                               and             A.     K.     Poznanski                                        MAY,          1974

and       io cc. was also given                         intramuscularly                                                       win,1                 Lamm,6                  and          McLaren.’#{176}                     One              of
in    the scapular             area. At 3 weeks                    of age, the                                                Lamm’s    3 cases developed                                      gangrene,                    slough-
patient          developed               induration               in all the                                                  ing of the buttock    area,                                  abscesses,                    and died.
previously           injected         areas.       There        was marked
                                                                                                                                                                    LABORATORY                   STUDY
 calcification             visible           roentgenographically
 throughout               the       soft        tissue         about         both
 femora          and       in the           interscapular                region.                                                       Initially                   4 cc.      of calcium                  gluconate                    was
 Progressive             clearing          of the calcific               masses                                               injected                   subcutaneously                      into           disarticulated
 occurred         at 2 and 3 months                       of age and at 6                                                     chicken    thighs     to determine                                      whether    or not
 months          there        was no evidence                       of calcific                                               the calcium       solution     itself                                 was radiopaque.
 deposit.                                                                                                                     Next,             I    ,   2,        or 4 cc.      of calcium                gluconate                    was
     Shannon’7             reported            2     additional            cases,                                             injected                   subcutaneously                          into        the         thighs               of
one        of which              showed              roentgenographic                                                         living             rabbits.                  These         were            observed                    clini-
 visualization             of blood            vessels         of the knee                                                    cally and roentgenologically                                            over the next 6
joint,       in the area where                     a mass          of calcium                                                 weeks   and the rabbits      were                                     sacrificed at var-
 also      was        located          secondary                to calcium                                                    ious            intervals          for               pathologic                examination.
gluconate              intramuscular                     injection.           The                                                      Four           additional                       rabbits               were        subse-
second         case showed               the startling              finding       of                                          quently                    studied              and        injected                with               either
 a “rather          massive          deposit           of calcium           pres-                                             normal             saline as controls or calcium                                                   gluco-
ent in the substance                     of the right lung.”                  The                                             nate             as shown    in Table    i.  These                                                   were
 calcific      densities          eventually              disappeared.                                                        sacrificed                      as     indicated            and           histologic                  speci-
     Additional             cases      were         reported           by Bak-                                                mens             obtained.                   The       injection              site         including

                                                                                                                  TABLE            I
                                                                            EXPERIMENTAL                        STUDY:       HISTOLOGIC                       FINDINGS

          .                         Agent                  Dose
                                                                                                         Sub-             Soft Tissue
                                                                                                                                 ‘     .
                                                                           and  Dermis              cutaneum             Calcification              Calcification             Involved

 24 hi.               Saline                               a cc.                  0                         +                          0                       0                     0       Focal        perivascular           eosino-
                                                                                                                                                                                             philic       infiltrate

 24       bX.         Calcium           gluconate          2 cc.                  o                    + +                         +                           0                  + +        Edema,          eosinophilia,
                                                                                                                                                                                             marked          histiocytic

 72       hr.         Calcium           gluconate          2 cc.                  o                      + +                       +                           0              + + +          Histiocytic         infiltrate,            occa-
                                                                                                                                                                                             sional      foreign     body
                                                                                                                                                                                             giant     cells

      7 da.           Saline                               a cc.                 o                          0                      0                           0                     0

      8   da.         Calcium           gluconate          2 cc.                  o                 + + +                     + +                             +               + + +          Granulation           tissue,   fibrous
                                                                                                                                                                                             tissue    proliferation       and
                                                                                                                                                                                             foreign     body granulomas

 I 5 da.              Calcium           gluconate          2 cc.                 0             + + + +                        + +                             +            + + + +           Same         as 8 days,         only      to a
                                                                                                                                                                                             greater extent

 30       da.             Calcium       gluconate          2 cc.                  0                      + +                       +                           +                   + +       Granuloma               formation

 37 da.               Calcium           gluconate          4 cc.       ++++                    ++        + +                       +                          +                   + +        Gross      calcified,         ulcerated
                                                                                                                                                                                             lesion    with     calcium-filled
                                                                                                                                                                                             inclusion      cyst formation

 45       da.         Calcium           gluconate          i cc.                  o                    + +                         +                           o                     +       5ubcutaneum            fibrotic,    focal
                                                                                                                                                                                             calcium       in foreign       body
                                                                                                                                                                                             giant    cells in muscle

      0         absent;        +    -   present;     + +           mild;     + + +       =   moderate;           + + + +       =   marked.
VOL.     121,       No.                              Extravasation                 of      Calcium               Gluconate                                                                                      113

skin,     subcutaneum            and underlying          muscle                               peak    (Fig.  4). After    30  days  the response
was excised           and fixed         in neutral     buffered                               was subsiding      and there was granuloma        for-
formalin.        Sections       were      cut at 7 microns                                    mation.     At 37 days,   however,   in the animal
and stained           with     Hematoxylin         and Eosin                                  which              received                the            largest                 dose           of calcium
and     the Von          Kossa      stain    for calcium.         If                          gluconate,    a large  ulcerated      calcified lesion
necessary,         the tissue        was decalcified        prior                             was present     (Fig.  5). This     is the only case
to sectioning.                                                                                in which    the epidermis        was involved       and
                                                                                              the       reaction                   was             present                 in         all      layers,            in-
                EXPERIMENTAL             STUDY      AND     RESULTS
                                                                                              cluding     calcification           of blood     vessel     walls
     Clinical            response             following           injection           of      below     muscle       bundles.
the calcium                 gluconate             was somewhat                 van-               The oldest        lesion,     but the one associated
able and appeared                        to be dose related.                 There            with    the smallest           calcium     gluconate        dose,
was        development                    of some            erythema           and           showed      primarily         subcutaneum          thickening
induration               by the second                  day.      By the fifth                with             more               foreign                     body               giant               cells           in
through              seventh              days         there         was       more           muscle.              The             vascular   calcification,                                         as well
erythema                and         firm        induration.               By      the         as the             muscle             and subcutaneum                                            histiocytic
tenth         day there              was a definite                  hard      mass           infiltrates                   had      resolved.
palpable.              Erythema                 and       mass         were      ob-                Roentgenologic                        Findings.                        Immediately                          fol-
served          with         as little         as i cc. calcium                 glu-          lowing              injection                 of           calcium              gluconate,                         no
conate;           however,              the degree             of associated                  evidence                  of        calcification                            was              seen         roent-
erythema              and the size of the mass appeared                                       genographically                             in either                       the         disarticulated
dose related.                  Only         I rabbit,          who received                   chicken               legs   or the      living                                          rabbits.               The
4      cc.       calcium               gluconate,              developed               a      earliest            definite   roentgenologic                                               change               ap-
necrotic           reaction.           In the other             rabbits       there           peared              at 4 days      following                                            injection               and
was progressive                       healing          with       decrease           in       consisted                     of      minimal                         linear                  calcification
erythema,              resorption              of calcium,            and grad-               which     appeared                        vascular.  The                                      calcification
ual disappearance                        of the mass.             By 6 weeks,                 increased       up                    to a maximum                                            at 2 weeks
the injected               site was clinically                 normal.                        post      injection,                   it was amorphous                                          with some
     The histologic                   results        are summarized                  in       linearity            representing                                     vascular                       calcifica-
Table         I Control
                .                     saline       injections          produced               tion          (Fig. 6). On                                follow-up                   examination
no reaction                  except          for focal           penivascular                 there         was a gradual                               decrease                  of the calcium
eosinophilia                 at 24 hours.                The       reaction          to       and         no      evidence                  of calcification                                  was        seen         6
calcium            gluconate               at the same                 time     was           weeks            post           injection.
more          eosinophilia,                 edema          and       a marked
histiocytic               reaction            with       calcification             in-
volving          muscle          fibers in groups                and individ-                       The          intravenous                        use ofcalcium                               gluconate
ually.        The reaction                  at 72 hours             was a pro-                should              be         attended                        with          great               care.          Cal-
gression            of that             at 24 hours,                with      more            cium          gluconate                    should                     not          be         injected            in-
muscle           calcification                and the formation                     of        tramuscularly                          even               though                   this          use       is ad-
foreign         body giant                cells, mostly            around        the          vocated                  in        Pharmacopoeia,2                                       the         pharma-
calcium           salts.                                                                     ceutical    reference       published       by the Council
     At 8 days,                the subcutaneum                      was mark-                of the      Pharmaceutical             Society      of Great
edly        thickened              with        areas       of calcification                  Britain.     It states             “as it does not cause
                                                                                                                                               .    .    .

which         were also seen in muscle.                          For the first               pain     or necrosis      it is also given         intramus-
time,        calcium            was seen in the walls                        of ar-          cularly,    though      in infants       it is advisable     to
teries       and veins.            The calcification                  was focal,             employ                the     oral             or intravenous                                         route          as
involving            different           layers       of the walls in dif-                   cases          of     abscess                formation      in                            the         buttocks
ferent        vessels.          No one layer was involved                           to       have     been                  reported.”
the exclusion                 of others.            At 15 days             the re-               Calcium                     gluconate                 has been shown                                    to be
action         was still further                     accentuated             to its          incompatible                        and               form    precipitates                                  when
 “4                                                                                   P. E.                        Berger,                K.            P. Heidelberger                                                and              A.           K. Poznanski                                                                                                MAY,          1974

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FIG.   .   Cross section                                                              of rabbit                       skin,       subcutaneum        and muscle       (epidermis      at top of photograph).                                                                                                                                           Fifteen    days
   post subcutaneous                                                                   injection                        of      2 cc.   calcium   gluconate.      Fibrosis,      edema    and granulation                                                                                                                                         tissue      with ex-
   tensive     calcification                                                             (black                     areas).         At  lower left center    (arrows)       is vein with calcified     intima.                                                                                                                                      (Hematoxylin
   and Eosin          X9.)

mixed       with   a variety        of pharmaceuticals                                                                                                                                                          The           histologic                                  changes                                        (Table                            i)       corre-
such     as prednisolone          sodium       phosphate,”                                                                                                                                          late              well              with                        our              roentgenographic                                                                   find-
prochlorperazine         maleate,      streptomycin        sul-                                                                                                                                     ings.      Thickening       of the subcutaneum          and
phate,’3                                       and           amphoteracin.’4                                                    Mizrahi                              et al.’2                       calcification         there    and  in the muscle        are
stated                                      that                     calcium                                       gluconate                            injection                                   dose        related.      Maximum       histologic      and
should      not be added              to a continuous              intra-                                                                                                                           roentgenographic            changes   occur     at 2 weeks
venous        infusion         containing          sodium         bicar-                                                                                                                            and               show              a gradual                                    decrease                                      thereafter.                                 By
bonate,      because         of the added          risk of calcium                                                                                                                                  6 weeks                          only                 minimal                                       changes                                       persist             his-
carbonate         precipitation.                                                                                                                                                                     tologically                              and                   roentgenographic                                                                      calcifica-
    Chemical          agents        other      than       those       con-                                                                                                                          tion      is no                                longer   evident.        The                                                                             vascular
taining       calcium          have      been      shown        experi-                                                                                                                             calcification                                   seen roentgenographically                                                                                      was
mentally         to produce             soft    tissue       calcifica-                                                                                                                             also               demonstrated                                                       histologically                                                          and            is
tion.     This      is dealt         with     in depth           in the                                                                                                                             maximum                                   at            2        weeks                              post                       extravasation.
monograph              by      Selye’5       on      calciphylaxis.                                                                                                                                 This               is in             keeping                               with                       the                  histologic                               find-
Soft tissue         calcification          has been produced                                                                                                                                        ings              of Leonard        et al.7                                                          They                                 injected                    cal-
using     lead acetate,9             vitamin         D and ferric                                                                                                                                   cium               ATP    subcutaneously                                                                                 in rats                      and           pro-
chloride.’6                                                                                                                                                                                         duced                      the                 formation                                            of                   white,                              circum-
VOL.           121,      No.      I                                 Extravasation                    of Calcium             Gluconate                                                       115

FIG.       .      Cross          section        of     skin,      subcutaneum         and muscle    of rabbit,       37 days                   post subcutaneous         injection        of
    cc.        calcium           gluconate.             Calcium        filled inclusion    cysts in upper      dermis    (top                  middle)   with additional         calcifica-
    tion         in fibrous            tissue        thickening         dermis    are seen. (Hematoxylin          and Eosin                     X9.)

scribed                   calcific              plaques.                They             demon-            scribed.            In     one of our       cases               the     clinical
strated   considerable                                 subcutaneous                    calcifica-          diagnosis                was  osteomyelitis                    and      despite
tion.   On histologic                                 section          the       mineraliza-               lack      of     roentgenographic                   evidence          support-
tion             was           especially                      pronounced                in        and     ing       this   diagnosis,            the       infant         was       still
around                   the         blood           vessel         walls        and          in    the    treated       with      intravenous               antibiotics           for 3
fascia.                                                                                                    weeks.      With       healing         of the lesions               there       is
       The            clinical    is variable
                                        response and may                                                  gradual        decrease         in soft tissue             calcification
be manifest        at i to 2 days     as erythema        and                                              both       clinically          and       roentgenographically
bulla     formation,       resembling         a localized                                                 and the calcium                may completely                  disappear.
burn   as was seen in our Case I. The lesion                                                              This was shown                in our Case iii and was also
may   also present        as erythema         and calcific                                                demonstrated              in our laboratory                   animals.
mass     as in Case         .,i.  Subsequent        eschar                                                     Roentgenographic                   evidence           of calcifica-
formation                      and         sloughing              of the        skin     is com-          tion may          be seen within                4 to 5 days              post-
mon     as occurred                             in 2 of our 3 cases              and                      extravasation.               The       calcification              is amor-
plastic     surgery                          may      be necessary.          Secon-                       phous,       may be localized                  or spread            through
dary     infection                           may      occur    and     there     has                      fascial       planes.        A rather            striking           finding,
been      I reported                            death       as previously         de-                     that     of vascular            calcification,            was seen in
 i     i6                                    P. E.             Berger,               K.      P. Heidelberger                and          A.      K.     Poznanski                                      MAY,         1974

                                                                                I                                 subcutaneum,            and the fascial         planes.       Vas-
                                                                                                                  cular    calcification        may also be seen.
                                                                                                                      Roentgenologic             recognition         and     aware-
                                                                                                                  ness of this diagnosis               is important,          as the
                                                                                                                  clinical     picture      is variable      and the etiology
                                                                                                                  of the presenting            inflammatory           response      or
                                                                                                                  mass     is often      unknown.
                                                                                                                  Andrew     K. Poznanski,        M.D.
                                                                                                                  Department       of Radiology
                                                                                                                  C. S. Mott     Children’s      Hospital
                                                                                                                  The University        of Michigan       Medical                            Center
                                                                                                                  Ann Arbor,      Michigan      48104
Fic.       6. Lower                extremity      ofrabbit,      popliteal       region,      4
       weeks      post            subcutaneous         injection     of      cc. calcium                             The           authors     wish   to thank    Mr.      Scott
       gluconate.                 Diffuse      amorphous         calcification           with
                                                                                                                  Harper           for allowing     us to use his rabbits.
       some lineari                ty suggesti     ng vascular       calcification.

Case              I.    This was                 also demonstrated                               clearly
                                                                                                                    I.   BAKWIN,              H. Pathogenesis                 of tetany           of newborn.
in          our         laboratory                  animals.    One                         case      pre-
                                                                                                                            Am. 7. Dis. Child.,                        1937,54,          121 1-1226.
viously                 reported                 by      Shannon’7                   also         showed            2.   BLACOW,        N. W., and WADE,           A. Editors.      Martin-
vascular                   calcification.                                                                                   dale, The Extra         Pharmacopoeia.          Twenty-sixth
                                                                                                                            edition.     The     Pharmaceutical          Press,     London,
                           DIFFERENTIAL                           DIAGNOSIS                                                 1972,     p. 369.
                                                                                                                    3.   BLAKE,       H. A., GOYETTE,           E. M., LYTER,           C. S.,
        As        stated             at     the         outset,               soft        tissue           cal-             and SWAN,         H. Subcutaneous         fat necrosis       com-
cification                   in      the     neonate                  and           young          infant                   plicating      hypothermia.         7. Pediat.,       1955,     6,
is          uncommon.                        The              most            commonly                      re-             78-80.

ported     etiology      is subcutaneous           fat necrosis                                                     4.   DUHN,     R., SCHOEN,            E. J., and Sw,              M. Subcu-
                                                                                                                          taneous         fat necrosis        with     extensive         calcifica-
of the     newborn.         This     entity     has been        de-
                                                                                                                          tion     after      hypothermia          in two newborn                   in-
scribed       associated          with      hypercalcemia,8                                                               fants.    Pediatrics, 1968, 4!, 66 1-664.
hypothermia,”4             and     asphyxia         and      anox-                                                  5. HOLZEL,         A. Subcutaneous              fat necrosis           of new-
emia.5     Calcification         of a hematoma              in the                                                        born. Arch. Dis. Chi/d/iood,                  1951,    26, 89-91.
soft          tissues             due       to        birth          trauma               could           con-      6. LAMM,      S. S. Danger         ofintramuscular              injection         of
                                                                                                                          calcium        gluconate       in infancy.        7.A.M.A.,           1945,
ceivably                   occur.            To           this         differential                  diag-
                                                                                                                            129,       347-348.
nosis             we     add        extravasation                      of an          intravenous                   7.   LEONARD,     F., BOKE,         J. W., RUDERMAN,             R. J.,
infusion                 of        calcium                gluconate.                   This          is      an          and HEGYEL,          A. F. Initiation       and inhibition        of
important        cause       of   soft      tissue       calcification,                                                  subcutaneous           calcification    .   Ca/cfled       Tissue
as our reported            cases and those                  reviewed    in                                               Research,      1972,   JO, 269-279.
                                                                                                                    8. MARTIN,      M. M., and STEVEN,             E. M. Subcutane-
the medical        literature          illustrate.
                                                                                                                         Otis fat necrosis        of newborn        with calcification
    The     roentgenographic                       findings         are of                                               of soft tissues.       Arch.      Dis. Childhood,:     I 957, 32,
great     importance            in that           they      are usually                                                     146-148.

the     key    to the diagnosis                      which       may    be                                          9.   MCCLURE,                J., and        BRIDGES,             J. B. Experimental
otherwise       unsuspected              clinically.                                                                        calcifications               of     soft      tissues.         Roy.       Soc. Med.
                                                                                                                            Proc., 1969,              62,     240-241.

                                                                                                                  10.    MCLAREN,                J.    W.       Calcium              gluconate          injection
                                                                                                                            into       muscle.        Brit. 7. Radiol.,                 1946,     19,314-317.
    Three      cases     of soft        tissue       calcification                                                II.    MISGEN,      R. Compatibilities             and incompatibili-
secondary         to   subcutaneous              extravas        ation                                                      ties  of some     intravenous         solution        admixtures.
of an intravenous              infusion        of calcium           glu-                                                    Am.    7. Hosp. Pharm.,          1965, 22,     92-94.

                                                                                                                  12.    MIZRAHI,      A., LONDON,          R. D., and GRIBETZ,               D.
conate      are reported.                                                                                                   Neonatal      hypocalcemia:           its causes        and treat-
    Histologic       changes         consist     of thickening                                                              ment.    New England          .7. Med., 1968, 278, 1163-
of the subcutaneum                and calcification             in the                                                      1165.
VOL.     121,    No.                        Extravasation           of Calcium         Gluconate                                                   “7

13.    PATEL,          J. A., and PHILLIPS,      G. L. Guide      to                Dermat.,   1961,37,      7-12.
          physical        compatibility     of intravenous   drug         17.    SHANNON,     W. R. Tetany             syndrome        in newborn
          admixtures.         Am.   7. Hosp.    Pharm.,     1966,   23,             infants:  remote      deposit       of calcium       gluconate.
          409-411.                                                                  Am. 7. Dis. Child., 1938,56,              1046-1054.
14.    RILEY,          B. B. Incompatibilities  in intravenous            18.    TUMPEER,     I. H., and DENENHOLZ,                E. J. Calcium
          solutions.       Am. 7. Hosp. Pharm., 1970,28,   228-                     deposits    following        therapeutic        injections        in
          240.                                                                      tetany   of newborn.           Arc/i. Pediat., 1936,            53,
i.     SELYE,H. Calciphylaxis. University of Chicago                                2 15-223.

       Press, Chicago, 1962.                                              19.    VAN Ho FE, F. H., and JENNINGS,                 R. E. Calcium
i6. SELYE,   H., MARIE,      A., and JEAN,    P. Systemic                          deposition      following      intramuscular          adminis-
       and topical factors involved in production          of                      tration    of calcium     gluconate.        7. Pediat.,    1936,
       experimental     cutaneous   calcinosis. 7. Invest.                         8,348-351.

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