THE
HAZARD
OF
INDUCTION
OF
SWEATING
IN CYSTIC
FIBROSIS
OF
THE
PANCREAS
Jack D. Gorvoy, M.D., Hedda Acs, M.D., and Martin L. Stein
Department of Pediatrics, Long Island JewLsh Hospital, New Hyde Park, New York
(Accepted November 30, 1959; submitted August 25.)
ADDRESS: (J.D.G., office) 79-04 256th Street, Floral Park, New York.
977
PmATnIcS, June lOGo
A
2-YEAR-OLD child died subsequent tothe performance of a “sweat test” for the diagmiosis of cystic fibrosis of the
pan-creas. While there were mitigating
circum-stances surrounding this situation, the
in-cident seemed so intimately related to the
test that it is being reported, with the hope
that open discussion of this experience will
help to avoid similar occurrences.
The diagmiosis of cystic fibrosis of the
pan-creas is now made with increasing
reia-bility as a result of the more general
ap-preciation of the clinical manifestations, and the greater dependability of the laboratory
tests used for confirmation. Kessler and
Anderson observed that patients with
cystic fibrosis of the pancreas are
panticu-larly liable to heat prostration during hot
weather. This observation became
explic-able when it was 5 that the sweat
of patients with cystic fibrosis contained
abnormally high concentrations of sodium
and chloride.
Sliwachrnan et a!. ‘ suggested the
tech-Iiique, using a I)lastic bag for the collection
of sweat. In their original description of this
test, the patient is placed in a “plastic suit
which has an elastic neck and a zipper in
front. He may be covered with a blanket,
and at the end of 30 to 90 minutes,
depend-ing on the rate of sweating, he is taken from
the bag.”
The performance of this test offers few
teclmical difficulties when carefully
super-vised. However, it is associated with
pos-sible dangers, especially when applied to
small infants and those with severe
pub-monary involvement.
To date we are aware of six fatalities as
a sequel to this thermal-stimulation test.
The case to be presented in this article is the only one of these known fatalities with proven cystic fibrosis of the pancreas.
Three of these fatalities occurred in in-fants a few weeks of age, with severe
pub-monary involvement.5’ The infants were kept in the plastic bag for “lengthy” periods in an endeavor to collect sweat, which in fact did not appear. The failure to obtain adequate sweat at this age might have been anticipated, since physiologically it is un-likely that an infant under 6 weeks of age will produce enough sweat for collection in this manner. These infants subsequently de-veloped hyperpyrexia and tachypnea. Death was rapid in each case. It was the opinion of the observers that these deaths resulted from heat stroke. Since there were no necropsies, cystic fibrosis of the pancreas was not confirmed, nor was it possible to demonstrate the changes of heat stroke.
Although as stated above, infants of this
age do not produce appreciable sensible sweat, Barbero7 demonstrated abnormal electrolyte concentrations in sweat from two infants convalescing from meconium ibeus at 7 to 10 days of age. However, he states that the production of sweat in these infants appeared to be the exception to the rule, and that he had generally no success in collecting sweat before 2 to 3 months of
age.
A half
hour
after
being
removed
from thebag, the child vomited and became
co-matose and developed a fever of 104#{176}F. Death occurred in coma 14 hours after
con-cbusion of the test. The necropsy report was
in keeping with the usual findings in heat
stroke, namely, flame-shaped visceral
hem-orrhages, edema of the brain and
conges-ti()n of the lungs. The pancreas was normal.
History
CASE REPORT
S.K., a white female child, was admitted to The Long Island Jewish Hospital, on May 10,
1958, at 2 years of age, for the performance of the sweat test for the diagnosis of cystic fibrosis
of the pamicreas.
She had been in apparent good health until 6 weeks prior to hospitalization, at which time
she developed a persistent productive cough,
associated with the presence of medium rales scattered throughout both lung fields.
Roent-genograms of the lungs taken 3 weeks, as well as 1 week, prior to admission to the hospital
showed diffuse infiltrations bilaterally. There
were no episodes of diarrhea, although the stools were described as having been softer
than usual for about 2 weeks. The birth weight
was 2,950 gm. At 1 year of age, her weight was 8,540 gm and the height was 72.5 cm.
The family history is quite pertinent, but the
details will be described at the end of this case
report.
Physical Examination
At the time of admission to the hospital, the patients general condition seemed to be
satis-factory. She was alert and playful. The weight
was 10. 1 kg and the height was 84 cm. The
temperature was 37.9#{176}C. The positive physical findings were confined to the lungs. There were
imispiratory coarse rhonchi and expiratory
musi-cab wheezes, bilaterally.
Initial Course
In the performance of the sweat test, the
child was placed in a plastic bag and covered
with an electric blanket. The parents were
per-mitted to sit next to the child throughout this
procedure. After 1 hour and 15 minutes in the bag, the child had a generalized clonic
convul-sion which lasted about 1 minute. She
sub-sequently vomited and then
lapsed
into
coma.Her color was slightly cyamiotic. The pulse was weak and the respirations were irregular. The
axillary temperature taken about 10 mimiutes
after removal from the bag was 39.1#{176}C.Al-though only 2 ml of sweat were collected, the child’s skin was moist. Nevertheless, because of the possibility that the patient may have
suffered depletion of electrolytes while
sweat-ing, 60 ml of 0.9% sodium chloride solution was
given subcutaneously immediately.
However, no chamige in her comidition
re-suited. The patient was placed in an oxygen tent, and 0.9% sodium chloride with 5% dextrose solution was begun imitravenously. About 1
hour after the onset of the first comivulsiomi,
another generalized seizure occurred, again
as-sociated with vomiting. At this time her axillar’
temperature was 40 #{176}C. Antipretic nieasures were applied (acetvlsalicvlic acid, 0.13 gui
per rectum, and alcohol spongimig). Sodium
phenobarbital, 0.09 gm, was given imitramuscu-lanly without benefit. The convulsions persisted
until paraldehyde, 1.5 ml in 5 nil glycerimie,
was given per rectum. A spinal tap was
per-formed; clear fluid was obtaimied under elevated pressure.
Initial Laboratory Findings
In the serum, the concentration of sodium
was 130 meq/l and of chloride 104 meq/l. In
the sweat, the concentration of sodium was 141 meq/l and of chloride 158 rneq,/l. A
catheterized urine sample showed a 2 + pro-tein, but was otherwise normal. The
comicen-tration of hemoglobin was 12.6 gm/100 ml;
hematocnit 38%, corrected; leukocytes 17,700/
mm3 with a differential count of 12% bamids, 36% segmented cells, 1% eosinophils, 1%
baso-phibes, 37% lymphocytes, 9% monocytes, 4%
metamyebocytes. The cerebrospinal fluid showed
normal cellular elements and normal
chem-istry. Coagubase positive Staphylococcus aureus
was cultured from the throat. Roentgenograms
of the chest taken about 1 hour after removal
from the bag revealed prominence of the pub-monary markings through the mesial half of both lung fields. There was no evidence of re-cent pulmonary infiltration.
Further Course
About 10 hours after the onset of coma, the child’s respiratory distress increased. She had several tonic and clonic convulsions. The fluid
ARTICLES 979
levulose in multiple electrolyte solution with
added calcium gbuconate (0.13 gm).
Erythro-rnvcin glucoheptonate (40 mg/kg) was
added to the intravenous solution. In the first 24 hours, the patient received 900 ml of fluid
intravenously. Her urinary output was
con-sidered adequate, although not measured. The following morning, Kussmaub respirations were
noted. There were moist rales present over 1)0th lung fields. The liver was enlarged to
about 3 cm below the costa! margin.
Further
Laboratory FindingsThe beukocyte count was 27,000/mm3 with
a shift to the left. In the serum, the
concentra-tion of sodium was 142 meq/l; chloride 112 mneq/l; potassium 5.6 meq/l; calcium 8 mg/ 100 ml; glucose 145 mg/100 ml. The content
of carbon chloride was 16 mmole/l. The blood
urea nitrogen was 29 mg/100 ml. Roentgeno-gram of the chest repeated at this time again
showed the diffuse fibrotic changes in both
lungs. There were also increased markings in
the periphery of the right base, interpreted as
bronchopneumonia of recent origin.
Terminal Course
Digoxin (15 mg) was administered. The
fluids being given intravenously were changed to Hartmann’s solution with 5% dextrose.
Peni-cillin (1.2 million units) and streptomycin
(200 mg) were added to the intravenous fluids. A tracheostomy was performed because
endo-tracheal intubation and suction yielded copious purulent material. She was bronchoscoped
and given a tracheo-bnonchiab lavage. Plasma,
cortisone and 12 ml of 0.2% levartenenol
bitar-trate were given without benefit. The patient expired 58 hours after the institution of the sweat test.
Necropsy Findings
Only the pertinent findings are recorded. The
lungs were voluminous, congested and mark-cdlv edematous. There was patchy emphysema
and atelectasis. Sectioning showed congested, edematous bronchiectatic parenchyma, which revealed patchy hemorrhagic pneumonitis,
es-pecially in the left lower lobe. In this area too, there was a suggestion of peripheral vein
thrombosis. The bronchial radicals were dilated
and thickened, especially in the right lung.
Thick tenacious mucopurulent material was
present in the bronchial radicals.
The pancreas was 11.0 cm in length, pink-white, lobular and firm in consistency. It
sug-gested a denser consistency than is ordinarily
encountered.
The brain weighed 1,100 gm. The cerebral
hemispheres were symmetrical and
well-devel-oped. There was moderate widening of the
gyni and flattening of the sulci. At the base the
blood vessels forming the circle of Willis were
normal. There was a mild cerebelbar pressure
cone. Multiple frontal sections through the
cerebral hemispheres revealed a sharp
demarca-tion between cortical gray and white matter.
No petechial hemorrhages were seen at any site. The choroid plexuses bilaterally were
slightly cystic in appearance. The brain stem
and cerebellum did not reveal an’ abnormality. The liver showed massive fatty infiltration and
necrosis.
Microscopic examination of the lungs
re-vealed suppurative fibrous tissue with focal
acute suppurative pneumonia. There were foci
of hemorrhagic pneumonia. The pancreas
showed interstitial fibrosis and focal bvmpho-cytic infiltrations. There was atrophy of the
acini and dilated ducts with inspissated plugs. The islets were intact. In the brain multiple
Nissl-stained preparations from the cerebrum,
basal ganglia, Ammon’s horn and cerebellum
were completely normal. There was no
cvi-dence of cell loss.
Family History
The patient’s family history is of considerable
interest. The patient’s father and her
6-month-old sibling had negative “fingerprint” tests for
excessive chloride in sweat. The child’s father
has one sister and two brothers. The paternal
aunt amid her 2-year-old daughter had negative “palm” tests for chloride. One paternal uncle
had a questionable “palm” test, but his 6-year-old daughter is known to have cystic fibrosis of the pancreas, and his 5-year-old son had a
questionable “palm” test, but normal proteo-lytic activity in duodenal secretions. The other
paternal uncle had a questionable “fingerprint”
test, as did two of his three children. One of these children had two alarming reactions
fol-lowing surgery. He had severe respiratory
diffi-culties following anesthesia for umbilical repair at 2 years of age. At 4 years, after repeated
episodes of follicular tonsillitis associated with
CYSTIC FIBROSIS
reacted well during the surgery but the
post-operative reaction was marked by severe
stni-dor, a temperature of 40.6#{176}C and labored
respirations. At 16 hours postoperatively, the child was in deep coma with complete areflexia. All laboratory data including roentgenogram of the chest, cerebrospinal fluid, and serum
electrolytes were normal. Supportive therapy
of fluids intravenously, antibiotics and digitalis
was given. An emergency tracheostomy was done at this time. During the following 2 days,
there was progressive improvement and after
23 days of coma the child became lucid and
alert. There were no focal neurobogic signs and the child was free of apparent residual effects and has remained presumably well.
DISCUSSION
Heat prostration (or exhaustion) and
heat-stroke must be foremost in our consideration of the cause of this fatality.
In heat prostration there is profuse sweat-ing and salt depletion. Patients with cystic fibrosis are known to be more susceptible to the danger of heat prostration due to cx-cessive loss of electrolytes in their sweat.
It
is noteworthy that in one report’ the only death among a group of five children with proven cystic fibrosis, who were brought into the hospital during a heat wave, was that of a 23-month-old child who was wrapped in a woolen blanket by the mother-thus to a degree simulating the plastic bag
by interference with the process of evapora-tion. This child was hyperpyretic and
corn-atose, and died within an hour of
admis-sion to the hospital. The necropsy failed to reveal any anatomic lesions to account for the death, but cystic fibrosis of the pancreas was confirmed.
In heat
stroke,
the
picture
is one
of
hyper-pyrexia with cessation of sweating. Its
dis-tinguishing features are: coma, convulsive seizures, cyanosis and circulatory failure. Salt depletion is not usually an important factor in this condition. Marked
hyper-pyrexia is usually present, although a few
cases have shown only slight fever, as noted
in a report on 125 fatal cases of heat stroke.#{176}
In
15% of these
cases,
the
temperature
was
below 103#{176}F (41.8#{176}C). None of the 125 cases were characterized by dehydration.
The sudden cessation of sweating is con-sidered to be an important Ominous sign; 70%
of these
cases
died
within
24 hours aftercessation of sweating.
It
is
agreed
by
most
authors
that
the
pathologic changes found in fatalities from heat stroke are neither striking nor specific.Most
cases
presented
edema
and
frequently
hemorrhages of the brain. No significantchanges could be found in the hypo-thalamus. In most cases the lungs were in-filtrated with blood. About 25% of the cases showed lobular pmieumonia. Such lung changes were found as early as 8 hours after the onset of hyperthermia. Petechial hemor-rhages of the mucosal surfaces and of the skin were commonly found, especially in those with marked hyperpyrexia. It is stated1#{176}that at an external temperature of over 90#{176}F,evaporation of sweat is almost the sole means of maintaining body tern-perature. When the plastic bag used in the sweat test enclosed the body, adequate evaporation was prevented and hyperpy-rexia followed.
One
report1’
on
heat
prostration
in
the
pediatric age group noted that infection,especially of the respiratory tract, predis-poses to the development of the high fever when patients were subjected to sustained high environmental temperature.
An
article
on
hyperpyretic
conditionslS
comments on the unfavorable effect which hyperpyrexia has on the organs of respira-tion and circulatiomi, especially in the oc-currence of convulsions and coma. This is likely to favor the appearance of grave af-fections of the air passages, especially if thepatient
has
already
suffered
from aninfec-tion of the respiratory tract. The findings in the present patient correspond to this de-scription. It is noteworthy that the hyper-pyrexia of heat stroke is considered excep-tionally resistant to antipyretic measures once it becomes established.
The cause of the fatal course in this
981
the likely explanation. Only 2 ml of sweat
was collected, and the child’s skin was
moist. The highest recorded temperature
was 104#{176}F(40.3#{176}C). The necropsy did not
reveal the changes observed in heat stroke
(
flame-shaped hemorrhages involving the muscles and internal organs.8) The necropsydid show quite severe pathology in the
lungs, which, together with the stress of the
sweat test, might have caused the fatal
out-come, for as already pointed out9 25% of the
fatalities from heat stroke showed pathology
in the lungs of severe degree.
It miiav he more than a coincidence that
severe reactions to stress, such as the
post-tonsillectomy coma and the death after the
sweat test, should have occurred in two
first cousins. These events, added to the
impressive family history of two proven
cases of cystic fibrosis in first cousins, and
several other members of the family with
questionably positive cutaneous sweat tests,
provoked the thought as to whether the
common denominator may be a sex-linked
genetically determined dysfunction of the
autonomic nervous system. The role of the
autonomic nervous system in cystic fibrosis
is obscure, but all the glandular structures
involved in this disease are believed to be
innervated by the parasympathetic system
or, as in the sweat glands, innervated by
sympathetic nerves which have a
neuro-humoral mediator that is cholinergic in
na-ture.
Recently, Gibson and Cooke33 described
a test for electrolyte concentration in sweat
utilizing pilocarpine administered by
ionto-pliresis. Their studies indicate that sweat induced by iontophoretic application of
pilocarpine nitrate is similar to that
result-ing from elevation of environmental
tem-perature. The test has appeared to be quite
safe, rapid and almost painless. This method
of determination of electrolytes in sweat
will probably replace the plastic-bag sweat
test.
CONCLUSION
A fatality
in a 2-year-old child with cystic fibrosis of the pancreas, which resulted froman attempt to collect sweat using a plastic
bag to enclose the patient, is described. It
is reported as a remimider of the potential danger of this procedure and of the need for caution in its performance.
This method should not be used in infants bess than 3 months of age, because they pro-duce so little sensible sweat.
A child
to be subjected
to this
procedure
should have a normal temperature, good hydration and little pulmonary involvement. The addition of external heat should beavoided.
The duration of time the patient is kept
in the plastic bag should rarely exceed 1 hour, and the temperature of the child should be determined repeatedly during the procedure. There should be constant close
supervision by medical personnel.
REFERENCES
1. Kessler, W. R., amid Andersen, D. H. : Heat prostration iii fibrocystic disease of the pancreas and other conditions. PEDIA-THICS, 8:648, 1951.
2. Darling, R. C., di Samit’Agnese, P. A., Perera, C. A., and Andersen, D. H.: Electrolyte abnormalities of sweat in fibrocystic disease of the pancreas. Am.
J.
M. Sc.,225:67,
1953.
3. di Sant’Agriese, P. A., Darling, R. C., Perera, G. A., and Shea, E. : Abnormal electrolyte composition of sweat in cystic fibrosis of pancreas; climiical significance and relationship to disease. PEDIATRICS, 12:549, 1955.
4. Shwachman, H., Leubmier, H. , amid Catzel,
P.: Mucoviscidosis. Advamices Pediat., 7: 249, 1955.
5. MacFarlane,
J.
C. \V., Norman, A. P., amidStroud, C. E. : Fingerprint sweat test in fibrocystic disease of the pancreas. Pre-liminary communication. Brit. M.J., 2:
274, 1957.
6. MacFarlane,
J.
C. \V. : Persomial communi-cation.7. Barbero, G.
J.
: Fibrocystic disease of the pancreas, in Report of the 18th Ross Pediatric Research Conference. Colum-bus, Ohio, Ross Laboratories, 1955, p. 58.8. Misch, K. A., and Holden, H. M. : A sweat test for the diagnosis of fibrocystic dis-ease of the pancreas. Arch. Dis. Child-hood, 33:179, 1958.
9. Mabamud, M., Haymaker, W., and Custer,
982
study of 125 fatal cases. Mil. Surgeon,
99:397, 1946.
10. Best, C. H., amid Taylor, N. B. : Physiologi-cab Basis of Medical Practice, 5th Ed. Baltimore, Williams and Wilkins, 1950,
pp. 720-731.
1 1. Cardulbo, H. M. : Sustained summer heat and fever in infants.
J.
Pediat., 35:24,1949.
CYSTIC
FIBROSIS
12. Akerren, Y. : On hyperpyretic conditions during infancy and childhood. Acta paediat., 31:1, 1943.
13. Gibson, L. E., and Cooke, R. E.: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing
pibocarpine by iontophoresis. PEDIATRICS, 23:545, 1959.
CATALOG OF THE CLIFFORD G. GRULEE
C0L-LECTION ON PEDIATRICS, edited by
Her-man H. Hinkle. Chicago, The John
Crerar Library, 1959, 340 pp., $15.00.
Many pediatricians know that in 1948 Clif-ford Grulee donated his private collection of
medical books to the John Crerar Library in
Chicago. Comparatively few have had an
op-porttmnitv to appreciate its quality and scope. With the publication of this catalogue, under
the editorial supervision of Herman H. Hinkle,
the librarian of the John Crerar Library, and
made possible by a grant from the Gerber Baby Food Fund of Fremont, Michigan, one
can now take its measure with some accuracy.
If, as seems inevitable, a man is to be judged
by the books he assembles, then the Grulee
Collection stands as a truly noble monument
to the scholarship and farsighted generosity of
its donor.
After a short introduction the listing begins,
arranged in the following sequence: 69 items
of general works-bibliographies, treatises,
his-tonical works; 372 items listing
periodicals-journals, reports of academies, institutes,
so-cieties, congresses, government agencies, hos-pitals; 1,071 books of the Fifteenth to
Nine-teenth Centuries, arranged alphabetically for each century; 2,892 books published in the
Twentieth Century; and, finally, separate
in-dexes by author, by organization, and by sub-ject. The number of volumes greatly exceeds the total of 4,404 items listed, for each
periodi-cal is cited but once under a single
identify-ing number; as an example, No. 85, Annales
paediatrici, includes the unbroken series of the
jahrbuch f#{252}rKinderheilkunde und physische
Erziehung commencing in 1857 and
progress-ing through various changes of title to its
cur-rent vigorous incarnation. Complete sets are
available of virtually every current pediatric journal in any language, and the terms of the
gift are such that they are assured of being
kept up-to-date.
The arrangement of books published in the
Twentieth Century differs from that of the rest of the collection in that items are listed by
sub-ject according to a scheme explained in a brief
but clear outline. Under each subject the most
recently published book is listed first, and
oth-ens follow in reverse chronological order. With this sequence the student of a current problem
can gauge at a glance the coverage of his sub-ject in the publications of today. When the
subject is comprehensive and is dealt with in
a relatively large number of titles, those
printed in English are listed first, then French, German, Italian and Spanish, and finally all other languages. Despite the fact that each
title is listed but once in the catalogue, the
careful system of cross-indexing by the author,
organization and subject makes it easy for the investigator to find what he is after and assures
him of locating every pertinent item.
Medical libraries everywhere, pediatric
his-tonians, bibliophiles, editors, publishers,
schol-ans-in short, all who are concerned with the printed word will welcome the publication of
this catalogue. One can only echo the editor’s carefully phrased statement: Certainly the
Clif-ford C. Grulee Collection on Pediatrics is an
important landmark in the history of pediatrics. Unfortunately, typographical
errors-particu-lanlv deplorable in a bibliographic
work-abound; but happily these detract little if at all from the usefulness of the volume.
