1088 LETTERS TO THE EDITOR

ate blood levels not exceeding 35 mgI syndrome.” This comprised abdominal dis-
100 ml are generally tolerated and spon- tention, pallid cyanosis and vasomotor col-
taneously diminished without specific treat- lapse, and was observed to appear within 2
ment. Much depends upon the availability to 3 days after institution of chlorampheni-
of this measurement, the speed with which col therapy in newborn infants. This entity
the results can be reported, and the time was not seen in neonates administered
interval since ingestion of the drug. chioramphenicol in doses less than 50 mg/
ALFRED M. BONGIOVANNI, M.D. kg/24 hours. The alarming nature of this
Philadelphw, Pa. problem seems to have been corroborated
by similar observations from several medi-
To THE EDITOR: cal centers.25
We would wholeheartedly agree with the These afflicted infants were administered
comments made by Dr. Bongiovanni. Per- chioramphenicol as well as other antibiotics
imps though, his last sentence should be because of premature rupture of uterine
amplified further and emphasized a bit. membranes in most instances. Occasionally
We should not like to leave the reader with the drug was also used prophylactically in
the impression that following acute inges- cases of prematurity or septic delivery. In
tion of salicylate one can be adequately me- only one reported instance did unusual
assured by finding a single level of salicyl- clinical behavior precede the use of chlor-
ate in tile blood below 35 mgIlOO ml; the amphenicol (Case 32) Dosages were always
dose ingested, the amount removed by considerably in excess of the limit stated
emesis on lavage, and the time of determi- above, and in three instances death was as-
nation all bear critically on the interpreta- sociated with chionamphenicol blood levels
tion of the level. Two of the patients re- of 70, 170 and 200 tg/ml.5’6
ported by us had striking rises in the con- A fairly consistent clinical pattern was
centration of salicylate in the blood 4 hours noted in these groups. If chloramphenicol
after the first determination. It is, therefore, had been started at birth, then by 72-96
necessary to take into account other factors hours of life anorexia, lethargy, poor suck
in evaluating the danger of acute salicylate and occasional emesis appeared. Soon after,
ingestion. In equivocal situations, two abdominal distension, irregular respirations,
salicylate level determinations a few hours cyanosis and eventually vascular collapse
apart can help resolve the matter. As Dr. occurred. Occasionally congestive heart fail-

Bongiovanni points out, levels of salicylate ure, edema, opisthotonos, seizures, bleeding
below 30 to 35 mgIlOO ml are not associ- tendencies, diarrhea and hypothermia were
ated with severe intoxication unless con- also noted. Death usually occurred 48-72
sidenable time has elapsed (12 or more hours after the onset of symptoms. In some
hours) after the acute ingestion and not cases symptoms abated after early cessation
necessarily even then. In such instances it of chlonamphenicol therapy.5
is important that the means employed to Histopathologic studies were never very
remove salicylate be less dangerous than remarkable, although hepatic and pneu-
the intoxication itself. monic changes of varied sorts were re-
LAURENCE FINBERG, M.D. ported. Bacteriologic studies were usually
Baltimore, Md. obtained, and viroiogic investigation occa-
sionally done, without significant findings.
On the “Gray Syndrome” and Chloram-
The “gray syndrome” as described me-
phenicol Toxicity sembles closely the toxicity usually charac-
teristic of overwhelming neonatal bacterial
To ms EDIToR:
and viral infections, except for the absence
Some time ago North American podia- of fever, ictemus and hepatosplenomeg-
tricians were introduced to the term “gray aly.7’1#{176}
As the early symptoms of such a syn.

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 LETTERS TO THE EDITOR 1089

(Irome suggest a failure to tilrive, the pli- have evolved many worthwhile facts.
sician IlluSt also consider specific neuroiogic Among tilese is the suggestion that, because
conditions, such as subdural effusion and of limitations of glucuronide conjugating
illtracranial hemorrhage as well as such ability and renal tubular function in the
metabolic problems as hypoglycemia and neonate, very adequate therapeutic levels
adrenal insufficiency. of chloramphenicol can be obtained using
Our own concern with this problem and a daily dose of only 50 mg/kg.12 In addition,
an attempt to eliminate or incriminate a the nicely controlled studies of Burns et al.,
bacterium or virus as the underlying fac- as well as the suggestive observations of
tor in the demise of these infants has pro- Kent and Wideman,4 warrant the need for
vided an interesting though puzzling ob- concern regarding the propriety of prophy-
servation.11 On two occasions we have lactic antibiotic therapeusis in the newborn.
been able to isolate an adenovirus type 4 One cannot accept cillonamphenicol in-
from the necropsy specimens of lungs of toxication as the only cause of the ‘gray
two infants wilo expired with ashen gray syndrome,” and to consider the adenovirus
color, abdominal distension and vasomotom mentioned here as a cause must also remain
collapse. The first isolation was from a full- speculation. It is our opinion tilat the “gray
term infant whose failure to thrive first be- syndrome” is a nonspecific clinical response
came manifest on the third day of life. After of the neonate, a severe departure from nor-
specimens were obtained for bacteriologic mal adaptation to extrauterine life, and may
study, chloramphenicol in a daily dosage result from many and varied etiologies.
greater than 100 mg/kg was started. The Only thorough investigation of these infants
infant expired on the tenth day of life. Post will supply the answers which are still so
mortem examination revealed only scat- wanting.
tered, well-circumscribed areas of intra- J OSEPH ST. GEME, M.D.
alveolar pulmonary hemorrhage. The other Department of Pediatrics
isolate was from a premature infant who University of Minnesota
had been given prophylactic antibiotics (in- Minneapolis 14, Minn.
eluding chioramphenicol in a daily dosage
greater than 100 mg/kg) because of aspima- References
tion of blood and amniotic fluid at delivery 1. Letter from Parke, Davis and Company:
by cesamian section. Failure to thrive ap- Chloromvcetin in the treatment of pre-
peared on the fifth day of life and the infant mature and newborn infants, January 21,
1959.
died 4 days later. Post-mortem examination
la Lambdin, M. A. : Chloramphenicol tox-
revealed complete atelectasis of the lungs,
icity in premature infants. PEDIATRICS,
focal degeneration of the liver and scattered 25:935, 1960.
petechiae in the brain. Bacteriologic studies 2. Sutherland, J. M. : Fatal cardiovascular col-
of both infants were negative. It must be lapse of mfants receiving large amounts
emphatically stated that our investigation ofchloramphenicol. A.M.A. J. Dis. Child.,
97:761, 1959.
of other neonates similarly afflicted failed to
3. Lischner, H., Latta, H., Seligman, S. J.
yield cytopathogenic agents. and Parmelee, A. H., Jr. : Association of
That the possibility of chlonamphenicol chioramphenicol administration with
intoxication of the newborn was recognized early neonatal death. Paper presented at
First Annual Meeting of the Central So-
almost simultaneously by scattered groups
ciety for Pediatric Research, October 26
of observers is certainly remarkable. Con-
and 27, 1959.
stant and repetitious evaluation of the bene- 4. Kent, S. P., and Wideman, G. L. : Prophy-
ficial and untoward effects of modern thera- lactic antibiotic therapy in infants born
peutic methods is always mandatory. From after premature rupture of membranes.
the aforementioned observations of appar- J.A.M.A., 171:1199, 1959.
5. Bums, L. E., Hodgman, J. E., and Cass,
ent deaths due to chiomamphenicol toxicity
A. B. : Fatal circulatory collapse in pre-

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 1090 LETTERS TO THE EDITOR

mature infants receiving chlorampheni- at that time was treated with chlonampheni-
col. New England J. Med., 261:1318, col. The other infant lived longer than those
1959.
in our experience who expired from the
6. Sutherland, J. M. : Personal communica-
tion. chioramphenicol alone. This I think would
7. Nvhan, W. L., and Fousek, M. D. : Septi- make one consider the possibility of an
eemia of the newborn. PEDIATRICS, 22: extra factor in these two individual infants
268, 1958. as a contributory factor in their demise. I
8. Medearis, D. N., Jr. : Cytomegalic inclu-
would be interested to know what relation-
51011 disease. PEDIATRICS, 19:467, 1957.
9. Kibrick, S., and Benirschke, K. : Severe gen- ship the isolation of this virus has with
eralized disease (encephalohepatomyo- other viral studies at tile time. Was there
carditis) occurring in the newborn period an epidemic current at that time? Was the
and due to infection with Coxsackie adenovirus type 4 isolated from otiler in-
virus group B. PEDIATRICS, 22:857, 1958.
fants who did not expire on from personnel
10. Zuelzer, W. W., and Stulberg, C. S. : Her-
pes simplex virus as the cause of fulmi- in the nursery?
nating visceral disease and hepatitis in It will be come evident that the mecogni-
infancy. A.M.A. J. Dis. Child., 83:421, tion of chloramphenicol intoxication did not
1952. occur simultaneously by a scattered group
11. St. Ceme, J. W., Jr., and Prince, J. T.: but was brought to the attention of Parke,
Adenovirus infections in the newborn
Davis and Company, and to others by our
infant. In preparation.
12. Reynolds, j. W. : Unpublished data. observation in the early months of 1958.
Therefore I feel it is not remarkable that
scattered groups of observers recognized
To THE EDITOR:
this syndrome simultaneously thereafter.
My reaction to the remarks of Dr. St. I would agree entirely witil Dr. St. Ceme,
Geme, which concern the “gray syndrome,” that chlomamphenicol intoxication may not
was one of agreement. I was pleased that be the only cause of the “gray syndrome,”
the problem had been so clearly outlined in fact the so-called “gray syndrome” does
and could again be brought to the attention not necessarily occur in all babies with
of all concerned with came of the newborn chioramphenicol intoxication . There are un-
infant. We here have not observed all of the doubtediy other causes for “failure to
symptoms and signs as outlined by Dr. St. thrive” in the newborn and especially in the
Geme, which have been variously quoted to prematurely born neonate. It is mandatory
be the result of excessive amounts of chlor- that the failure to thrive of the newborn
amphenicol. We have no instance suggest- must be investigated in each individual in-
ing congestive heart failure, edema, opis- stance and it can only be hoped that the
thotonos or seizures, however, the other improper use of chlomamphenicoi will be
signs of distress have been noted and re- eliminated as one of the causes thereof.
corded. It seems unnecessary to say that I feel
It is certainly true that this picture pre- prophylactic antibiotic therapy in the pre-
sented by this group of infants would make mature is unwise; however I feel that now
one consider many possibilities of variable chlonamphenicol can be administered to
etiology and yet when we reviewed our the premature infant, as well as the full-
cases, the syndrome seemed to be quite term infant, if administered with proper
definite in its individuality. It was most in- restrictions and
cane.
teresting to me that a cytopathogenic agent Thank you for the privilege of reviewing
has been isolated from two infants who cx- the letter of Dr. St. Geme.
hibited this syndrome, and it is even more MORRIS A. LAMBDIN, M.D.
intriguing that that isolate is the same virus Department of Pediatrics
in each instance. One of these infants was University of Virginia

noted to be ill on the third day of life and Charlottesville, Va.

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 On the "Gray Syndrome" and Chloramphenicol Toxicity
JOSEPH ST. GEME
Pediatrics 1960;25;1088

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 On the "Gray Syndrome" and Chloramphenicol Toxicity
JOSEPH ST. GEME
Pediatrics 1960;25;1088

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
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