SEVERE HYPOTHERMIA IN INFANTS

1009 the M.R.C.P. as a requirement in psychiatry. Those who wish to follow an academic career in psychiatry can fortify themselves with an M.D. or PH.D. During the interim period all present consultants would be granted the Fellowship without Mamination.

Hospital Humberstone,

The Towers

H. B. KIDD.

Leicester.

SICKLE-CELL GENE IN ITALY

SIR,ńWe

are

at

present studying the geographical

distribution of the sickle-cell gene in Italy. We know that instances of sickle-cell anxmia, sicklecell thalasssemia, and sickle-cell trait among people of Italian descent have been found in other countries in Europe and in the United States. We would greatly appreciate your help in asking other workers and laboratories for information about the name and the exact place of origin of any patient of Italian ancestry with sickle-cell disease or trait. Istituto di Semejotica Medica, ALBERTO BESTETTI University of Milan, UMBERTO ROSSI. Milan, Italy. SEVERE HYPOTHERMIA IN INFANTS

SIR,-We read with interest the letter by Professor Macgregor and Dr. Smylie (Oct. 26), commenting on our use of chloramphenicol (25 mg. per kg. per day intramuscularly) in severe neonatal hypothermia. The format of the criticism surely indicates a lack of first-hand experience in treating newborn infants. Severe infection in the first weeks of life is usually due either to a gram-

negative organism or to Staphylococcus aureus which is practically always resistant to penicillin and often to tetracycline. As well as this drawback, tetracycline is not free from dangerand cannot today be recommended for routine

use

in

an

unidentified

severe

infection of the

newborn, either alone or in combination with streptomycin, itself not the safest antibiotic discovered

to

date.

The casual assumption that newborn infants are but little adults and should be treated accordingly is one of the more dangerous aspects of these criticisms. Infected neonates are peculiarly different in their antibody responses and bacterial flora, and if not treated promptly they may die while the pathogen is sought and tested in the laboratory for antibiotic sensitivity. Furthermore these babies do not produce sputum, and diagnostic procedures such as lung puncture are hazardous and unreliable. Even if the laboratory is provided with a presumed pathogen the " in-vitro " estimate of antibiotic sensitivity will not be available in many instances until after antibiotic treatment has started or the baby is dead. A suitable antibiotic must overcome infections which may be due either to Staph. aureus (resistant to penicillin and tetracycline) or one of a range of gram-negative pathogens. In our considered opinion there is, in 1963, only one antibiotic provenly efficacious over a period of years which has these properties-and that is chloramphenicol. Ampicillin is useful against gram-negative organisms but not against penicillinaseproducing staphylococci; cloxacillin or methicillin is effective against such staphylococci but not against many gram-negative organisms. A reversion to polytherapy by the combined use of ampicillin and cloxacillin intramuscularly might appear a possible solution for organisms other than Pseudomonas pyocyanea. There is certainly no evidence of toxicity due to this combination used in neonatal infections in the literature, since there is as yet no published literature according to the manufacturers.2 It is clear that, although trials are in progress, several years must pass before the continued efficacy or the toxicity of these antibiotics can be known (vide tetracycline). Professor Macgregor’s condemnation of our use of chloram1.

Lischner, H., Seligman, S. J., Krammer, A., Parmelie, A. H. J. Pediat. 1961, 59, 21. 2. Personal communication, Oct. 25, 1963.

in the newborn infant lacked references or scientific evidence and would be justifiable only if he spoke from personal experience. In fact, marrow dyscrasia produced in a newborn infant by one course of chloramphenicol is so excessively rare that no further consideration is needed in the context of severe hypothermia with a mortality of 45%. The grey-baby syndrome " due to overdosage of the newborn with chloramphenicol is real, but today represents a failure of the prescriber rather than of the antibiotic. We were surprised at his unsubstantiated innuendo that we failed to detect deaths from chloramphenicol poisoning in our patients. We were keenly aware of this possibility and diligently watched for such cases, and the mortality was no higher than might have been anticipated from previous studies of comparable cases. Furthermore the rather offensive phrase ill-considered advice " referring to the antibiotic treatment which we employed is untrue. On the contrary the type of treatment had been most carefully considered and in 1963, as in 1961, we still consider chloramphenicol in proper dosage to be the antibiotic of choice for unidentified severe neonatal infection. The excellent results of treatment of the respiratory distress syndrome by a regimen which included routine chloramphenicol3 have strengthened this view.

phenicol

"

"

We suggest that before reconsidering the their criticisms Professor Macgregor and Dr. themselves three questions:

validity of Smylie ask

(1) How many cases of neonatal hypothermia (< 90°F) have they treated or supervised ? (2) Have they ever caused, or seen, marrow dyscrasia due to a single course of chloramphenicol given to a newborn baby ? (3) Have they ever caused, or seen, death due to proven chloramphenicol poisoning in a newborn infant when dosage did not exceed 25 mg. per kg. per day ? We would agree entirely that chloramphenicol should be used in the newborn when the presumed pathogen is known to be sensitive to a safer antibiotic. Furthermore chloramphenicol is not the antibiotic of choice for routine emergency use in older children and adults, except in certain specific instances and the risk of marrow dyscrasia is then greater. Perhaps we can even find peaceful coexistence in agreeing that a combination of ampicillin and cloxacillin intramuscularly may one day be proved to be as effective as and safer than chloramphenicol in the treatment of severe neonatal infection, but that day is not yet here. GAVIN C. ARNEIL

not

Department of Child Health,

University of Glasgow.

MARGARET M. KERR.

SIR,-The article by Dr. Arneil and Dr. Kerr (Oct. 12) has good practical points, but their advice about the method of humidifying the room air is inadequate. During freezing weather the humidity of the air in

a heated is much below that of the outside air owing to the evaporation loss produced by the heat during the frequent air changes that occur in the home (the room air is changed at least three or four times every hour, even without artificial ventilation). Under such circumstances, even when the humidity of the outside air was normal (and in freezing temperatures it is usually far below normal), the humidity of the room air may be

room

only 5%

or

10%.

To maintain a normal humidity in a medium-sized bedroom under these circumstances about 8 or 10 gallons of vaporised water per 24 hours are needed. Most of the commercial humidifiers on the market are highly inadequate to supply this amount of vapour; the best and the only one that approaches this aim is a model with a spinning wheel that launches a jet of finely sprayed water in the air. Compared with this, the damp blanket of Dr. Arneil achieves near to nothing in humidifying. A damp blanket may hold at the most 1 or 2 pints of water and takes more than 24 hours to dry at the room temperature. 3.

Hutchison, J. H., Kerr, M. M., McPhail, M. Flora M., Douglas, T. A., Smith, G., Norman, J. N., Bates, E. H. Lancet, 1962, ii, 465.

1010 Therefore if one wants to use Dr. Arneil’s " humidifiers " one would have to use at the same time 30 or 40 damp blankets in a room, continuously for 24 hours a day! For those who cannot have an adequate commercial humidifier, the old and still effective method of boiling water in a pan or kettle over an inexpensive electric fire can supply several gallons of water vapour daily; its only drawback is that the container has to be filled every few hours, and few will be able to keep this schedule during the night. The best answer is, of course, complete home air-conditioning. Saint Mary’s Hospital, M. SANCHEZ.

FLUID

ENCEPHALOPATHY AND FATTY DEGENERATION OF THE VISCERA SIR,-We read with much interest the paper by Dr. Reye and others (Oct. 12). Over the past ten years we have encountered 16 identical cases and we are at present completing a paper describing the clinical picture, the investigations, and the pathological findings. The patients were all under the age of two years, and all well-nourished White children. Before admission to hospital, they had one or two days’ symptoms, mainly associated with respiratory infection, followed by rapid deterioration of consciousness and often convulsions. Clinically all the cases showed signs of hypoglycasmia and acidosis. All but 2 died shortly after being admitted to hospital in spite of heroic attempts at treatment. The essential features at the necropsy examinations were a slightly enlarged but completely fatty liver and cerebral oedema. Attempts at isolating causative viruses were made; but in only 1 case was a virus found, a Coxsackie. There was no evidence in any history of poisoning. were

We have delayed presenting our findings for so long because we have never been able to find a cause nor any explanation of the true nature of the disease, though we feel it is probably the end-result of either a virus infection or, as in Jamaican vomiting sickness, poisoning. Transvaal Memorial Hospital for Children, Milner Park, Johannesburg.

H. L. UTIAN J. M. WAGNER

STEROIDS IN OVARIAN CYST FLUID SIR,-Recent work on the steroid content of ovarian

cyst fluid has revealed interesting differences between fluid from patients with the Stein-Leventhal syndrome and fluid from patients in whom ovarian cysts were associated with various gynaecological disorders.]2 In general, cyst fluid from patients with the syndrome was found to contain relatively high concentrations of &Dgr;4 -androstenedione, low concentrations of progesterone and 17&agr;hydroxyprogesterone, and low or undetectable amounts of oestrogens. But, since the cyst fluid was extracted without previous hydrolysis, some oestrogens bound to proteins or conjugated as sulphates or glucuronides would not be extracted. The protein content of cyst fluid is comparable Short, R. V., London, D. Giorgi, E. P. J. Endocrin.

R. Brit. med. J. 1961, 1963 (in the press).

i,

1724.

([4g.

per 100

5 ml. ALIQUOTS

OF A CYST

ml.)

A. Ether-ethyl acetate extract. B. Hydrolysate of aqueous residue from A. C. Hydrolysate of cyst fluid without previous extraction.

J.

Troy, New York.

1. 2.

TABLE I-REPLICATE DETERMINATIONS UPON

both quantitatively and qualitatively with that of plasma,3 and some binding between cestrogens and proteins could take place. Again, the presence of oestrogen conjugates cannot be excluded, and, indeed, evidence of the presence of small amounts of these conjugates in the cyst fluid of normally menstruating women has been obtained.4 The object of the present study was to investigate whether cyst fluid from the ovaries of patients with the SteinLeventhal syndrome and other conditions contained additional amounts of oestrogens in a bound form. Acid hydrolysis was chosen as a first approach to the problem as this form of hydrolysis should affect protein-binding as well as conjugation.55 The method was a modification of that previously employed for the determination of &Dgr;4-3-ketosteroids and &Dgr;5-3&bgr;-hydroxysteroids, oestrone and œstradiol-17&bgr; in small volumes of cyst fluid.2 Experiments with isotopically labelled oestrogens showed that the extraction of " free " oestrogens was quantitative, and, for the present study, after extraction of the cyst fluid the aqueous residue was subjected to hydrolysis by the addition of concentrated hydrochloric acid and refluxing for 45 minutes. The hydrolysate was extracted with ether, the phenolic fraction separated by means of solvent partition and then purified by chromatography as described elsewhere.2 progesterone, &Dgr;4-androstenedione, cestrone, and aestradiol17&bgr; were used as internal standards for correction of losses. In a preliminary experiment on cyst fluid from a patient with menorrhagia, there was satisfactory agreement between the values for total oestrogens as determined by direct hydrolysis of the fluid or by summation of the amounts obtained before and after hydrolysis (table i). This procedure was then applied to cyst fluids from 8 patients, 5 of whom had oligomenorrhoea or secondary amenorrhoea and sterility and were considered to be examples of the Stein-Leventhal syndrome. Hirsutism was present in 4 (nos. 4, 6, 7, 8); in 1 (no. 5) the hair distribution was normal. Enlarged bilateral polycystic ovaries were found at laparotomy in all 5. The results are shown in table 11. Hydrolysis of the cyst fluid of the 3 patients with disorders other than the Stein-Leventhal syndrome revealed the presence of bound " oestrogens in amounts comparable with those of " free " oestrogens. The cyst fluid of 4 of the 5 patients with the syndrome contained no detectable oestrogens after acid 3. Perloff, W. H., Schultz, J., Farris, E. J., Balin, H. Fertil. and Stenl.

Isotopically-labelled

"

4. 5.

1955, 6, 11. Smith, O. W. Endocrinology, 1960, 7, 698. Preedy, J. K. R., Aitken, E. H. J. biol Chem. 1961, 236,

TABLE II-DETERMINATION OF STEROIDS IN CYST FLUID OF VARIOUS PATIENTS

1300.