SERUM REACTIONS AFTER INJECTION OF CONCENTRATED THERAPEUTIC SERUM

193 not mean in the least to deny the many fine results obtained. The management of an apparently straightforward ambulatory pneumothorax is not so simple as it is said to be and, above all, requires considerably more individual treatment than is generally supposed. A successful operation does not justify us in regarding the tuberculosis as having been overcome, for relapses speak only too clearly to the contrary. Conservative treatment, especially a strict restcure, continues to be the foundation of all treatment of tuberculosis. This, I think, is the conclusion reached by every unprejudiced physician if he carefully examines the results obtained in his own

that, I do

and signs such as fever, oedema, and arthritis which may occur in the absence of a rash. Local reaction, where the rash is limited to the site of

injection serum

injection.

Albuminuria, which is accepted

as a sign of serum reaction when appearing during the potential period of reaction to serum injection and in the absence of other

causes.

The

following

experience.

is

an

analysis

of the

cases :-

ASSOCIATED FACTORS

I am much indebted to Dr. N. L. Rusby for his the arrangement and phrasing of this paper.

help

in

SERUM REACTIONS AFTER INJECTION OF CONCENTRATED THERAPEUTIC SERUM BY HILDA M.

DAVIS, M.D. Liverp., D.P.H.

ASSISTANT MEDICAL OFFICER IN THE ROYAL BOROUGH OF KENSINGTON

sex.-Serum reactions occurred with Age greatest frequency in the 0-5 year age-group. There was no difference in sex incidence (males 17-1 per cent., females 17.8 per cent. in this series). Dose.-The amount of serum injected had a noticeable influence on the incidence of serum reaction, high dosage being accompanied by an increase as illustrated by Table II. and

TABLE II-PERCENTAGE OF SERUM REACTIONS IN

4835

CASES

IN recent years the practice of concentrating therapeutic sera has been generally adopted. The consequent reduction in bulk and amount of protein injected has resulted in a lower incidence of reactions attributable to the presence of foreign protein. Table I shows a comparison of the incidence of the main signs of serum reaction after injection with whole and concentrated diphtheria antitoxic serum. TABLE

I-INCIDENCE

OF REACTION WITH CONCENTRATED

ANTIDIPHTHERITIC

SERUM

Note.-Figures refer only to those general reaction.

*

Figures taken from

Since the incidence of

a

comparable series. serum

reactions is still

quoted from figures for unconcentrated serum, it might be of interest to study a series of cases given

the concentrated serum now in use. These were found in a series of 4835 consecutive (non-fatal) cases of diphtheria treated at the North-Western (L.C.C.) Hospital during the five-year period 1929-33 with concentrated and refined serum as ’prepared for the Council’s hospitals at their antitoxin establishment (Belmont Laboratories). INCIDENCE AND MANIFESTATIONS

For the purpose of this analysis serum reaction is interpreted as including any reaction that may be attributed to the injected serum, apart from the immediate thermal reaction of intravenous therapy. Serum reactions are divided into : General reaction.-Results of reaction due to circulating including rashes occurring apart from the site of

serum,

cases

showing evidence of

Previous serum injection was also an important factor in determining the occurrence of’serum reaction. Thus of 4662 patients with no history of previous serum injection 16-4 per cent. developed general serum reaction, whereas of 173 patients who had received previous serum 47.4 per cent. showed reaction, a threefold increase. Of the cases receiving reinjection of 24,000 units or more, no fewer than 66-7 per cent. developed reaction. Boute.-The effect of intravenous therapy was not so great, an increase of only 4 per cent. being noted where part of the dosage of 24,000 and more was given by this route compared with the similar group treated by the intramuscular route only. Variation in serum.-The percentage of reaction in each of the five-yearly periods ranged from 14.1 to 21.8. Since this difference did not depend on the number of cases reinjected with serum or receiving high dosage, it is concluded that batches of serum vary in power to produce reaction. Asthma in the history was not a factor in producing serum reaction in this series. It was recorded in 15 cases (no type specified), two of which developed general reaction-a rate of 13-3 per cent. Two other cases showed local serum reaction only. GENERAL REACTIONS

There were altogether 845 general serum reactions in the series. Incubation period.-The average day of occurrence of the reaction was the eighth after injection, the greatest number of cases showing an incubation

194

period of 8-10 days (span 1-52 days), the day of injection being counted as the first. Previous serum injection shortened the incubation period in the majority of cases, reducing the average day of occurrence

in less than 10 days, but no one type to a particular period of incubation. TABLE V-ANALYSIS OF

861 RASHES

limited

was

OCCURRING IN

’

837

CASES

to the sixth.

TABLE in——INCUBATION PERIOD

Recurrent rashes developed in 2-4 per cent. of general serum reactions. They appeared with greater frequency in females of the younger age-groups and in cases that had received previous serum injection. In 19 cases in this series two, and in one case three, separate reactions were noted, and 3 additional cases developed two distinct types of rash simultaneously. The incidence of recurrent rashes was not confined to any particular batches of serum, being scattered throughout the series, and was evidently due to

individual

As

originally

defined

by

von

Pirquet and Schick

immediate serum reaction is one occurring within 24 hours of injection, and an accelerated reaction appears from the second to sixth day. After first injections of serum 1-05 per cent. of cases showed immediate reaction and 15’5 per cent. reaction of the accelerated type. When serum was reinjected, after an interval of more than 10 to 14 days an incidence of 7-3 per cent. immediate and 69 per cent. accelerated reactions occurred. Few cases have been recorded that present signs of serum reaction after There were an interval of longer than four weeks. 3 of these in this series, diagnosed in the absence of other known cause. The first developed general urticaria, accompanied by fever and oedema of the face, on the 32nd day after serum injection. In two other cases urticaria of a mixed type appeared on the 39th and 52nd days subsequent to injection of serum. Duration.-In over 80 per cent. of cases serum reaction was completed within 48 hours ; but in a few instances it was prolonged, the maximum duration being 9 days. Previous serum injection tended to shorten the period of reaction.

(1905),

an

RASHES

Three main

types

of rash

occur

in

serum

reactions-

urticaria, erythematous (including scarlatiniform), and morbilliform. In this series rashes have been subdivided into five groups and Table V shows their relative frequency and difference in incubation period. Urticaria was by far the most often met (80-1 per cent. of total rashes). Circinate rashes tended to appear late and the polymorphous type

idiosyncrasy in the patient.

OTHER REACTIONS (Edema of the face and hands was recorded in 2 per cent. of general reactions, was twice as common in males as in females, and tended to occur in the lower age-groups and in reinjected cases. High dosage and intravenous therapy were not factors in its causation. Arthritis or joint-pains occurred in 1.9 per cent. of general reactions, 50 per cent. of cases being adult and all female in this series. It was also more prevalent in reinjected cases. Arthritis or oedema may develop as the result of serum injection without an accompanying rash (0-95 per cent. of reacting cases). Fever.-3-4 per cent. of general reactions developed pyrexia of a mild degree (up to 102° F.). This sign appeared most frequently in females of the younger age-groups, previous serum injection having no effect upon its incidence. Adenitis is rare and was only noted in 0.2 per cent. of this series. The two cases were treated with the same batch of serum. Neurological complications.-No case was recorded in this series. Local serum rash limited to the site of injection may be the only evidence of reaction to the foreign protein, or it may precede or accompany a generalised rash, which it tends to resemble in type. Albuminuria, which may be accepted as a serum phenomenon, occurred in 2-8 per cent. of all cases treated with diphtheria antitoxic serum and was present in 13 per cent. of all cases of reaction. It appeared most often 6-12 days after serum injection and in the majority lasted less than six days. Thermal reactions directly after intravenous injection cannot be regarded as serum reactions and have no relation to the rare acute reactions, accompanied by dyspnoea, that occur in horse-allergic individuals and are similar in mechanism to anaphylaxis in animals. Reactions of this type have been recorded after many types of intravenous injection and are due to shock following the introduction of a foreign substance into the circulation.

195 In this series 6 of the 145 cases treated by intratherapy (4-2 per cent.) were recorded as developing immediate rigors, accompanied by slight pyrexia and occasional cyanosis but no dyspnoea. In each instance the serum dosage was above 24,000 units, and 5 of the 6 cases later developed general None had received previous serum serum reaction. or injection gave any history of allergy. Mild degrees of chill were of more frequent occurrence. "serum accidents."-The occasional severe and rarely fatal reaction seen in allergic individuals subsequent to serum injection did. not occur in this series, although 3.6 per cent. of the cases had received previous serum injection and 0.31 per cent. gave a history of asthma.

PREPARATION 2020

venous

SUMMARY

An analysis is presented of the incidence and manifestations of serum reaction occurring in a series of 4835 cases treated with concentrated diphtheria antitoxic serum. General serum reaction developed in 17-5 per cent. of all cases treated, and if local reaction and albuminuria are included the figure was raised to 21-9 per cent. The main factors responsible for increasing the incidence of serum reactions are high dosage, necessitating the introduction of greater amounts of foreign protein, sensitivity to serum due to previous injection of serum, and the variation in power of different batches of serum to produce reaction. An account is

of the incubation period, duraof 845 general reactions that occurred in this series. The most frequent day of occurrence was the eighth after injection, but in reinjected cases this was reduced to the sixth. In over 80 per cent. of cases the reaction was mild, being completed within 48 hours. Five types of rash are recorded, 80-1per cent. of the total rashes being urticarial and 9-5 per cent. erythematous and scarlatiniform. Recurrent rashes occurred in 2-4 per cent. of general reactions. (Edema of face and hands developed in 2 per cent., jointpains in 1.9 per cent., and mild pyrexia in 3-4 per cent. of general reactions. Albuminuria, which may be accepted as a serum phenomenon, occurred in 2-8 per cent. of all treated cases and was present in 13 per cent. of serum reactions. Immediate thermal reactions following intravenous injection were not regarded as serum reactions. No case of severe or fatal reaction to serum injection occurred in this series.

given

tion, and manifestation

CONCLUSION

Concentrated horse-serum used for the treatment of diphtheria rarely causes any anxiety from possible serious developments, though it may be responsible for some days of discomfort to the patient. I

am

much indebted to Dr. A.

Joe, formerly medical

superintendent of the North-Western Hospital, L.C.C., for allowing me access to the case records while I was a member of his staff and for permission to publish this analysis, which is compiled mainly from his personal observations.

Also to Dr. J. A. H. Brincker, chief medical officer, L.C.C., and Dr. R. G. White, of the Belmont Laboratories, for their kindly criticism of this paper. REFERENCES A Textbook of Infectious Diseases, London. Hunt, L. W. (1932) J. Amer. med. Ass. 99, 909. Rep. Met. Asylums Bd. (1928) The Relative Value of Concentrated and Unconc. Diph. Antitoxin. Rolleston, J. D. (1929) Acute Infectious Diseases, London. von Pirquet, C. E., and Schick, B. (1905) Die Serumkrankheit,

Goodall,

E. W.

Leipzig.

(1928)

A NEW BLOOD-PRESSURE RAISING DRUG *

BY F. AVERY

JONES, M.D., M.R.C.P. Lond.

ACTING FIRST ASSISTANT, MEDICAL PROFESSORIAL UNIT, ST. BARTHOLOMEW’S HOSPITAL, LONDON

With observations BY CLIFFORD

on

its

use

in Asthma

WILSON, D.M. Oxon.

ASSISTANT IN THE MEDICAL UNIT, LONDON HOSPITAL

AN important phase in modern therapeutics has been the introduction of drugs chemically related to adrenaline and acetylcholine, and there are already many variations on these two themes. A striking feature of these new drugs is the way in which they reproduce mainly one action of their parent substance. Carbaminoylcholine (Doryl) acts powerfully on the bladder and is used for the treatment of post-operative retention of urine. Acetylp-methylcholine (Mecholin) with its chief action on the heart, finds its application in paroxysmal tachycardia. Benzedrine, too, with its remarkable cerebral effects, is another example of this new group. The preparation 2020 (Ciba Ltd.), a sympathomimetic drug, is a distant relation of adrenaline. Its chemical name is trimethoxybenzyl-dihydroimidoazol hydrochloride (Fig. 1). In laboratory animals it was found to produce prolonged elevation of the blood pressure. In man it appears to act predominantly on the smooth muscle of the bloodvessels and skin, producing a rise in blood pressure, pallor, and goose-skin. FIG. 1

Clinical trial has demonstrated its pressor effect. After injection there is a sharp rise in the blood pressure, and then a gradual fall to the original level. There is also slowing of the pulse, which may outlast the corresponding rise in blood pressure. With 0.1 gramme intravenously (Fig. 2) there is a rise of 30-80 mm. Hg, the total effect lasting about thirty minutes. There is considerable variation in the degree of response of individuals, and even on different occasions with the same patient. This is, however, a feature of drugs which reproduce the action of the autonomic nervous sytem. Inconstant response has been obtained with the same dose intra-

muscularly,

but with doses of 0-2 and 0.3 g. there is

greater and more prolonged effect (Fig. 3). The preparation is also active when given by mouth. The slowing of the pulse is prevented or abolished by atropine, without loss ofthe pressor effect (Fig. 4). Electrocardiograms taken after intravenous injection in six patients show that the slowing That it is possible to was a sinus bradycardia. a

* A report to the Therapeutic Trials Committee of the Medical Research Council.