A MONTHLY RECORD OF THE

Progress of Medical Science.

ACID INTOXICATION SUI GENERIS.

By J. DRESCHFELD, M.D., B.Sc., F.R.C.P., Professor of Medicine in the Victoria University of Manchester; Senior Physician to the Manchester Royal Infirmary; and

F. CRAVEN MOORE, M.D., M.Sc., M.R.C.P., Assistant to the Professor of Medecine, and Lecturer in the Victoria University of Manchester.

WITHIN recent years there has been growing the belief that certain morbid phenomena are to be ascribed to the presence in the organism of acid products of metabolism, which, acting in virtue of their base combining powers rather than by any specific toxicity, prove pathogenic indirectly by inducing a disturbance of the basic constitution of the tissue fluids. The basis of this doctrine of acid intoxication is of a two-fold nature; on the one hand, clinical observation has abundantly demonstrated the frequent co-existence of certain morbid manifestations with the presence in the blood and urine of abnormal acids (in basic combination); whilst, on the other hand, direct experimentation has shown that the administration of acids devoid of specific toxicity and in such dilution as to obviate local irritation, will produce in animals disturbances of function which closely approximate to those observed in the human subject in the above relations.

The phenomena regarded as characteristic of acid intoxication in the human subject, as exemplified in its prototype, diabetic coma, are drowsiness, stupor and coma occasionally preceded by excitement and rarely convulsions, peculiar deep respirations (" air hunger" of Kussmaul), accelerated pulse-rate, subnormal temperature and certain gastro-intestinal disturbances, as vomiting and epigastric pain. Associated with these manifestations there is

invariably the excretion in abnormal abundance of certain products of metabolism, viz., acetone in the breath, acetone, acetoacetic acid and ẞ-oxybutyric acid in the urine, which also presents an ammonia content increased in proportion to the amount of the two alien acids.

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In animals experimental acid intoxication is characterised by unsteadiness, ataxia, and finally flaccid paralysis, deep respirations with some acceleration of rhythm, acceleration of the pulse-rate which rapidly becomes uncountable, a progressive fall in temperature, a diminution in the alkalinity and CO content of the blood, the excretion of the exhibited acid in the urine in association with an increased output of ammonia, and death from respiratory failure. As such manifestations are not due to any specific toxicity of the exhibited acid, nor to any local irritant action, it remains that they are to be associated with some disturbance of the basic constitution of the tissue fluids induced by its base combining powers.

The inorganic constituents of the tissue fluids, of which sodium carbonate may be regarded as the chief representative, appear to be related in some way with the elimination of CO2 from the organism, and possibly the whole complex of internal respiration depends on their integrity. Under normal conditions the tissue fluids maintain a remarkably constant composition as regards these inorganic constituents, and this in spite of the facts that they are comprised of bases combined with feeble and readily dissociated acids, while the products of normal metabolism include many acid substances of considerably greater strength. The elimination of these latter from the organism probably involves a continual loss of basic elements in the tissue fluids, a loss which is exactly compensated by the retention of an equivalent amount from the excess ingested with the food.

When the balance of this mechanism becomes deranged, as experimentally by the exhibition of excessive quantities of acid or by the elimination of those mineral constituents from the ingesta necessary to recompense the normal loss, and as is morbid states in the human subject by the excessive production or diminished destruction of normal or abnormal acid products of metabolism, there results a net loss in the basic constituents of the tissue fluids,

disturbance of internal respiration with the manifestations of acid intoxication so-called.

In experimental acid intoxication an interesting difference has been noted in the reaction of herbivorous and carnivorous animals to acids, in that the latter are able to withstand much larger quantities, viz., three times the dose fatal to the former. This relative immunity of the carnivor being associated with the appearance of the exhibited acid in the urine in combination with ammonia; in fact it would seem that in carnivors, and also in the human subject, the appearance in the organism of undue quantities of acid threatening the inorganic constituents of the tissue fluids is met by some perversion of the final stages of nitrogenous metabolism yielding ammonia which serves to combine with, and so render innocuous, the acid. To this protective mechanism also it must be assumed there is a superior limit.

Such a general statement of the doctrine of acid intoxication will suffice as an introduction to several aspects of the condition as met with in the human subject and which are exemplified in several cases which have recently come under our observation. The bulk of the observations relating to the human subject have dealt with diabetic intoxication or coma, and all with morbid conditions diabetic or non-diabetic-which have been associated with the excretion of ß-oxybutyric acid and its derivatives acetoacetic acid and acetone. Of these three substances, the "acetone bodies" as they have been termed, the two acids possess no specific toxicity, in fact on exhibition to the normal organism they are readily and completely oxidised to H2O and CO2, and prove quite innocuous, their pathogenicity in the above conditions being of the indirect kind considered.

The occurrence of the "acetone bodies" in the urine apart from diabetes mellitus has long been recognised, most frequently in some grave general disorder, as cancer, severe anæmia, acute febrile disease, severe gastro-intestinal disturbance and states of marked inanition, to which the metabolic disturbance implied by their appearance may be regarded as sequential; occasionally they have been noted along with the most profound manifestations of acid intoxication in individuals in whom, by the absence or insignificance of any general disease, the metabolic disturbance appeared

primary. Accordingly acid intoxication is conveniently grouped into (1) the diabetic form; (2) the secondary form; and (3) the cryptogenetic form or acid intoxication sui generis, each form presenting many degrees of intensity from the transient and symptomless acetonuria through the types in which acetonuria and diaceturia are associated with such manifestations as headache, drowsiness, vomiting, often in the secondary forms masked by the symptoms of the primary disorder, to the most intense comatose and frequently fatal types familiar in the coma of diabetes.

The following case affords a striking example of the severe type of acid intoxication sui generis:

A female, aged 30, had suffered for some two months from attacks of vomiting, epigastric pain, constipation, pallor, general weakness and slight loss of flesh. On admission to hospital, the patient, a fairly nourished, pale, somewhat flabby and neurotic woman, presented all the manifestations of severe acid intoxication-drowsiness, prostration, "air hunger," rapid pulse (98), acetone in the breath and acetonuria and diaceturia without glycosuria. The gastric disturbance, vomiting and pain, ceased in a few hours. Two days after admission she suddenly became very excited and then gradually lapsed into a comatose condition which persisted till death occurred, two days later. The air hunger, the excretion of the "acetone bodies" and the pulse acceleration remained till the end, the pulse finally counting 140. The temperature, at first subnormal, 97·4°F., rose during the last twelve hours to 103.6°F. The urine was acid, sp. gr. 1021, it contained a slight trace of albumen, smelt strongly of acetone and gave well-marked reactions for that substance and also for acetoacetic acid (Gerhardt's reaction). A filtered sample in a 2dm. tube exhibited a rotation of -3°, an acidified ethereal extract presented similar negative rotation, and on distillation with H2SO, crotonic acid was obtained, phenomena demonstrating the presence in the urine of 6-oxybutyric acid. No reaction for sugar was obtained with Fehling's solution or phenyl hydrazine. Microscopic examination showed the absence of casts. Unfortunately no autopsy was obtained.

The diagnosis of acid intoxication was made on the analogy of the symptoms with those of diabetic coma and on the presence

of urinary signs of disturbed acid metabolism in the absence of glycosuria. The relegation of this example to the class of cryptogenetic acid intoxication appeared justified by the absence of manifestations of serious organic disease.

The most notable examples of this class of acid intoxication have been recorded by Lorenz, Litten, Kraus, Edsall and Rooney. Amongst them there is general agreement in the principal manifestations, with variations in intensity, and in the majority more or less marked gastro-intestinal disturbance had preceded the onset of the symptoms of acid intoxication. As further emphasising the association which obtains between acid intoxication and disturbance of gastro-intestinal functions are cases recorded by Marfan, Gunion, Edsall and Rooney, in which they have found the excretion of the "acetone bodies" coincident with, or in Edsall's experience shortly preceding, the phenomena of “recurrent” or cyclical vomiting," a symptom-complex which Edsall found to be rapidly relieved by the administration of large doses of alkalies and which he believes depends on

intoxication.

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an acid

In the following case signs of acid intoxication were associated with recurrent vomiting, but whether the acid intoxication was primary or merely a consequence of the resulting inanition (which, however, was only slight) we had no means to determine:

A female, aged 14, had suffered from recurrent attacks of vomiting, during which she was unable to retain food of any kind; the bowels were constipated, but there was no evidence of any lesion of the gastro-intestinal tract. On admission to hospital during one of these attacks the presence of acetone in the breath was noted, and of acetone, aceto-acetic acid and ß-oxybutyric acid (rotation in 2dm. tube=-46°) in the urine. With the exhibition of alkalies and aperient remedies the symptoms disappeared and also the signs of acid intoxication.

A third case apparently belonging to the class of secondary acid intoxication was observed about the same time:

A female, admitted to hospital suffering from mitral disease with broken compensation, general passive congestion, disturbed gastro-intestinal functions and constipation, exhibited for a few