Current Topics

Pharmacological Aspect of Digitalis Therapy

By A. FRAENKEL, m.d.

(Abstracted from the Lancet, Vol. II, No. 16, 1935,

p. 1101)

Digitalis and strophanthin

The intravenous administration of strophanthin has made it possible to study the effect of digitalis upon he course of these processes in man with^ methods as exact as those used in experiments on animals. Only Patients with severe dyspnoea have to be excluded

from such investigations. Now recent experiments

leave no room for doubt that the main effect of digitalis in heart failure is an increase in the stroke volume and a change in the distribution of blood resulting from the increased circulation rate. Such an effect can be obtained with no other drug. The absence of appre- ciable effect on the healthy, as on the diseased heart when functionally compensated, and its appearance after minute doses in decompensation, may perhaps be explained in part by the intramuscular development of a specific sensitivity to digitalis in this latter group. For it is known from Weese's experiments that the intravenous injection of the glucoside is followed by the fixation of about 10 per cent of the dose by the heart,

158 THE INDIAN MEDICAL GAZETTE [Mabch, 1936

If, as has been done by Clark, we calculate the amount of strophanthin fixed per gramme of heart muscle, the astonishing fact is revealed that 1 g. adsorbs at most 0.002 mg. of the drug. If, moreover, we assume that a compensated heart has undergone an increase in

weight by 50 per cent, and if we further take into account the fact that one-tenth of the lethal dose has a detectable effect upon the diseased heart exhibiting a high sensitivity to digitalis, we arrive at the conclu- sion that the concentration in which digitalis acts is of the same order as that found in the case of the hormones. To the question whether or no there arises a specific

increase in sensitivity to digitalis when the heart fails, no definite answer can as yet be given, owing to lack of clinical and especially experimental evidence. Weese

points out that since the minute output of the '

decompensated' heart is diminished, the possibility arises of a greater proportion of the total strophanthin injected reaching tfie coronary system and being fixed by the heart muscle. The fact that disagreement in the theory of stroph-

anthin therapy is associated with unanimity as regards the practical success of treatment with the drug, snows that much still remains to be accomplished by clinical investigation. Unfortunately we still lack methods which are easily applicable in everyday practice for the estimation of stroke volume and minute output. It is true that the physician finds a possible indication of these values in measurements of systolic, diastolic, and pulse pressures. In addition z-ray photography and measurement of the venous pressure (the latter rightly emphasized by Lewis) are at his disposal for assess-

ment of the degree of heart failure and of its therapy. Here, however, I should like to invite attention to two further methods of value in this connection.

First, the daily measurement of body-weight excludes the possibility of neglecting the extrarenal loss of water?an error which easily occurs if only the urine output is determined?and indicates by direct means

the day on which the removal of oedema fluid is com- pleted, and so the time when the minute volume has in all probability reached its optimum. Exact observa- tion of this kind enables us to avoid overdosage and at the same time, b}' gradation of the dose within 0.1 mg., to control accurately the rate of fluid removal, and so to delimit precisely the period allowed for com- plete elimination of the retained water; a realization of the therapeutic ideal of obtaining optimal effects from the smallest doses. This is illustrated in the case of a patient who showed no improvement from treat- ment with digitalis by mouth. After a preliminary observation for two days, treat-

ment with strophanthin was begun, and during the period of treatment a decrease in body-weight from 86 kg. to 71 kg. occurred. This effect was obtained by 14 injections of K-strophanthin, the initial dose being 0.3 mg. and thereafter doses of 0.4 mg. were given. A total of 5.2 mg. was given in 33 days. On an average, therefore, the daily dose of strophanthin was 0.15 msr. and the amount of fluid eliminated was 0.5 kg. per day. Such is a characteristic case of heart failure therapy with intravenous injection of strophanthin, the removal of oedema fluid and the course of recompensation being completely under control. At the end of treatment with strophanthin an injection of salyrgan was given, and this had no influence on the excretion of water. The giving of a provocative dose of salyrgan in such cases indicates whether or no latent oedema exists, and so supplies information of great importance in their after-treatment.

Since analogous conditions have not as yet been investigated in animals, we have already overstepped the border of experimental pharmacology. Indeed, we are immersed in the pharmacology of man immediately we ask for information from a patient as to the onset of the drug's action. And this brings us to the second means of gaining an insight into the functional state of the heart. In illness which, in the light of subsequent treatment, is shown to respond to digitalis, almost every

patient, irrespective of his position in life, feels and comments upon a favourable reaction to the first injection, provided the dose which has been chosen is not too small. The patient uses the word

' leicht'? linguistically similar and conceptually identical in both English and German?and he expresses in this way a feeling of happiness for the relief he has found. This '

subjective indicator' either appears once only, or it may be met with after subsequent injections. Its disappearance is characteristic of the completion or

approach of compensation; its reappearance signifies new failure, threatened or already present. The cause of this '

subjective indicator' has not yet been ascertained; all that seems to be certain is that it precedes the demonstrable increase in the minute- volume. The presumption is that it is the expression of the first return to normal in the tension of C02 and O2 in the respiratory centre, resulting rapidly and indirectly from the increased circulation rate. This self-observation of the patient receives its full import- ance from the fact that, unlike with morphine, therapy with strophanthin is not complicated by the pheno- menon of tolerance. The necessity of increasing the dose or reducing the intervals, between successive

injections, which may occur in the case of intravenous

strophanthin therapy, always depends upon either an anatomical or a functional deterioration in the heart as a result of progressive disease.

Principles of strophanthin therapy

The essence and limitations of therapy with intra- venous injections of strophanthin can be formulated in the following way:?

(1) There is no degree and no phase of cardiac insuffi- ciencjr from the beginning of the disease?often difficult to gauge?to the stage of extreme abnormality in the distribution of blood along with its accompaniments, which does not respond to the intravenous administra- tion of strophanthin. Only the compensated heart on the one hand or the dying heart on the other not yet responds or no longer responds to this treatment.

Indeed, it is possible to draw conclusions of the greatest value for diagnostic and prognostic purposes from the absence of response as well as from its presence, and in the latter case from the amount of drug and the

period found necessary for functional recovery to

occur.

This can be seen from the collection of a group of cases characterized especially by large hearts with myo- carditis?transverse diameter from 19 to 23 cm.?and

by very marked cedema. In some of these cases hyper- tonia, in some irregularities in rhythm were present; others were free from either of these complicating factors. All were treated with series of injections of

strophanthin, only after treatment with digitalis by mouth had proved unsuccessful. The doses of stroph- anthin were so chosen that the patients lost weight to a degree not greater than 1 kg. per day. Those patients who needed little strophanthin and

displayed a marked diuresis lived long. Those on the other hand who received more strophanthin and yet eliminated their retained water more slowly died within a shorter period.

(2) In strophanthin therapy it is necessary to adhere to exact dosage, and to take careful records of the effects' of each and every dose, just as in experiments with animals, and even if the treatment be continued for a long time. This demand?a matter of course in the laboratory?is, in the application of most thera- peutic measures, for the most part neglected. Such a

procedure, being based on scientific methods, raises strophanthin therapy to the level of controlled experi- ment, and furnishes at the same time a guarantee of its safety. Although the clinic considers the oral administration

of digitalis to be contra-indicated in certain cases of valvular defect and disordered rhythm, the systematic use of strophanthin by the intravenous route finds successful application in such cases too. The aetio- logical factor becomes of less importance; the decisive

March, 1936] CURRENT TOPICS 159

(actor is the functional impairment of the heart with its accompaniments of venous stasis and deranged distribution of blood. I should like at this stage to invite attention to

two

Points which can best be illustrated by reference to

individual cases. In mitral stenosis, in which treat-

ment with digitalis by mouth is often difficult and even

dangerous, it is possible to obtain an ideal therapeutic effect if the doses of strophanthin are small and are

given at proper intervals of time. Moreover, it is by Do means exclusively cases of heart failure with auri-

cular fibrillation or frequent and regular pulse which

respond to strophanthin administration. Complete success is met with even when the pulse is infrequent and regular.. In these cases the muscular effect of

strophanthin is more prominent than the vagal. (3) The prognosis of cardiac insufficiency has en-

tirely changed since the possibility has*arisen through the use of strophanthin not only of enlarging the

field

m which treatment with digitalis is indicated, but also of making success in the treatment of certain cases

Jpore assured. The features of this disease have been

further allayed since we have had at our disposal a

suitable mercurial diuretic which can be given

intravenously. The heroic treatment of heart failure

^!th calomel and digitalis by mouth, dating back to

? .ergill, is now replaced by one which involves the administration of salyrgan, and so supplements the

effect of strophanthin in this disease. Salyrgan acts on the tissues as well as the kidneys, and possesses the

outstanding advantage that it can be given intraven- ?"sIy, and so in an exact dosage, which when properly chosen ensures freedom from danger. The appropriate combination of both remedies, not simultaneously or

hwt same day even, but one after the other on

different days, makes possible the removal of oedema 0' the severest degree as well as that of very long standing. Drainage of the legs, so irksome to patients, is avoided, and reappearance of oedema in large part Prevented. Cardiac oedema is a secondary disease which can be avoided if the failing heart is treated early enough, and if, after recompensation has become established, treatment is continued for a still longer Period, the duration of which must be determined in

each case by circumstances. In illustration we may

quote the following case: A patient, 60 years old, with arteriosclerosis and

hypertonia, a large heart (transverse diameter 18.6 cm.)

<fnd auricular fibrillation, had shown signs of heart

lailure for a year. His physician treated him with

digitalis, giving small doses at first and large later. No

improvement was detected, but instead signs of over-

dose (pulsus bigeminus) supervened. _

After a short

Period of observation without medication, the loss of

water was initiated by salyrgan and the failure of the

heart abolished by strophanthin. It may be added that

we were able to avoid the appearance of pulsus bige- uiinus as well as other signs of toxic_ action, in spite of the fact that the patient received in the

course of

60 days 25 injections of strophanthin of about 0.3 mg. each, amounting to 6.3 mg. of the drug. In aduition

a, total of 16 c.cm. of salyrgan in 12 injections was

Siven. The elimination of water resulted in a decrease of 21 kg. in body-weight, a fact which shows that the

normal weight of the patient had increased by as much

as 40 per cent during the development of the failure. ?Notice should also be taken of the

_

fact that the

elimination of oedema fluid under the influence of the

diuretic salyrgan, acting on the tissues and kidney, occurs characteristically in steps, whereas during the

Quantitatively controlled treatment with strophanthin this loss proceeds steadily. From the first experiments with digitalis on the

'rog s heart to the more recent and complicated investi- gations on the action of digitalis on the heart and

circulation of the mammal, the path has been long and iresome. We must not be surprised, therefore, if the

Practical application of pharmacological research to the reduction of the suffering and to the prolongation of

he lives of patients with heart disease takes long to

achieve. This attempt, however, to evolve a rational digitalis therapy from a knowledge of experimental pharmacology, and to describe the peculiar importance of the intravenous route in connection with the glucoside which is most suitable for this mode of administration, is not to be regarded as a revolt from the customary empirical use of preparations of digitalis by mouth. By no means Withering's therapy retains its position in the treatment of heart failure where such is of not too severe a degree or of not too long a standing.

Artificial Pneumothorax in the Treatment of Lobar Pneumonia

By F. G. BLAKE, mj>.

M. E. HOWARD, m.d.

and

W. S. HULL, m.d.

(Abstracted from the Journal oj the American Medical Association, Vol. CV, 9th November, 1935, p. 1489)

In general the procedure followed has been that used by Friedmann. Thus, thirty-four of the ninety-three patients received only one treatment, usually in the

neighbourhood of from 300 to 500 c.c., forty-six received only two treatments usually given from eighteen to

foriy-eight hours apart, while only eleven received a

third and only two a fourth. Furthermore, only nine

patients were given a total of more than 1,000 c.c. of

air, the maximum amount given being 1,650 c.c. in each of two cases. From these data it would seem that

insufficient air was introduced to cause more than a

moderate collapse or retraction of the involved lobe in the great majority of the cases. As will appear later, tne method of treatment which has been evolved during the course of our study differs considerably from that generally used. The four most frequent clinical effects reported are

prompt relief of pleural pain, relief of dyspnoea, diminu- tion, often striking, in the general toxic phenomena of the disease, and a critical fall in temperature shortly after the induction of artificial pneumothorax, sometimes permanent, though often only temporary. Clear evidence is lacking, however, that pneumothorax treatment serves to cure the disease, since in the majority of the recorded cases in which treatment was not started until the fourth day of the disease or later, approximately one-half failed to exhibit any apparent modification of the natural course and outcome of the disease, and prompt critical recovery without relapse appears to have occurred in only one of nine cases

treated on the second day of the disease and in only three of fifteen treated on the third.

Selection of cases

In the selection of cases for treatment it seemed to us of importance to direct our efforts primarily to a

study of the effect of artificial pneumothorax on the early stages of pneumonia. Consequently all patients with unilateral pneumonia admitted to the medical service of the New Haven Hospital not later than the third calendar day of the disease during the period covered by this report have been treated without selec- tion, twenty-four in number. The remaining eighteen patients, in whom treatment was begun on the fourth or fifth day of the disease, were arbitrarily selected.

Method of treatment

The technique employed has been that commonly used. Immediately following the preliminary examina- tion of the patient an .T-ray film of the chest is taken to confirm the clinical diagnosis and to make certain that the pneumonia is unilateral. Following a prelim- inary dose of morphine, artificial pneumothorax treat- ment is started. Treatments are ordinarily given with the patient in the lateral position with the pneumonic

160 THE INDIAN MEDICAL GAZETTE [March, 1936

side up, since the intrapleural pressure established with the patient in this position does not become lower in any other position that the patient may subsequently take. Air is allowed to How in under the negative pressure developed during inspiration until the intra-

pleural pressure has nearly reached the atmospheric level, when a slightly positive pressure is used. Pressure readings are taken aiter eveiy 50 to 100 cubic centimetres of air have been introduced, the treatment being continued until the desired intrapleural pressure is attained. If (for any reason) it is found necessary to have the patient in the prone or sitting position during the treatment, the mean pressure should ordinarily be raised to about 4 cm. higher than the desired level in the lateral position since the pressure will fall approximately 4 cm. whenever the patient changes from the prone to the lateral position with tne

pneumothorax side up. li, during the treatment, the patient complains of a dragging or pulling pain, adhesions may be suspected and the treatment may be interrupted. Following the first, second or third treat-

ment, as seems indicated, another a>ray him is taken to determine the degree of collapse oi the lung and the presence or absence of pleural adhesions. The procedure followed with respect to the frequency,

rate and volume of pneumothorax treatments has been evolutionary and empirical and will be illustrated by early, intermediate and recent cases in the series. In the beginning it was hoped that two initial treats

ments of approximately 300 to 500 c.c. each, given six hours apart and followed, if necessary, by a third treatment eighteen hours later, might be sufficient to

accomplish the desired result. This procedure was

found to establish a mantle pneumothorax without selective collapse of the involved lobe and to raise the mean intrapleural pressure to 3 to 0.5 cm. It

appeared to be satisfactory in the first two cases treated. By the time nine cases had been treated, however, it had become apparent that this procedure was inade-

quate, since, following temporary clinical improvement, relapse was found to occur as the intrapleural pressure fell, provided antibodies had not appeared in the blood, as was subsequently found to have happened in the first two cases. In view of these results the procedure was changed.

From three to five initial treatments were given at

intervals of approximately four hours in order to establish a mean intrapleural pressure in the neighbour- hood of + 1 cm. to -f- 2 cm. and to induce a complete collapse of the whole lung on the involved side, pro- vided adhesions did not interfere. The first three treatments were ordinarily of 500 to 800 c.c. each. Subsequent treatments were given at irregular intervals in an effort to maintain a positive intrapleural pressure and complete collapse of the lung until permanent recovery seemed assured or further treatment inadvisable. Gradually a further modification was

tried, in which the initial treatment was increased in amount and the early refills were given at somewhat less frequent intervals. At the same time, with the

purpose of avoiding temporary increase in dyspnoea, the rate of introduction of air was cut down from a a

average rate of approximately 30 to 40 c.c. per minute, which had been previously used, to an average rate of 10 to 15 c.c. per minute. At this slow rate, large amounts of air can apparently be administered without difficulty. The volume of air required to raise the mean intra-

pleural pressure to + 1 cm. to + 2 cm. has been found to vary greatly from case to case and cannot at present be correlated with any measurable factors, nor can it be predicted. Ordinarily it will range from 1.800 to

2,400 c.c. The time required for the large initial treat- ment consequently will vary. If 1,800 c.c. is given and it is administered at an average rate of 12 c.c. per

minute, the treatment will take two and one-half hours to complete. The rate of fall in intrapleural pressure

following the first treatment has been found to be very variable and unpredictable, ranging from 0 to 1.33 cm.

hour in the cases studied. The rate of fall following

refills is likewise variable, though commonly less rapid than after the first treatment. Consequently the

frequency and volume of renlls required to maintain a

positive intrapleural pressure and complete collapse of tlie lung are at present empirical, in our experience not more than four to eight hours should be allowed to elapse between the first and second and the second and third treatments, decision as to time in the individual case depending in part on the pressure level attained at the end of the first treatment, in part on the volume of air previously introduced and in part on the clinical response. The use of subsequent refills depends on tlie coarse oi events in the individual case. In general, an effort is made to keep the intrapleural pressure positive until recovery seems assured.

Effect of pneumothorax treatment

Review of the forty-two cases treated suggests that the most important factor influencing the results, apart from the method of treatment used, is the duration of the disease at the time treatment is instituted. Conse- quently our cases have been divided into four groups, according to duration. Group A comprises four cases

in which treatment was begun within twenty-four hours after onset in the preconsolidative stage; group B, nine cases in which treatment was started between twenty- four and forty-eight hours after onset in the eariy consolidative stage; group C, fifteen cases in which treatment was initiated between forty-eight and

seventy-two hours after onset with hepatization more or less advanced, and group D, fourteen advanced cases of more than seventy-two hours' duration when treat- ment was begun. Another important factor apparently influencing the results in groups li and C at least is the absence or presence of pre-existing fibrous pleural adhesions; consequently these two groups have been subdivided accordingly. Since the effect of artificial

pneumothorax in relieving some of the distressing symptoms of lobar pneumonia, such as pleural pain, restlessness, dyspnoea and toxaemia, has been well described by others and our experience is in harmony with theirs, this subject will not be elaborated here and attention will be directed towards the effect of

pneumothorax therapy on the course, duration and outcome of the disease. Group A: Treatment begun within twenty-four

hours after onset.?It will be seen that all four patients were treated with large initial amounts of air, the mean intrapleural pressure being raised to the positive level. Complete collapse of the whole left lung occurred in all but one case in whom adhesions between the parietal and the visceral pleura over the uninvolved left upper lobe prevented collapse of this lobe. All four patients recovered promptly without further extension of the pneumonia and without com- plications, except for a transient acute psychosis in \V. L., a patient suffering from severe chronic alcoholism. Group B: Treatment begun between twenty-four

and forty-eight hours after onset.?In the first six cases without adhesions all but one, who was treated early in the series, received initial treatments adequate to

raise the mean intrapleural pressure to atmospheric level or above and to collapse the whole lung on the involved side. All showed prompt clinical improvement with relief of distressing symptoms. Recovery was rapid in one and apparently accelerated in all but R. F., who nevertheless was much improved symptomatically. None showed further spread of the pneumonia. In

two cases sterile pleural effusions developed that were sufficiently large to warrant withdrawal by aspiration. No notable effect on the symptoms or course of the disease resulted in the three cases in which pleural adhesions were present, presumably because the adhe- sions interfered with adequate collapse of the involved lung. Three patients in group B showed a transient bacteremia following the institution of pneumothorax therapy, apparently without ill effect.

Group C: Treatment begun between forty-eight and seventy-two hours after onset.?Of the 6ix patienta

Mabch, 1936] CURRENT TOPICS 161

without pleural adhesions four recovered promptly by crisis, two showed temporary improvement but relapsed, with a spread to the opposite side. Three, however, showed antibodies in the blood on the fifth, third and sixth days, respectively, so that early recovery may have been the natural crisis rather than related to the pneumothorax treatment. Among the nine patients with fibrous pleural adhesions no beneficial therapeutic effect was observed, with one possible exception. Group D: Treatment later than seventy-two hours

niter onset.?Artificial pneumothorax exerted no appa- rent effect on the duration or outcome of the disease in this group of advanced cases. In fact, even tem- porary symptomatic relief was observed in only one

patient. In none of the six cases in which bacterajmia was present did the treatment terminate the blood stream infection.

Comment The observations on the use of artificial pneumo-

thorax in the treatment of forty-two cases of lobar pneumonia that have been presented appear to indicate that the procedure is of definite therapeutic value but ?nly under certain limited conditions; namely, (1) when the volume of air introduced into the pleural cavity is sufficient to raise the mean intrapleural pressure Promptly to a level of + 1 to + 2 centimetres with the Patient in the lateral position, pneumonic side up, resulting in complete retraction of the affected lung; (2) when the frequency of refills is sufficient to maintain the mean pressure at this level and the lung is retracted until the danger of relapse is past; (3) when treatment js instituted early in the disease; i.e., certainly within less than seventy-two hours after onset, probably within less than forty-eight hours in most cases; (4) when the pleura is free from adhesions that interfere with retraction of the involved lung. The signal importance of the time factor is clearly shown in figure 10, which summarizes the results in the forty-two cases treated. Experimental observations bearing on the mechanism

by which artificial pneumothorax exerts its apparent effects have been presented elsewhere and will not be discussed in detail here. In brief, they show (1) that, respiratory motion of the involved lung can be abolished by artificial pneumothorax, provided the amount of air introduced is sufficient to cause maximum retraction of the lung on the treated side, (2) that antibody pro- duction is not demonstrably accelerated by pneumo- thorax therapy, and (3) that there is little evidence to support the view that relief of a hypothetical bronchial occlusion takes place following pneumothorax treat- ment. Consequently the theory that the effects of artificial pneumothorax depend on immobilization of the infected lung would appear to be the most accept- able one at present.

Conclusions 1. Artificial pneumothorax, when administered so as to induce and maintain complete collapse of the lung on the involved side, would appear to be a useful thera-

peutic procedure in the treatment of lobar pneumonia but only when used early in the disease, preferably within twenty-four hours after onset. .

2. There is no evidence to support the view that it is of curative value later than seventy-two hours after onset. * 3.. Further trial of artificial pneumothorax in lobar pneumonia is desirable and should be carried out before any statistical analysis of results obtained is warranted.

Haemorrhage and Anaemia in the Newborn % REGINALD LIGHTWOOD, m.d., m.r.c.p., d.p.h. (From the Medical Press and Circular Supplement,

23rd October, 1935, Symposium No. 4, p. xi) In the neonatal period haemorrhage and ansemia ore

closely linked. The bleeding and coagulation time,

and the number of platelets conform to the average standards which are given as the '

normals' for all ages, and quantitative analyses of the substance concerned in clotting indicate that during the first four days every factor favours increased coagulability. Nevertheless, in practice somewhat wide variations are not uncommon, and a tendency to bleed excessively must be recog- nized as an occasional feature of the first two weeks of life. Moreover, a little bleeding may be a serious matter when the infant's blood volume is small and when the bone marrow is already working at high pressure to supply physiological requirements. Further, when haemorrhage causes anaemia, a vicious circle may arise, for anaemia in turn may interfere with the mechanism responsible for the arrest of bleeding.

Spontaneous hemorrhage Soon after birth haemorrhage from the umbilicus may

be seen. It is due to slipping of the ligature, which will require to be re-tied; or a ligature, too thin, may cut through the delicate tissues of the cord. It is advisable, therefore, to use a stout ligature and to apply it at such distance from the umbilicus as to make re-ligature possible. From the second day until after separation of the cord, secondary haemorrhage due to infection may occur. Its treatment is (1) preventive and (2) immediate. The former consists in thorough asepsis and the proper care of infection if it occurs.

The latter lies in the application of pressure. This

may be effectively carried out by means of a long needle passed transversely under the umbilicus. Pressure can then be exerted by a figure-of-eight of coarse silk wound round the needle. Small bleeding granulomata may be touched with a stick of silver nitrate. To confer a measure of passive resistance to

infection, an intramuscular injection of 5 to 10 cubic centimetres of the mother's whole blood may be given. Melcena neonatorum, the haemorrhagic disease of the

newborn, is a well-defined clinical entity, probably due to some qualitative alteration in the blood. The nature of this alteration is not known. Shallow duo- denal ulcers have been found in a few fatal cases, but their causal relationship has not been satisfactorily established, for they have also been found in cases

without haemorrhage. The number of platelets is within normal limits; in some of the patients the coagulation time is prolonged. In the majority of cases the bleeding comes from the gastro-intestinal tract, consequently melsena is the chief symptom, though haematemesis alone or in association with melaena is frequently seen. More rarely the hsemorrhage takes its origin from some other mucous surface or from the umbilicus; if from the latter, signs of infection should be sought. The onset of melaena neonatorum is from the first to the third day, though occasionally it may be delayed, and cases beginning as late as the tenth day have been recorded. Quite healthy-looking infants may be affected. In so far as untreated cases may prove rapidly fatal,

this melaena must be regarded as a medical emergency. On the other hand, mild, untreated cases often recover spontaneously, though liable to anaemia at a later date. Few diseases are more easily treated. As soon as the condition is recognized, 10 to 15 cubic centimetres of human whole blood (the serum does equally well, but the added trouble of removing the cells is not

necessary) should be injected intramuscularly. Sometimes more than one injection is required; when this is the case, the second injection should follow within two to four hours. A total of 30 cubic centi- metres in all may be required. There is direct evidence that the bleeding may abruptly cease about ten minutes after a successful injection. The blood need not be

grouped; citration may be carried out, but only as a convenience to prevent clotting in the syringe. (For citration, dissolve a two-grain tablet of sodium citrate in 3 cubic centimetres of water and add 1 cubic centi- metre to 10 cubic centimetres of blood). The injection is made into the muscles on the outer side of the

thigh, avoiding the napkin area. Afterwards the infant

162 THE INDIAN MEDICAL GAZETTE [March, 1936

must be kept warm and quiet in its cot for twenty- four hours. Three hours after effective treatment, feeding is begun again with due caution. Occasionally a severe haemorrhage, or delay in giving the treatment, results in a state of anaemia dangerous enough 10

demand blood transfusion, which is indicated if the blood count falls below three million cells; but the intramuscular injection must not be delayed during preparation of the transfusion. In convalescence, iron

deficiency may become unmasked, and to prevent this, reduced iron, one-half grain, powdered, mixed with

sugar and placed on the infant's tongue, three times a day, is valuable.

All other causes of spontaneous haemorrhage are

rarer than the foregoing. Purpura may be seen, either the thrombocytopenic variety or secondary purpura due to septicaemia. Haemophilia may show itself when an hereditary affected infant is circumcised. Leukaemia is a very rare cause of bleeding in the newborn. Hemorrhage associated with jaundice.?An increased

tendency to bleed is a notable feature of jaundice whatever its cause, so that it may arise in any of the icteric conditions encountered in the neonatal period. In icterus gravis neonatorum spontaneous haemorrhage is one of the recognized causes of death. It may be gastro-intestinal, umbilical, subcutaneous or intracranial. Similarly in congenital obliteration of the bile ducts, sepsis neonatorum and congenital syphilis with jaun- dice, bleeding may occur and, indeed, prove fatal. There are also two kinds of severe neonatal infection distinguished by the eponyms of Winckel's disease and Buhl's disease; both used to have rare epidemic incidence until the introduction of aseptic technique in obstetric practice, and now they have virtually disappeared. Winckel's disease, also called epidemic haemoglobinuria, was a septicaemic condition due to umbilical infection in which grave toxaemia caused jaundice, rapid blood destruction, haemoglobinuria and haemorrhages. The combination of jaundice and cya- nosis induced different observers to mention the occur- rence in their cases of a somewhat characteristic bronze or slaty-grey colour. Buhl's disease was a fatal gastro- enteritis featured by jaundice, haemorrhage, oedema, intense fatty changes in the viscera and enlargement of the liver. In these syndromes an hepatitis was the cause of the jaundice and haemorrhage was a manifesta- tion of toxaemia. Suprarenal hoetnorrhage may occur in the newly born,

and the condition, when bilateral, is incompatible with life. Characteristic are the presence of high tempera- ture and rapid respiration, with normal lungs, so that differential diagnosis includes pneumonia. A mass may be felt at the adrenal site; convulsions, petechiae, purpura, erythematous rashes and jaundice may later appear.

Anaemia in the neonatal period

We have much to learn in regard to the aetiology and pathology of the clinical varieties of anaemia, some common and some very rare, which occur in the neo- natal period. Their classification is therefore difficult. Provisionally, the following scheme may be followed:

Category Examples I. Haemolvtic anae- Icterus gravis neonatorum;

mias. haemolytic anaemia of the newly born; anaemia of neonatal syphilis, and family acholuric jaundice.

II. Anhaemopoietic Hypoplastic anaemias due to anaemias. bone marrow insufficiency,

iron-deficiency, infections. III. Mixed types, both Anaemia of prematurity;

haemolytic . and erythronoclastic anaemia anhaemopoietic. resulting from infection in

the newly born. IV. Leukaemias

Hcemolytic ancemias.?It is well known that during the first seven to ten days of life the majority of

infants show evidence of a physiological haemolysis (physiological icterus) which is explained by the theory that the full time unborn infant, depending on placental respiration, requires a higher proportion of red cells and of haemoglobin than will be necessary after pulmonary respiration becomes established. The mechanism by which the excess of circulating erythro- cytes is broken down has not been explained. An hyperchronic anaemia developing rapidly in the

first few days after birth is the rule in the already mentioned icterus gravis neonatorum. Its hsemolytic character is shown by a positive indirect van den Bergh reaction (the direct reaction may also be positive at the height of the jaundice), a high colour index, brisk regeneration of blood and, in fatal cases, haemosiderosis of the viscera. Some would see in this condition au exaggeration of the physiological haemolysis of healthy neonates, while others have preferred to postulate a

primary disorder of erythropoiesis. Pathologically many of the cases show widespread extramedullary haematopoiesis in the liver, spleen and other tissues. Nucleated red cells are numerous in the blood (erythroblastaemia). The death rate from anaemia and jaundice, and sometimes from haemorrhage or infec- tion, is high, and destructive changes in the nuclei of the medulla and basal ganglia (kernicterus) also con- tribute to the mortality. Treatment may be directed (1) towards an attempt to check further blood destruction. This is essayed by intramuscular injec- tions of human blood serum; 5 to 15 c.c. given as early as possible and repeated daily until improvement begins; (2) towards prevention of an issue fatal through anaemia b.y the use of whole blood transfusions.

Similar in type is the condition of hcernolylic anwmia of the newly born, which may be related to icterus gravis, but differs from it in the absence or mildness of jaundice and the lesser number of nucleated red cells in the blood. It is unusual to discover the cause of this kind of neonatal anaemia, but sometimes an infec- tion, e.g., severe neonatal syphilis, streptococcal or

staphylococcal fever, is present; and the anaemia and haemoglobinuria of Winckel's disease may be recalled.

Anhcemopoietic ancemias.?Defective blood formation in the neonate is seldom due to any known specific deficiency. For example unless the mother herself is

the subject of severe hypoferrism, iron lack is rare at this age. On the other hand, we are ignorant of nearly all other possible causes. Scantiness of marrow tissue, the anatomical result of limited medullary bone space, which overcrowds and restricts the output of blood cells, suggests an attractive hypothesis. Certain cases

may result from infection through depressed marrow function (inhibitory anhaemopoietic anaemia). For all our ignorance of their causation, clinically these cases are striking. A sudden pallor, without trace of jaun- dice or haemolysis, comes a few days after birth (' congenital anaemia '). The van den Bergh reaction is negative and signs of blood regeneration are absent. Iron is without effect, and liver extract, though not of proven value, is worth trial. In all cases except the mildest whole blood transfusion is the only effective treatment. If after a time spontaneous regeneration begins the prognosis is good, but failing this the aspect of idiopathic aplastic anaemia is assumed and the infant dies.

Mixed types of ancemia.?It must be recognized that the causes of any one case of anaemia may be multiple; for example, during a pyogenic infection, haemoglobin may be lost through secondary haemorrhage, and sub-

sequent regenerative activity of the bone marrow may be prevented by toxaemia. The ancemia of premature infants has a background equally complex. In them the ordinarv physiological haemolysis is apt to be

excessive; then, from immaturity of the bone marrow, from defective iron storage and perhaps from other

factors, subsequent erythrogenesis is delayed. For these reasons moderate haemolytic anaemia is common in the premature's first few weeks, recovery from it is slow, and Inter, from about the third month, the effects of iron deficiency are increasingly evident. As a rule

March, 1936] CURRENT TOPICS 163

the early increased haemolysis must be left to run its course, but if, soon after birth, severe anaemia is

Present, blood transfusion will be of value. The period of haemolysis and icterus being past, half-grain doses of reduced iron mixed with sugar may be given three times a day. It has been shown that some prematures nave a

'

negative iron balance' during their first few Months, so that these prophylactic doses of iron, mcapable of preventing moderate anaemia from arising, will ensure that when the infant's ability to use iron increases there will be no shortage.

In certain (haemolytic) cases, related on the one hand to haemolytic anaemia of the newly born and to hypo- Plastic anaemia on the other, following an initial destruction of blood, regeneration temporarily or

Permanently fails; to these the comprehensive term

erVthronoclastic anaemia is applied. In the group wi'h temporary failure, early blood transfusions are of the greatest value. They may keep the infant alive

'^?bstitution therapy) until the bone marrow becomes efficient some three or four weeks after birth, this state ?t efficiency being heralded bv a spontaneous reticulo- cytosis. . Leukcemia.?Instances are on record of infants show- ing leukaemia at or soon after birth. In no case, though. has the mother suffered from the disease, nor has a leukaemic mother been delivered of a leuksemic

jnfant, evidence against any possible infective origin or leukaemia. Leukaemia in the newborn does not differ materially from the same disease occurring at a later period of childhood except that the myelogenous ypes, so rare in children past the age of infancy, are ^countered relatively more often. Difficulties have

er^M? 'u distinguishing severe haemolytic anaemias with ythroblastaemia (icterus gravis, etc.) from neon'ilal

eukaemias but the signs of haemolysis in the erythro- iastic syndrome (icterus, etc.), together with the cyto- ?gy of the blood films, should enable leukaemia, which s much the rarer, to be easily excluded.

. . . '

Recent Advances in Dietetics

By S. ,T. COWELL. m.a.. m.b.. f.r.c.p.

(From the Practitioner, Vol. CXXXV, October 1935, p. 384)

The past year or two has witnessed an exceptional degree of interest, on the part of the general public Jn problems connected with ' food valuesOnly tot- often, however, Ihis legitimate interest has had to b? satisfied with half-truths or guesses at the truth. The relation of diet to human health and development is

stijl ^ only beginning to be understood. Modern Principles of nutrition have been applied for so short a time to problems of human dietaries lhat it will not

possible for many years to judge .what may and what may not be achieved by

' correct' feeding throughout the whole span of men's lives. As far as the medical profession is concerned there are two main aspects of dietetics which merit separate consideration. 1 hem is first the use of diet for the treatment of established disease and, secondly, the use of diet for promoting good physical development and lessening tiic Predisposition to various diseases.

Treatment by diet As regards the use of diet therapeutically, many of the most valuable recent advances have been in the

direction of supplying dietetic factors the absence of which from the habitual diet has led to deficiency states or diseases. Such deficiency diseases, though often caused primarily by dietetic faults, are sometimes treated more satisfactorily by massive doses of the hissing food elements than by natural foods containing those elements. Treatment by the former method can scarcely be distinguished from treatment on orthodox Pharmacological lines, although the prevention of such diseased conditions can usually be assured by adjust- m?nt of the diet alone. A good illustration of this Principle is to be found in the recent work which haa

been done on nutritional anaemia, particularly by Professor L. S. P. Davidson and his colleagues in Aberdeen. Anannia, often severe, was found by them to be widespread among the women of that city, and the evidence which they laboriously collected pointed to a deficient iron_ intake in the daily food as one of the chief determining causes. Treatment o? the condi- tion by a good diet containing natural foods compara- tively rich in iron was slow and uncertain, whereas treatment by massive doses of medicinal iron was

usually effective in quite a short time. Again, deficiency diseases are now recognized in people whose diets have not been lacking in any known food factor, the deficiency having arisen either from an acquired inability to absorb some specific food factor or from some breakdown on the part of certain tissues of the body which interferes with the normal metabolism of a specific food factor. Thus among the victims of chronic intestinal diseases '

secondary pellagra' has been recognized not infrequently and its origin is probably to be sought in mal-absorption of the pellagra- preventing substance or substances. Pernicious anaemia is an example of a secondary deficiency disease in which the fault lies not in an actual food deficiency, but rather in a defective mechanism in the stomach for elaborating from certain food elements the neces-

sary specific substance which stimulates the formation of red cells. Such secondary deficiencv diseases, though not always readily amenable to simple dietary adjust-

ment, may be readily amenable to comparatively large dosns of the appropriate factors. This tendency to employ pharmacological substances

in place of natural foods is met with in the treatment of chronic urinary infections. The high fat: low

carbohydrate diet which has been used with considerable success in such conditions has already a serious rival. The therapeutic effect of this diet probably depends on the production and excretion in sufficient concen-

tration in the urine of B-oxvbutyric acid, and it is well known that for the attainment of this end the diet must be most rigorously controlled, usually to the patient's great discomfort. It is now claimed that equally good results may be obtained by keeping the patient on his usual diet and giving him by mouth mandelic acid, which apparently has the same sort of effect as naturally produced B-oxybutyric acid.

Diet and preventive medicine

Although many of the modern discoveries of nutri- tional science have been divorced from their natural

application by way of dietary control in so far as the treatment of disease is concerned, preventive medicine should still rely mainly on the selection of a suitable dietary of natural foods to foster that state of good nutrition which favours good physical development and raises the resistance of tissues to disease. This the general public is beginning to realize. There would appear to be no doubt whatever that a great deal of preventable illness is caused directly and indirectly by imperfect diet in countries such as ours where definite deficiency diseases are, with one or two exceptions, uncommon. The difficulty at present is to define with any certainty the requisite qualities of a good diet for human beings. To collect direct evidence on such a

point is obviously an undertaking of enormous magni- tude which would require an elaborate organization. To judge from the newspaper controversy which raged last year on the subject, the nutrition of human beings would seem to depend on supplving them with an exact number of calories and a precise amount of first-class

protein. This was, of course, due to general ignorance; every medical man knows how variable is the amount of food consumed by different individuals in comparable states of nutrition. Probably the most practical^ sugges- tion which can be given to the ordinary individual in the present state of knowledge will turn out to be the advice to include regularly in his diet liberal quan- tities of the so-called protective foods, dairy produce, fresh vegetable and fruit, and to leave the rest of the

diet to the individual taste.

164 THE INDIAN MEDICAL GAZETTE [March, 1936

Special cases

In the case of certain classes of individuals, however, it is becoming generally recognized that more precise care in the choice of diet will have to be exercised if

adequate nutrition is to be fully attained. Children, especially during their first years of growth, and women during pregnancy, require larger proportions of protec- tive foods to ensure that their tissues do not suffer under the strain of rapid development to which they are subject. Certain food elements are already known which are particularly likely to be lacking in the ordi-

nary diets of individuals belonging to these classes, their deficiency not uncommonly resulting in recog- nizable symptoms of disease. Among these may be included the mineral elements calcium, iron and iodine and certain of the vitamins. So much has been written about the calcium requirements of children that it is not necessary to stress it in any detail. A generous supply of calcium and phosphorus, together with a

liberal supply of vitamin D, is essential for the perfect development of the bones and teeth of the child. Since milk is one of the richest sources of calcium among common foods, its provision for children on a liberal scale would seem to be justified for this reason alone, and the recent agitation for making it more readily available in poor households is all to the good. It is, however, not perhaps so generally realized that the pregnant woman, especially during the last few months of her pregnancy, requires large quantities of calcium in her diet to supply her rapidly developing foetus with all it needs without sacrificing her own valuable stores. A severe degree of calcium deficiency, particularly if combined with a deficiency of vitamin D,

_ leads, as is

now well known, to osteomalacia. But minor degrees of deficiency of these elements are almost certainly related to some of the common disorders associated with pregnancy. The spread of dental caries and the painful muscular cramps which are common features of pregnancy would appear to be due to this cause and to be preventable to a large extent_ by appropriate measures to make good the deficiencies. Evidence is now being accumulated to show that some of the toxaemias of pregnancy may be prevented by similar means, that is by increasing the supply of calcium and vitamin D.

The question of the iron requirements during infancy and pregnancy has recentlv been receiving a good deal of attention. Dr. Helen Mackay has worked out with great care the frequency of anaemia among infants in the East End of London and has shown that it is of nutritional origin associated with diminished resistance to infections and that it can readily be prevented or

cured by adding to the milk diet some simple prepara- tion of iron. Of equal importance to this nutritional anaemia of infancy would seem to be the anaemia which is frequently associated with pregnancy. The common form of anaemia during pregnancy in this country, though almost certainly of nutritional origin and asso-

ciated with a deficiency of iron in the habitual diet, is most satisfactorily treated by liberal doses of medi- cinal iron. The recognition of this anaemia and its correction by suitable treatment are rapidly becoming more widespread in this country, and it may be possible in the next few years to determine the extent to which some of the difficulties and dangers of labour and the puerperium are due to its presence. A word may be said on the question of iodine

deficiency. An adequate supply of iodine is still to be regarded as the key to goitre prevention, but there seems little doubt that successful prophylaxis depends largely on ensuring a sufficient supply of iodine to the developing foetus, which means giving the pregnant mother iodine in some form or other. The simplest method of doing this in our country is that sea-fish should be eaten once or twice a week during pregnancy. These few examples may serve as indications of the

special food requirements of pregnant women and children. It would be idle to pretend that the knowledge exists at present to enable ideal diets to be devised which would ensure perfect physical develop- ment of the human child and promote perfect health of the mother during her pregnancy, labour and lactation. Nevertheless, it is becoming more and more apparent that wise feeding plays a large part not only in deter- mining the health of women throughout the period of their reproduction and in regulating the development of the growing child, but it is also capable of affecting the health of the offspring in later life. It is known that the body adapts itself in a remarkable way to

changes of environment, including drastic changes in dietaries. Yet there is no doubt that dietary defi- ciencies in early life can lead to imperfections in the growth of the tissues which cannot be repaired in later life by the most perfect diet. Direct evidence on such a point as this is not easy to obtain when dealing with human material, but the truth of the general principle is suggested most strongly by a mass of experimental data obtained from animals. In the nature of things advances in knowledge of the full prophylactic effects on human beings of a good diet are bound to be slow. The general awakening of interest in the subject both within and outside the medical profession should foster the collection of further facts dealing directly with human material without which permanent progress in dietetics must be uncertain.