the further reduction of THE MOR- /TALITY OF CHOLERA TO 11 PER CENT.

/ JBY

/ the addition of atropine HYPODER-

mically to the hypertonic and

permanganate treatment, with an ADDENDUM SUMMARISING THE SYSTEM

OF TREATMENT.*

By Sir LEONARD ROGERS, m.d., f.r.C.p., i.m.s..

Professor of Pathology, Calcutta.

In a recent paper (Lancet, July 31st 1915), on the results of the hypertonic and permanganate treatment in 1,000 cases of cholera, I recorded a trial of atropine sulphate hypodennically, as

long ago advocated by Sir Lauder Brunton, in

seventy-five cases, with a death-rate of only 10*7 per cent, against 24 per cent, in an equal number of control cases, one hundredth of a

grain being injected morning and evening until

convalescence set in. I now have 100 atropine cases, with as many controls in alternate cases,

extending over almost a year, and so including all seasons with their varying mortalities, and have made a detailed analysis of the two series to determine if they are strictly comparable and thus furnish a reliable test of the drug. I am

much indebted to my House Physicians, Drs. B. C. Mukerjee, D. M. Chatterjee, and H. S.

Kakshit for their help in treating and keeping accurate records of the cases.

The first point to be considered is the severity of the cases on admission in the two series. This can best be judged from the figures of the blood pressures and specific gravities of the blood on

arrival at the hospital, which are shown in Tables I and II.

Table I.

Blood Pressures on Admission.

Atropine. No Atropine.

Blood Pressure.

70 ram. & over Under 70 mm. Pulseless

73

20 6 f14 3

LOO 22

10-7

3m}26'25 100

It appears from Table I that the number of

patients admitted pulseless was almost equal in the two series, thus showing no appreciable difference in the number of very severe cases.

Table II.

Specific Gravities of the Blood on Admission.

Specific Gravity.

Atropine. No Atropine.

S^S

O

3-S

Below 1060 1060-1063 1064?1065 Over 1065

89 11

12 21 29 38

100

8*3 14-3 in-3 10-5

78 22

18 23 21 38

100

22*8 21-8 14 3 26 25

It appears from Table II that there were an

equal number of cases in each series with the

very high specific gravities of over 10G5 (normal 1056), which means great loss of fluid before

admission with a correspondingly grave prog- nosis. ?

The ages of the two series were also closely similar, two deaths having occurred in each in

patients over 50 years of age, so that the series

are also comparable from this point of view, so that in all important respects the two series of

patients are strictly comparable as regards the

severity of the cases on admission to hospital. Any great difference in the death-rate in favour of the atropine treatment may, therefore, safely be attributed to the action of the drug.

The mortality in the tivo series.?On turning to the last columns in Tables I and II showing the death-rates, it is at once apparent that in each line of both tables those of the atropine series were markedly lower than in those of the con- trol cases. The total result is the reduction of the mortalily in the atropine series to just one- half of that of the control cases, namely to 11

per cent, against 22 per cent. 1 am now giving the atropine injections in every case, and up to the date of writing have treated 117 cases with

* Read before the Medical Section of the Asiatic Sooiety ,

of Bengal. 1 1

THE INDIAN MEDICAL GAZETTE. [Jan., 1916

24 or 11*1 per cent, of deaths. When it is

remembered that the death-rate of the control

series is but little over one-third of the old

mortality in the Calcutta Medical College Hospital before I introduced the hypertonic and

permanganate treatment, and that in the present atropine series the rate of 11 per cent, is only just over one-sixth of the former mortality, the results are seen to be indeed remarkable, and gratifying.

In view of this result it will be of interest to

analyse the records of the cases further to ascer- tain in what respects atropine exerts its good effects. For this purpose I have worked out the

following tables :? Table III.

The causes of death in the tivo series of cases.

Atropine No Atropine

Col- lapse.

Ure- mia.

Pneu- monia,

Other causes.

Total.

11 23

The noteworthy features in Table III are the

following. The number of patients dying in the collapse stage was reduced to one-third in the

atropine series, while it is worthy of note that

only one of the three patients who died of

collapse was under the age of GO years ; a period after which, as I have previously pointed out, the stamina of the patients seldom allows of the successful treatment of a severe attack of cholera. There was thus but one death from collapse among 98 successive cholera cases under the

age of 60 treated with atropine, although no less than 91 per cent, of the patients were sufficiently ill on admission as to require one or more intra- venous injections during the course of the

disease. Only a few years ago the great majority of cholera patients died of collapse, but this

formerly deadly stage can now be nearly invaria- bly tided over in all but very feeble young or old subjects,

Urcemia.?As recorded in my recent Lancet

paper, the death-rate from post-clioleraic uraemia has recently been reduced in my wards to about one-third of the rate during the previous three

years by the addition of alkalies to the saline solution. This addition is based on a large- number of observations on the alkalinity of the blood in the disease, which were kindly carried out for me by Captain A. J. Shorten, i.m.s., and later by Dr. Satis Chandra

Banerjee, Assistant Professor of Physiology, Cal- cutta Medical College, which showed clearly that post-choleraic uraemia is essentially an acidosis, as suspected by A. W. Sellards, who was the first to obtain good results by intravenous injections of sodium bicarbonate in cholera in the Philippine Islands. Our alkalinity observations in Calcutta, however, go much further, and demonstrate that

the alkalinity of the blood is greatly reduced in

all cases of cholera of any severity. My routine method of combating this during the past year has been to give one pint (and sometimes two) of the following solution in all late admissions

with suppression of urine, and also in every

patient requiring a second or further intravenous injection :?Sodium bicarbonate, grains 160 (2/Q) and sodium chloride, grains 60, in one pint of water. I have found it most convenient to

sterilize weighed powders of bicarbonate of soda

wrapped up in paper in an autoclave, and to add

them to already sterilized sodium chloride solution, in order to avoid the chemical changes produced by boiling the solution of sodium bicarbonate.

One pint of this alkaline solution is given first at each subsequent injection, and hypertonic or

isotonic saline continued to make up the full

amount of fluid indicated by the specific gravity of the blood, as described in my book on cholera.

As a result of this addition to the treatment

the death-rate from uraemia during 1915 has

fallen to 3*8 per cent. The ursemia cases were

distributed as equally as an uneven number allows between the atropine and non-atropine cases,

with the slight difference in favour of atropine. Pneumonia.?I have previously pointed out

the deadliness of this complication of cholera, in some cases of which

'

Major Greig has found

comma bacilli in the pulmonary lesions. It is

very noteworthy that only one death took place from this cause in the 100 atropine cases, while no less than six occurred in the non-atropine series, which, however, is an unusually high figure so that the difference may be partly accidental. Never-

theless, the well-known action of atropine in

lessening the danger of oedema of the lungs was

probably an important factor, as the intravenous

injections, even when they are controlled by the

specific gravity test, must throw a great strain on the pulmonary circulation, especially in severe

cases of cholera requiring their frequent repetition. The deaths among

" other causes" were

equally divided between the two series of cases, so call for no comment.

Table IV.

Blood pressure on the day after admission.

Blood Pressure.

To 70mm. 71-80 mm. 81?90mm. 91?100 mm. 101-110 mm. Ill?120 mm. 0verl20 mm.

Total

Atropine.

Total.

2 -1 2

21 35 0 19 0 6 0 1 0

4 6

26 35

jo4 (55-7%.) 6 1

97

No Atropine.

u ! a

2 i 4 9 1

22 4 09 3 ill 0 7.

76 15

Total.

25) 34 (37-3%.) 9 4

91

Jan., 1916 ] THE TREATMENT OF CHOLERA.

The data in this and the two following tables

represent the average of the morning and evening estimations on the first complete day in hospital, the reduction of the total cases to below 100

being due to the unavoidable omission of those who did not survive so long.

It appears from Table IV that among the

atropine cases there were a smaller proportion of very low blood pressures not exceeding 80 mm., and a higher one with blood pressures over 90

mm., than in the control series. The raising of the blood pressures in the atropine cases is parti- cularly marked in the critical decades above and below 100 mm. Thus there were 54 cases, or

55 "7 per cent., with pressures between 91 and 110 in the atropine series, as against 34, or 37'3 per cent, in the non-atropine ones ; thus indicat- ing that the drug had a good effect in raising the blood pressures and so diminishing the degree of shock, to which its life-saving action is pro- bably largely attributable.

Table A'.

Respiration Rates on day after Admission.

Atropine.

Rates per Minute.

To 20 21 to 25 2G to 30 31 to 40 Over 40

Total .. 89

Total.

5 } 3

60

98

No Atropine.

78 15

Total.

34 9 ) 3 I

47

12

93

Table V shows that the drug appears to have had a material effect in diminishing the number of respirations, a larger proportion of the atrojnne cases showing under 26 respirations per minute and fewer over 30 than in the control series. As 1 have previously shown a high respiratory rate is of bad prognostic significance, the much smaller proportion of the atropine cases with a rate of over 26, and still more of those over 30 per minute, appears to be of importance as an indi- cation of the beneficial action of the drug.

Table VI.

Pulse rates on day after admission.

Rates per Minute.

To 70 71 to 80 81 to 90 91 to 100

101 to 110 Over 110

Total

Atropine.

Cured. Died. Total

10 ! 0 7 0

23 2 24 3 14 2 11 | 2

89 9

10 7

25 27 16 13

No Atropine.

Cured. Died. Total

3 8

24 17 12 14

78

0 3 0 8 5 29 6 23 0 12 4 18

15 93

It appears from Table VI that the atropine injections had no material effect on the pulse rate

except that there were a larger number of pulses under 70 per minute in the atropine series.

Table VII.

The number of intravenous transfusions required.

Nil 1 to 3 4 to 7

Total

Atropine.

o

9 70 10

89 11

9 77 14

100

o-o 9-1

28-6

No Atropine.

11 57 10

22

12 69 19

100

8-33 17-1 47-3

It appears from Table VII that slightly fewer of the non-atrojrine series required intravenous salines, indicating that they were in this respect a slightly milder series, but the difference is immaterial. On the other hand a much larger proportion of the control cases required more than three transfusions, which points to the atrojnne having somewhat reduced the number of intraven- ous injections required in the very severe cases, pro- bably by raising the blood pressure as already shown. The greatly lowered mortality in the atropine cases is seen in each class, and is especially note- worthy in the very severe cases requiring four to seven intravenous injections, in which the death

rate was 47*3 per cent, in the non-atropine cases, but only 28'6 per cent, in those receiving the

atropine injections.

Table VIII.

Sickness up to the end of the second complete day in hospital.

No Atropine.

Nil ... ... - 26 42 1 to 5 times ... ...

<"?' 30 Over 5 times ... ...

17 16

Total ... 80 88

The records of the sickness are not quite complete, but the cases in which it was regularly recorded are shown in Table VIII which shows a

larger number of cases without sickness in the

non-atropine cases, so the drug had no effect in

diminishing that symptom. With the hypertonic and permanganate treatment, however, vomiting is not a marked or important condition.

?10 the INDIAN MEDICAL GAZETTE. [Jan-. 191G-

Table IX.

Urine passed up to the end of the second day in hospital.

Average of 100 cases in ounces

Atropine. j No Atropine.

95-0 87-57

Table IX sliows a slightly greater amount of

urine passed up to the end of the second com-

plete day in hospital in those cases receiving atropine than in the control cases without it.

The difference is not very great, but such as it is, it is in favour of the atropine, and is no doubt

due to the higher blood pressure produced by the

drug. Conclusions regarding the action of Atropine

in Cholera.?Atropine hypodermically in cholera has further greatly reduced the death-rate in

cholera. It appears to act by lessening shock, raising the blood pressure, diminishing the fre-

quency of the respirations, increasing the flow of

urine, and diminishing slightly the number of intravenous injections required. The number of

deaths from collapse and from pneumonia has

been greatly diminished, while the total mortality in the atropine series has fallen to one-half that

of the controls, and to but little more than one-

sixth of the death-rate before I introduced the

present system of treatment: a reduction in the

mortality of a very serious specific disease by means of simple measures, based on prolonged scientific research, controlled by minute clinical

observations, which, even in these days of rapid advance, has probably only been equalled by the

1

antiseptic treatment of wounds, anti-diphtheritic serum and emetine in amoebic disease.

Addendum Summarising the Principal Points

in my Present Treatment of Cholera.

In view of the importance of the addition of

atropine and alkalies to the hypertonic saline and permanganate treatment of cholera, it may be well to take this opportunity of briefly sum-

marising the principal points in my present system of treatment. On admission give one-hundredth of a grain

of atropine sulphate hypodermically and repeat it

morning and evening. Take the specific gravity of the blood, the blood pressure, and the tempera- ture in the mouth and rectum. If the blood

pressure is not over 70 mm., or the specific gravity is 1,0G3 or over, give an intravenous

injection of sterile hypertonic saline of three, four, five, or even six pints, in accordance with whether the sp. gr. is 1,063, 64, 65, or 66 and

over in male adults, and correspondingly less in females and children in proportion to their

approximate weights. Unless the rectal tem-

perature is below 99?F. the saline should never be injected at above blood heat (98?F.) for fear of producing hyperpyrexia. If the rectal

temperature is 100?F. or over, the fluid should be given at a temperature between 80? and 90?F. The hypertonic solution should contain 120

grains (8 grammes) of sodium chloride and 4

grains (0'4 grammes) of calcium chloride. I for

long added 6 grains of potassium chloride, but some physiologists consider it unnecessary and

possibly harmful, so I now omit it. Permanga- nate of potash to be given in two-grain pills, made up with kaolin and vaseline and preferably, coated with salol or keratin, two pills every

quarter of an hour for two to four hours, in

accordance with the severity of the case, and then two every half-hour until the stools change to green or yellow and become comparatively small. Barley water and plain water by the

mouth in small quantities at a time (three or

four ounces) to be given frequently, but no other food during the attack. Normal saline (sodium chloride, grains 90 to a pint) half a pint every two hours by the rectum until the collapse stage is passed and urine is being excreted regularly, and then reduced in frequency to every four

hours and continued until tw6 pints of urine are

passed in twenty-four hours. The fall of the blood pressure to 70 and under,

or the rise of the sp. gr. to 1,063 or above are

indications for a repetition of the intravenous

injection, estimations being made regularly morn-

ning and evening, and at any time that the pulse tends to fail or the patient becomes restless. At

each repetition of the injection, and at the first

injection in all cases admitted late with sup-

pression of urine for twenty-four hours or more, give one pint of the following alkaline solution:? Sodium chloride grains 60, and sodium bicarbon- ate grains 160 (2%), and continue with the

ordinary hypertonic solution up to the total

amount indicated by the sp. gr. of the blood. The alkaline solution counteracts the tendency to acidosis, which is the most essential cause of

post-choleraic uraemia. If the urinary excretion is deficient in the later

stages with a blood pressure of 100 mm. or more and a specific gravity of below 1,063 but not much below the normal point of from 1,056 (in Indians) to 1,058 (in Europeans), give one pint of the above alkaline solution either subcutaneously, or better intravenously, to increase the urinary flow. The alkaline solution in such eases should also be

given by the rectum, instead of normal saline. If the blood pressure remains persistently much

below 100 mm. and urine is deficient, give pituit- arin hypodermically and caffeine sodio-salicilate in five-grain doses by the mouth every four

hours, and dry cup and foment over the kidneys repeatedly.

Jan., 1916.] THE CONJUNCTIVAL FLAP IN CATARACT EXTRACTION. 11

In very young children and feeble old patients glucose may be given in the rectal saline to

support the strength. The above are the main points in the treatment

of cholera on my system, worked out from a

minute study of over 1,000 cases in which detail- ed notes have been kept, tabulated and analysed. Full details regarding the technique of intravenous injections will be found in my book on the

subject.