The' Intermittent 
Administration of Quinine in Malaria, 
WITH THE 
Temperature as a Guide. 
- 
FRANCIS H. WILLIAMS, M.D 
Reprinted from the Boston Medical and Surgical Journal of March 9, 1893. The Intermittent Administration of Quinine in Malaria, 
with the Temperature as a Guide. 
In the vicinity of Boston, as well as in the city itself, most 
physicians have observed, during the past summer, an unusual 
increase in the cases of malaria. It is, however, a disease of the 
country rather than of the city, and especially affects those who 
have to do with the soil. I desire to call attention to some of the 
points that are of practical interest in the treatment of this disease, 
especially to the intermittent method of administering quinine, 
with the temperature as a guide, and not the chill, that I 
have had the pleasure of introducing into this community. The 
bearing of this method will be made more clear if I first recall 
some points relating to the parasite of this disease, but I shall not 
attempt to consider here the various types of malaria nor the dif- 
fering views of Laveran and of the Italian school concerning the 
parasites. More than ten years ago Laveran, then a French army 
surgeon in Algiers, discovered the parasite of malaria and years 
of careful study on his part, together with that of many other 
observers in various and widely-separated parts of the world, have 
confirmed and extended his first observations. Laveran’s haema- 
tozoon, more generally known as the plasmodium malariae. has never 
been found in any other disease. It is not a bacterium, but, accord- 
ing to Biitschli’s classification, belongs to the group of Gregarinida, 
order of Sporozoa, class of Protozoa. The history of these prim- 
itive animals outside of the body is at present unknown, A warm, 
moist soil, such as would be found in hot seasons after a rain, is 
followed by an increase in the number of cases of malaria, but 
where the marshy areas are completely submerged, there seems to 
be much less danger. It is thought to be carried to man both by 4 
the air and by water. Many facts point to the latter as one source 
of infection. 
Inside the body these haematozoa find their homes and food 
in the blood. According to Laveran, their minimum period of incu- 
bation is from six to ten days. They have a cycle of development 
and at certain stages of their growth are more and at others less 
susceptible to the action of quinine. Most observers think that 
they penetrate the red corpuscles of the blood in which at first they 
occupy but a small space; they gradually enlarge, however, at the 
expense of the haemoglobin until have absorbed the endoglob- 
ular substance; segmentation takes place and the spores break out 
into the blood serum: the presence of large numbers of spores in 
the blood produces an attack of the fever; the maturing of different 
generations of parasites the return of the fever. 
The successive development of the parasites indicates successive 
treatment, so timed as to anticipate the recurrence. Laveran com- 
pares such a method of giving quinine to the way in which liquids 
are rendered sterile by boiling. The first boiling is sufficient to 
kill most of the bacteria, but some spores remain. If, however, 
the boiling is repeated on the following day the spores, then having 
developed into bacteria, are destroyed. If the water is boiled a third 
time after an interval of twenty-four hours it is made sterile. 
When an enemy such as the haematozoa, however, attacks the 
organism, it is not wholly indefensible; there are bodies normally 
present known as phagocytes which are capable of overcoming the 
enemy if it is not too numerous. To assist nature in this encounter, 
we should place the system in as good a condition as possible, and 
some cases recover after rest in bed, aided by good food. The mor- 
tality from malaria in Southern India is aggravated by the system of 
starvation to which the inhabitants subject themselves when suffering 
from this disease. But if, on the contrary, the parasites have the 
upper hand, rest alone is not sufficient, we must have recourse to 
quinine. It is a serious matter to have the blood deteriorated by 
the loss of an element that carries oxygen to every part of the body, 
and in severe cases there may be a great diminution in the number 
of red corpuscles within two or three days. 
Dock, in his article on malarial diseases, dwells at some length 
upon the proper time for the administration of quinine and finally 
suggests the following plan “ for the routine treatment of simple 
cases.” First day, in the decline, 20 grains of quinine; second 
day, if necessary, 10 grains; seventh day, 20 grains; fifteenth day, 
20 grains; twenty-second day, 20 grains. He also states that 5 
instead of one large dose, three or four 5-grain doses may be given 
at intervals of two hours during the decline. 
The result of the intermittent method of using quinine with the 
temperature as a guide, and not the chill, in such cases of 
malaria as came into my service at the Boston City Hospital last 
summer, will be seen below. There were eighteen cases in all, 
twelve tertians, five quotidians, and one of irregular type. In some 
instances the diagnosis was established by finding the parasites 
in the blood. One of the cases is interesting in this con- 
nection, as the patient was sent to the hospital with the diagnosis 
of typhoid fever, but an examination of the blood showed the pres- 
ence of parasites and proved it to be a case of malaria. In treating 
these cases I gave 20 grains of sulphate of quinine in solution, when 
the temperature began to fall, without reference to the chill. With 
this treatment it is of course necessary to have the temperature 
taken at frequent intervals, and this was done in most of the cases 
every four hours. On leaving the hospital, the patients were given 
a prescription and directed to take the medicine on the seventh, 
fifteenth and twenty-second days. It was not found necessary to give 
quinine on the second day (see the preceding paragraph), as there 
was no chill after the first dose of quinine was administered, except 
in two cases, No. 3 and No. 15, the charts of which are not given. 
In these cases the fever returned on the second day, but in No. 3 the 
dose given on the first day was not administered at the right time ; 
in No. 15 it is possible that this was also the case. The patients had 
no cinchonism while in the hospital. The intermittent method of 
administering quinine seems to lessen the risk of the cinchonism that 
is apt to follow after continuous doses ; further, it leaves the beds 
in the hospital earlier for other patients and saves quinine, 
much less being used than in the continuous method. 
The charts are numbered in the order in which the patients 
were received at the hospital, and I give on pages 7 and 8 the even- 
numbered ones, omitting, however, No. 18, as it was a very mild case. 
The odd-numbered charts are of the same character, but the 
average time in the hospital, of the patients there described, was 
about two days less, and the average temperature rather higher, 
than in the even-numbered cases. All cases were given 20 grains 
of sulphate of quinine in solution when the temperature was falling, 
without reference to the chill, and the dose was repeated on the 
seventh, fifteenth and twenty-second days. When this rule was 
followed, there was no chill after the first dose was administered 
while the patients were in the hospital, except in case No. 15 6 
referred to above, nor after they were discharged, so far as I am 
aware. In view of further experience, it seems to me that 
in the forms of malaria most common here, a smaller amount of 
quinine, fifteen grains or less, would answer, or where it seems 
probable that the patient may be especially susceptible, 5-grain 
doses repeated once, or if no symptoms are produced, twice, at 
intervals of two hours, may be sufficient. 
Charts 4, 6, 8, 12, 14, 16, on page 7, and charts 2 and 10 on 
page 8, show the effect of a single dose of quinine given on the 
decline of the temperature. 
Chart 8, page 7, illustrates especially the advantage of con- 
sulting the temperature in administering the quinine, as this patient 
had no chill while in the hospital. He was given quinine on July 
27 while the temperature was falling. 
In cases 2 and 10, page 8, the intermittent method of treat- 
ment was not fully carried out, and they therefore illustrate well the 
importance of following the first dose by a dose on the seventh, 
fifteenth and twenty-second days, respectively. 
Case 2, page 8, entered the hospital June 13, 1892, and on June 
15, when the temperature began to fall, quinine was administered. 
On June 21 the patient did not take the quinine, as she should have 
done, and the fever returned. On June 28 another dose of quinine 
was given and there were no more chills. 
Case 10, page 8. J. K., 38 years old, entered the hospital 
August 1, 1892. History of slight malaria the preceding year and 
of chills every second day since July 4of this year. From August 
Ito 7, temperature normal. An examination of the blood on 
August 7 showed 2,880,000 red corpuscles and 40,000 microcytes, 
and diminished tendency to rouleaux. Haemoglobin, 60%. Iron 
given. August 8, quinine was administered during the decline of 
the temperature, likewise on August 14 and 15. August 18, the 
blood was again examined and there were 3,340,000 red corpuscles 
and 10,000 white corpuscles. No abnormal sizes seen. Haem- 
oglobin, 90%. The patient was discharged August 20. After 
leaving the hospital he did not take the quinine on August 22, as 
directed. Returned September 2 and reported having had chills 
on August 28 and 30 and September 1. Quinine was administered 
on September 7 ; the patient was discharged September 8 and 
given a prescription for quinine to be taken September 15 and 22. 
This was the only case that returned to the hospital. 
Case 2 shows that when the quinine was not administered on 
the seventh day, the fever returned. Case 10 shows that when it 7 8 
CHARTS 2 AND lO 9 
was not administered on the fifteenth day, as well as on the first and 
seventh days, the fever returned. 
It is known that there is no definite relation between the 
time of the chill and that of the maximum temperature. In my 18 
cases the time both of the chill and of the maximum temperature, 
before quinine was given, was noted in 5 cases only. In one case 
the chill followed the rise in temperature and in four cases preceded 
the rise in temperature, coming in the first three of the four cases, 
six hours, three hours and thirteen hours, respectively, before the 
rise. In the fourth case, the time both of the chill and of the max- 
imum temperature was noted three times, and in this case the chill 
preceded the rise in temperature seven hours, eight hours and one 
hour, respectively. In case No. 8, as already stated, there was no 
chill. 
Charts I. and 11., page 10, which the courtesy of another 
physician permits me to use, show what may happen under another 
method of administering quinine in cases similar to mine. 
Case I. entered the hospital July 11, and was given 
July 13, 10 grains of quinine. 
July 14, 16 grains of quinine (4 at 4 A.M., 8 at 8 A.M., 4 at 8 P.M.) 
July 15, 30 grains of quinine (10 grains at 4, 6 and 8 P.M.) 
and this dose seems to have been continued on July 16, 17 and 18. 
In spite of the 30 grains of quinine given on July 15, the patient 
had a chill on July 16. 
Case 11. entered the hospital June 1, and was given 
June 5, 12 grains of quinine. 
June 6, 4 grains of quinine at 6 P.M. 
June 7, 16 grains of quinine (8 at 6 A.M. and Bat 10 A.M.) 
June 8, 4 grains of quinine. 
June 9, 16 grains of quinine. 
June 10, 4 grains of quinine. 
June 11, 16 grains of quinine. 
June 12, 4 grains of quinine. 
Notwithstanding this, the chills returned in about four weeks, 
and this patient entered my service July 17, as it happened during 
a chill and just before the temperature had reached the maximum. 
He had one dose of quinine when the temperature began to fall. 
There were no more chills. See Chart 6, page 7. 
The intermittent method of giving quinine applies, according to 
Plehn’s experience, to prevention as well as to cure. Plehn, a 
surgeon on board a Dutch vessel, found that, in spite of daily doses 10 
TEMPERATURE, (FAHRENHEIT’S SCALE.) 
CHARTS I AND 11. 
TEMPERATURE, (FAHRENHEIT’S SCALE.)| 11 
of 3 to 5 grains of quinine, malaria appeared regularly among those 
under his charge while about the coast of Java. He then tried 
giving quinine in 15-grain doses, at intervals of seven days, to 73 
persons, 40% of whom were old sufferers from malaria. To their 
astonishment, of the 73 persons so treated, only one had malaria, 
and this was a rudimentary attack ten days after the last dose of 
quinine; he had previously shown symptoms of malarial cachexia 
from an old attack. 
In severe forms, such as occur in warmer climates, one does 
not wait, however, for intermissions or remissions before giving 
quinine, and if the stomach be intolerant, high rectal injections may 
be used, and when there is urgency, it should be given subcutaneously. 
This latter method, however, requires special precautions. Bacelli 
found that in severe forms, especially the pernicious, 9to 10 x/2 grains 
of quinine injected inti-avenously was not sufficient to make it a 
sure parasiticide, but that it was necessary to give 15 grains. 
In the administration of quinine by the mouth, which is ordi- 
narily sufficient, there are simple precautions to be taken which are 
too often overlooked. As the taste is disagreeable, physicians seek 
to disguise it by giving the drug in pills. This method ought not 
to be employed; quinine pills should be wholly discarded; they 
are frequently old and hard and in many cases are not absorbed but 
carried off in the stools. A case in point is that of one of my 
patients who, contrary to my directions, was given quinine in 
pills. Of the ten pills taken, nine were subsequently found in the 
discharges. To avbid this element of uncertainty, quinine should 
be given in solution, or, if it is important to consider the taste, it 
may be given in powder or capsule. 
It has been found advantageous to give a cathartic with quinine 
and it has occurred to me that the usefulness of the cathartic may 
be due in part to the fact that it reduces the volume of the blood 
and thus in effect the dose is made stronger. Warburg’s tincture, 
which experience shows to be a good way of giving quinine, acts 
both upon the bowels and as a diaphoretic, and thus withdraws 
water from the blood in two ways. 
In treating patients suffering from malaria we should not over- 
look the anaemia which is often produced by the parasites, nor fail 
to relieve it by appropriate treatment with iron, or in some cases 
with arsenic. It is desirable to examine the blood with Fleischl’s 
haemometer, in order to determine the presence and extent of the 
anaemia. 
The increase of malaria in this vicinity, and the presence of 12 
certain forms of malaria which are not easily recognized by the 
older methods, prompt me to emphasize the importance of examin- 
ing the blood for purposes of diagnosis in suspicious cases. Such 
examinations are of great importance when we remember that we 
may have malaria without intermittence and also that we may have 
fotms which intermit that are not of malarial origin. A very small 
drop of fresh blood may be examined at the bedside, or, if more 
convenient, the blood may be spread very thin on a glass slide, 
dried by treating it with equal parts of ether and alcohol and studied 
later after being colored with methyl blue. Laveran warns against 
negative results, and in these cases advocates repeated examina- 
tions, for experience shows that in pernicious forms, for instance, 
the parasites may be abundant in the viscera, although they may 
not be found in the blood of the finger. Councilman and Golgi 
have found them especially abundant in the spleen. 
It gives me pleasure to recognize here the interest shown by 
the senior house officer, Dr. E. G. Bryant, in carrying out my 
directions in the cases here described. 
SUMMARY. 
The important points to be borne in mind are : 
1. In treating malaria quinine should be given when the tem- 
perature falls. The temperature should be the guide, and not the 
chill which may come before or after the rise in temperature. 
2. Quinine should be given at intervals rather than con- 
tinuously. 
3. Quinine should be given in such a way that its absorption 
is assured.