Chapter I: Malaria (3)

Golgi believes that quinine is most effective at the time of
liberation of merozoites from the bursting merocytes, hence he
administered quinine four hours before the attack with a view to
having it in its greatest concentration in the blood at such times.
When given intravenously the full concentration is obtained in a
very few minutes but with other methods this is a matter of great
variation.

It is usual to give the quinine in capsules or cachets, the pills and tablets being often so hard that they do not dissolve in the alimentary tract.

The method usually in vogue in military services is to give quinine
sulphate in acid solution. This method is trying to the stomach.

_By Subcutaneous Injections._—This method is liable to be followed by necrosis and abscess formation or fibrous indurations. Quinine and urea hydrochloride is preferable either for subcutaneous or intramuscular injection.

Cohen holds that quinine and urea hydrochloride controls malarial
infection more rapidly and efficaciously than any other salt of
quinine when given intramuscularly. In order to prevent tetanus or
other infections he is very careful about asepsis. He recommends
that a 10 to 15-grain dose be injected every day for a week, then
once a week for a month, then once every two weeks for another
month. He considers a 33% solution as best, thus one could give 10
grains in the contents of an all-glass 2 cc. syringe.

James has recommended very dilute solutions for subcutaneous
injections (1-150). There are practical objections to this method.
It is usual to give about 1 gram (15 grains) of a soluble salt in
10 cc. of water. _The present view is that subcutaneous injections
deserve condemnation._

_Intramuscular Injections._—It is now recognized that when quinine is not well borne when given by mouth the two modes of administration to be followed are either by intramuscular injection or introduction of the drug into a vein. For intramuscular use we dissolve a soluble salt of quinine, as the bimuriate or chlorhydrosulphate, in distilled water or sterile saline. A 50% solution is commonly used and from 6 to 10 grains of quinine is injected into the gluteal muscles of one side about 3 inches below the iliac crest. Repeat the injection on the other side. Repeat this daily dose of 12 to 20 grains for 3 or 4 days; then give quinine by mouth.

The solution should be autoclaved before use and the skin at the
site of injection painted with iodine. Dudgeon has called attention
to the constant production of oedema and necrosis in the area of
the injection. This tissue necrosis occurs immediately and persists
for a long time. If the injection is made in the neighborhood of an
important nerve, neuritis may ensue. Repeated injections should not
be given in the same area.

Of course in the use of quinine salts through the medium of the
hypodermic needle everything must be sterile.

_Intravenous Injections._—Bass and many others think that when quinine cannot be administered by mouth it should be given intravenously. Not only is there the objection of inflammatory reactions or necrosis when the drug is given subcutaneously or intramuscularly but the absorption of the drug is so slow that the patient may die before we obtain the desired effect. Ross condemns the subcutaneous method and recognizes the advantages of the intravenous method over the intramuscular one when rapidity of action is desirable.

In giving quinine intravenously Bass thinks that 10 grains at one
time is sufficient and that a 20-grain dose is not without danger.

He does not think it necessary to give more than 30 grains daily
in this way. Intravenous quinine seems to be entirely eliminated
within twenty-four hours and most of it within twelve hours.

When used in cerebral malaria he repeats the 10 grains
intravenously in eight hours if the drug cannot then be given by
mouth. Bass thinks that theoretically amyl nitrite might relax the
cerebral capillaries which are obstructed by parasite-infected red
cells and thus enable the quinine in the circulation to reach such
cells.

The best known method of administering quinine intravenously is
that of Bacelli. In this method 1 gram (15 grains) of a soluble
salt of quinine is given in 10 cc. of water.

MacGilchrist has shown experimentally that such a strength of
quinine (1-10) will coagulate blood serum.

In my opinion this is a dangerous method if the injection is made
rapidly. There is no doubt as to the necessity for using the
intravenous channel in cerebral or algid types of perniciousness
when intramuscular injections do not give results. The generally
accepted method is to use a salvarsan technique with a dilute
solution of quinine, giving 1 gram (15 grains) of some soluble
salt of quinine in 250 cc. salt solution. Such injections should
be given cautiously. Quinine hydrochloride, which is soluble in
40 parts of water, is the salt usually recommended. MacGilchrist
considers the very soluble acid salts as haemolytic and prefers
to give quinine base—3 pints of a solution of the alkaloid,
containing about 12 grains.

McLean has used concentrated solutions of quinine intravenously several hundred times in cases of malaria (6 being blackwater fever ones) without any untoward results. He autoclaves his 10-grain solution of hydrochlor-sulphate in 10 cc. of sterile water for twenty minutes at 15 pounds, and injects it slowly into an arm vein, allowing about two minutes for the injection. The patients complain of a slight cough and hot feeling in the lungs with a succeeding dizziness which rapidly disappears. He is opposed to intramuscular injections and found intravenous ones diluted 1 to 250 often to cause shock and collapse.

_Rectal Administration._—Some authorities recommend the
administration per rectum of a soluble salt of quinine in about 3
times the usual dose by mouth or hypodermically. It is considered
applicable in cases where there is marked vomiting. It certainly is
the least satisfactory way of giving quinine.

_Dosage and Length of Treatment._—In Panama the standard preliminary treatment is to give from 3 to 5 grains of calomel followed by 1 or 2 ounces of 50% magnesium sulphate.

Fayrer holds that a torpid liver interferes with the efficient
action of quinine, hence the value of calomel and salts. I prefer
to give 2 or 3 grains of calomel, in divided doses, followed by
sodium phosphate, 2 drams, every two hours, for three or four doses.

_Standard Method._—The National Malaria Committee of the United States recommends the following treatment: Give 30 grains of quinine daily in three 10-grain doses. Keep this up for 4 days and follow by 10 grains every night for 8 weeks. Where the infection does not present acute symptoms give the 10 grains daily for 8 weeks.

_Canal Zone Treatment._—So soon as the diagnosis is made give 15 grains of quinine 3 times daily (45 grains in twenty-four hours) and continue such treatment for a week or until the temperature has been normal for five or six days. Then give 10 grains 3 times daily for ten or twelve days.

It is considered that by employing such thorough treatment from the beginning the tendency to latency or relapse is prevented—in other words the disease is really cured. It is interesting to note that Torti recommended large single doses at the commencement of treatment.

Espach has noted that he had frequent relapses in many cases
treated by this method. In my opinion the Canal Zone treatment
should be followed by 10 grain doses daily for 8 weeks.

Tonics of iron, arsenic and strychnine are valuable in treating the
anaemia, but it is not advisable to add small doses of quinine to
such tonic mixture.

_Repeated Small Doses._—In Nocht’s method we give the quinine in
small doses repeated several times in the day, as 3 or 4 grains
given 5 or 6 times daily. Such treatment is thought advisable when
there is a tendency to haemoglobinuria or when giving quinine to
pregnant women.

In giving the small doses one should see that they are given during the night as well as the day.

_Quinine and Pregnancy._—There is frequently hesitancy in giving
quinine to a pregnant woman but unless the malaria is controlled
the patient will be apt to abort. Potassium bromide is thought to
control the ecbolic influences of quinine.

Clark states that the experience at Ancon Hospital would indicate
that quinine can be given with impunity to pregnant women. In
malarial subjects quinine after parturition is of value not only in
controlling a fever due to malaria but it also favors involution
and aids in the healing of perineal tears. The quinine also is
beneficial in improving the quality of the mother’s milk and does
no harm to the child.

_Manson’s Method._—In a benign malarial infection Manson prefers to wait until the hot stage has been passed and the patient is beginning to perspire, this idea being that the headache and other symptoms are aggravated and that very little advantage is gained by treatment during the early part of the paroxysm. He gives 10 grains at the onset of the sweating stage and afterward 5 grains, 3 or 4 times daily, for the following week. He then gives a daily tonic containing arsenic and iron, with a quinine treatment every seventh day for about two months.

For regularity he advises the quinine treatment on Sunday giving a
dose of salts in the morning followed by three 5-grain doses during
the day.

Manson notes the danger of large doses of quinine as producing
not only serious disturbances of sight and hearing but pronounced
cardiac depression as well.

There are many who speak highly of Warburg’s tincture in treatment.
It is both laxative and sudorific. The dose is ½ ounce (15 cc.)
which contains about 5 grains of quinine sulphate and 4 grains of
extract of aloes. As a rule it is better to give the quinine and
the laxative separately.

More recently the tendency has been to give large doses of
quinine, not only for its greater curative value but, as well, for
the prevention of relapses. Craig, however, states that in his
experience with aestivo-autumnal infections he has yet to see a
single case, in which treatment was promptly instituted, that did
not recover with a daily treatment of 30 grains.

_Koch’s Method._—Koch recommended 15 grains each day for a week, then three days without quinine. Then three days with 15-grain doses each day. Then one week without quinine, followed by three days of treatment. This plan of a weekly interval followed by three days of treatment is continued until not fewer than 30 15-grain doses are given over nine or ten weeks.

_Drugs Other than Quinine._—Salvarsan and neosalvarsan have been extensively used and with some success in benign infections but without material effect in malignant tertian ones.

_Intermittent Treatment._—There are those who consider a treatment
in which days of quinine administration are followed by days
without quinine as equally efficient and less trying on the
patient. Some of the experiences of Stephens and his colleagues
indicated that 45 grains on two consecutive days of each week and
continued for 8 weeks gave better results than 30 grains daily over
such a period. In their experiments a dosage above 45 grains in a
day did not seem any more efficient than 45 grains, so that this
may well be considered as a maximum dose. On the whole however
there seems to be a greater tendency to relapse following an
intermittent treatment and Acton, as a result of his comparison of
intermittent and continuous methods, deprecates the intermittent
one.

Some have thought that salvarsan aided the specific action of
quinine.

Many physicians recommend arsenic in the form of Fowler’s solution
or as sodium cacodylate. It is most useful in chronic cases. Some
preparation of iron is, of course, indicated in malarial anaemias.

It has been claimed that radium and X-ray treatment, when directed to the spleen, assist the action of quinine.

Methylene blue, next to quinine, has been considered as the most valuable drug. It is given in 2-grain doses every four hours. It is also given intravenously.

The form of methylene blue to use is that labelled “Medicinal.”

It is often stated that the opium fiends of the tropics are immune to malaria and some physicians have claimed antiperiodic properties for the drug. Dover’s powder is lauded by some as of value in symptomatic treatment.

Surveyor has recommended picric acid in the treatment of malaria in
doses of 2 grains two or three times daily.

Recently hectine, a remedy somewhat similar to the cacodylates,
has been strongly recommended by the French. It is given
intramuscularly in 2-grain doses. It is said to be valuable when
there is a leucopenia as it has a tonic action. It has been
recommended to combine this treatment with quinine.

It is said to be a good substitute for quinine in blackwater fever.

Rogers has recently noted the value of tartar emetic injections in eradicating the sexual parasites of carriers.

After rather extended trial of this drug for the above purpose and
as a method of treating ordinary infections the general opinion is
against its value.

_General and Symptomatic Treatment._—During the course of the
fever the patient should remain in bed and given only broths.
In the intermissions of the benign forms one may allow a more
generous diet. It is important that the patient be not allowed
to become constipated and as a laxative one grain of calomel in
divided doses followed by effervescing phosphate of soda is very
satisfactory.

For the nausea sips of an ice-cold alkaline mineral water or
cracked ice will generally prove effective. In more refractory
cases spirits of chloroform or even a hypodermic of morphine
may be necessary. Counterirritation to the epigastrium is often
a help. Phenacetine may be given for the headache although ice
water compresses are generally sufficient. In algid states hot
water bottles should be applied to the body. During convalescence
excesses in food or drink should be avoided as well as fatigue or
exposure to wet or cold.