Extracted from the American Journal of the Medical Sciences for July, 1881. 
ARE ALL AN/ESTHETICS DANGEROUS WHICH 
CONTAIN CHLORINE, BROMINE, 
OR IODINE? 
BY 
EDWARD T/REICHERT, M. D., 
OF NEWARK, NEW JERSEY, 
Formerly Demonstrator of Experimental Therapeutics and Instructor in Experimental Physiology 
in the Post-Graduate Course of Medicine in the University of Pennsylvania. [Extracted from the American Journal of the Medical Sciences for July, 1881.] 
ARE ALL AESTHETICS DANGEROUS WHICH CONTAIN CHLORINE, 
BROMINE, OR IODINE!1 
By EDWARD T. REICHERT, M.D., 
OF NEWARK, NEW JERSEY, 
FORMERLY DEMONSTRATOR OF EXPERIMENTAL THERAPEUTICS AND INSTRUCTOR IN 
EXPERIMENTAL PHYSIOLOGY IN THE POST-GRADUATE COURSE OF 
MEDICINE IN THE UNIVERSITY OF PENNSYLVANIA. 
As early as 1849, Nunnelly ( Trans. Prov. Med. and Surg. Association,, 
xvi. 1849) stated that the effects produced by chloroform by a like quan- 
tity and in parallel circumstances, as far as could be ascertained, were 
similar but not identical, and that they were far more considerable in some 
cases than in others, and even upon the same animal the effects of the 
same dose were greater at one time than at another. Proof of this truth 
is not wanting, but is unfortunately only too plentiful, as is instanced 
in the frequent deaths which have been reported as occurring from the use of' 
this agent, and by doses wholly out of proportion to the effects produced.. 
To the experimental physiologist and therapeutist, similar cases occurring 
in animals during anesthetization with chloroform must be numerous, if' 
this agent has to any extent been employed ; and, in speaking from per- 
sonal experience in the chloroformization of some hundreds of animals, 
many such instances are recalled to mind,—some indeed, which are 
even the more striking because of sudden death occurring after the re- 
moval of the inhaler, and before complete anaesthesia was induced (see also 
Report Brit. Med. Assoc. Committee, Brit. Med. Journ., 1879); and even 
deaths taking place in patients under similar circumstances are not want- 
1 It was the author’s intention to give, in connection with the following notes, the 
results of a physiological research which has been commenced in this connection, but 
upon a second consideration it appeared doubtful as to how soon this investigation 
would he completed. As anything of practical value relating to anaesthetics must al- - 
ways be of momentary importance to the profession, and as there is much to be learned 
from the literature of the subject alone, and as there are many facts herein contained 
which are of considerable interest and not generally known, and may prove of imme- 
diate value to both the therapeutist and experimenter, it was deemed best not to with- 
hold this portion of the paper, but rather to let the record of the experiments follow 
as a separate article. 2 
ing, as is attested by Kappeler (Part XX., German Surgery, by Billroth 
and Luecke, quoted by Reeve), and by records of chloroform deaths 
already reported. In Kappeler’s case death occurred in two minutes 
after the administration of chloroform had been stopped. In the report 
of the British Association’s Committee on their experiments on animals it 
is stated that in two instances sudden and unlooked-for effects on the heart 
occurred after more than a minute had elapsed since the administration of 
any chloroform. My own experiments on animals with the ethyl bromide 
have yielded similar results, and so strikingly analogous that I can safely 
assert, that, were the results of my experience with the deaths following the 
use of chloroform and the ethyl bromide in anesthetization tabulated in 
parallel columns, not even the keenest observer would be able to tell which 
was which. In the laboratory the bottles containing these compounds 
were on the table together, and were employed without any special choice, 
the nearest or handiest being used; and I must acknowledge that, where 
death ensued, as it did in quite a number of instances, the only way I 
knew which one of the two was the cause of it was by resorting to the 
odours of the two, and thus distinguishing them—their toxicological effects 
being so similar as to be beyond the power of discrimination. The same 
remarks apply equally well and with equal positiveness to several other 
chlorinated and brominated anaesthetics, and the list could be consider- 
ably amplified were it necessary, or did space permit. 
That the halogens are decided and general depressants of the animal or- 
ganism is a fact undisputed by the therapeutist; that they exert a special 
depressant influence on the heart is universally conceded ; and that most 
of the compounds in which either of these elements enters, especially in an 
elementary form and in any well-marked or appreciable proportions, par- 
take to a greater or less extent of this depressant quality, and more espe- 
cially so, if the elements are in a loosely molecular condition, such as is 
probably the condition in all ethers, is also acknowledged. Consequently, 
in looking over the list of compounds used as anaesthetics (some thirty 
or forty in number), it was a noticeable fact that the compounds contain- 
ing either of these elements were, as a rule, unmistakably more dangerous 
than others; and the obvious reason of this was the presence of one or 
the other of these principles, which, being in a probably loosely molecu- 
lar combination, acted either in combination as such, or were readily dis- 
sociated under favourable conditions, and at such times made their de- 
cidedly paretic action on the heart manifest. The writer would not here 
be understood as inferring that either in these toxic elements, or in their 
probable liberation in the system alone, resides the power of causing sud- 
den, abnormal, and overwhelming effects, or of being invariably the cause 
-of sudden death ; for it must be apparent that peculiar idiosyncrasies, gene- 
ral asthenic conditions and especially so of the heart, the greater impres- 
sionability of the heart or of its nervous mechanism at times than at others 3 
(even in apparently normal states of the economy), variations in the tem- 
perature of the surrounding media causing a greater volatility of the com- 
pound used, and the necessarily greater concentration of the vapour inhaled, 
etc. etc., must play at times a very important part in such cases. How- 
ever, that all chlorinated, brominated, and iodated anaesthetics may act 
at times altogether out of proportion to the dose and under similar circum- 
stances, and that those which have already been used to any extent have 
done so, is well attested in the papers already written, or by experiments 
recently made by myself on animals, as well as by the numerous deaths 
which have been reported from the needless use of this group of substances. 
To look over the death-list from anesthetization by this particular class 
of compounds, and in cases in which they were not especially indicated, and 
where some of the safer anesthetics, such as ether, would have answered 
the purposes required, and where they have been unjustifiably used before 
their physiological actions were previously determined by experimentation 
on animals, and their safety assured or their dangers indicated, is posi- 
tively appalling ; while the number of cases, almost innumerable, where 
life’s fragile thread was almost broken, the trusting patient but snatched 
from the chasm of death by the timely administration of physiological 
antidotes or the almost superhuman efforts of the physician and attend- 
ants, is alike shocking. Let us but glance at the chloroform death-list, 
and, as horrible and incredible as it may seem, there have been reported an 
average of about a death for every month since the time of its introduc- 
tion. With this array of fully authenticated cases before us, what, indeed, 
must be the actual number ?—for it must be conceded that probably double, 
triple, or quadruple as many more were not reported, and will never come 
to light. Even Kappeler alone says that he knows of four cases never 
reported, and personally I know of two. However, it needs no words of 
mine to remind the profession of the dangers of chloroform; so let us but 
briefly notice several others of this class of anaesthetics. 
Methylene Bichloride, which was introduced by Richardson (Med. 
Times and Gaz., 1867, p. 478) as a pleasant anaesthetic, but in connec- 
tion with which he expressed no definite opinion as to its safety, has now 
been entirely cast aside by the profession as being entirely too unsafe. 
Kappeler says that experience shows it to be as dangerous, if not more so, 
as chloroform, and furnishes a list of nine cases of death from its use. 
Unfortunately, I have not had a copy of Kappeler’s work at my disposal; 
but in looking over the details of cases published in the journals to which 
I have had access (Med. Times and Gaz., 1869, ii. p. 524; Lancet, 
1869, p. 582 ; British Medical Journal, Sept. 1871 ; Pharmaceutical 
Journal, 1871, p. 875, two cases ; British Medical Journal, August, 1872 ; 
Lancet, 1873, i. p. 23 ; Ibid., 1877, ii. p. 26), I have found that in several 
of them doses of a drachm and a half caused death, and, judging from the 
symptoms, it must be undoubted that death ensued in some of them at least 4 
from cardiac paralysis. The experiments made by the British Committee 
on frogs show that the heart becomes slowed and is soon stopped, and that 
the heart was affected the same as by chloroform, the first sign of paralysis 
being the distension of the right ventricle. Even were it not certified by the 
above Committee that it affects the heart like chloroform, the fact of death 
occurring after doses but ordinarily sufficient to produce anajsthesia is suf- 
ficient to impress everyone with the truth that it acts, like chloroform and 
ethyl bromide, wholly out of proportion to the dose. 
Let me revert to ethyl bromide or hydrobromic ether, which has but 
recently come into vogue through the recommendation of Turnbull and of 
Levis, and which has, during the few months of its usage, and indeed very 
limited usage, added proof to the above-asserted toxic properties of all the 
brominated anaesthetics. In referring to the articles published by these 
gentlemen, one is at once impressed with the strong recommendations 
given the ether, and the enthusiasm experienced in the discovery of so 
valuable a compound ; and Levis (reprint from Medical Record) stated, 
that practically it was the best anajsthetic now in use. But, if what he 
previously asserted, that “ the physiological action of the bromide of ethyl 
did not incline to the dangers of cerebral anaemia and cardiac syncope, 
which sometimes occur in chloroform, and that no tendencies in such a 
direction seemed to threaten,” were proven true by subsequent investiga- 
tion, the ether would not so early have fallen into disuse. And had ex- 
perimental investigations been pursued in the lower animals previous to 
those on man, like those by Wood (Phila. Med. Times, 1880, p. 370), such 
unfortunate results would probably not have followed in Levis’s, as well 
as in the hands of others who have followed in his footsteps. While advising 
his practitioners to be cautious in its use, Levis describes the method of 
administration preferred by himself, which, in our opinion, is of itself 
dangerous. His method is this, that “ in commencing the inhalation 
of bromide of ethyl to make a rapid and decided impression, with the 
lint and napkin held closely over the nose and mouth of the patient.” 
If we have here an agent proven to be dangerous, if not quite as dangerous 
as chloroform, it needs no further argument to show that the same pre- 
cautions must necessarily be observed in its administration as with its 
more popular predecessor. 
Squibb (Medical Record, 1880, p. 379) warns those who use bromide of 
ethyl to be cautious, because he deems it of the nature of a loosely molecu- 
lar compound, and hence he argues its liability to become broken up in the 
system and bromine liberated. Although the experiments of Wolff (Ameri- 
can Journal of Pharmacy, 1880) would seem toshow that this change does 
not occur out of the body, yet as we do not know in what form the ether 
is eliminated, and that fatal effects have followed its use, which resem- 
bled those in bromine-poisoning, we are bound to accept Squibb’s assertion 
with deference, at least until it is proven to be otherwise than correct. 5 
But whether bromine is liberated or not does not affect the argument, for we 
do know that Wolff (loc. cit.) found that death occurred in one of his experi- 
ments on rabbits, and that it typically resembled that caused by chloro- 
form by sudden cardiac failure; and Wood (loc. cit.) has proved that it 
is a direct cardiac depressant, which I have fully corroborated by my 
own experiments, and have further indisputably proven that it at times 
acts altogether out of proportion to the dose used, as already stated; 
and that at least two deaths have followed its use (Sims, Medical Record, 
1880, p. 361 ; Levis, Medical News and Abstract, June, 1880). More- 
over, several cases have occurred in Philadelphia hospitals in which 
such alarming symptoms occurred that only by the most strenuous efforts 
could the patients be rescued from impending death ; and a case of this 
nature is reported by Little (Medical Record, April 3, 1880); and other 
instances, where the administration Avas stopped, or the ether was refused 
to be given by resident physicians through absolute fear of disaster, could 
also be given. 
It will, however, undoubtedly be said, and indeed has been said, that 
neither of the cases reported by Sims or Levis was due to the use of 
anaesthetics per se: in the former instance because of the very depressed 
condition of the patient; and in the latter because death did not occur 
until many hours following the administration of the an,-esthetic. But in 
connection with these cases we know, first, that Emmet ( Gynaecology, 2d 
edition, p. 746) called the attention of the profession to the danger of admin- 
istering anaesthetics where any disease of the kidneys exists because of the 
active part taken by these organs in the elimination of them ; second, that 
Squibb asserts that bromide of ethyl is a loosely molecular article, 
prone to undergo decomposition in the system and to liberate free bro- 
mine ; 3d, that ethyl bromide is a marked cardiac depressant, as proven 
by both Wood and myself, by actual examination. Sims’s case certainly 
did have symptoms in harmony with those caused by some toxic agent 
such as bromine. The woman also had a marked scantiness in the secre- 
tion of the urine, and on post-mortem examination it was found that she 
had acute catarrhal nephritis, indicating that the kidneys were disabled 
from performing their function in eliminating the ether, hence its retention 
and its probable decomposition in the economy, with the subsequent 
toxic symptoms. In Levis’s case it seems plain that a simple expla- 
nation of the death of the patient lies in the fact that the heart, which had 
become so enfeebled from exhausting chronic disease, was unable to bear the 
strain of the powerful depression of its already diminished powers that 
ensued upon the administration of the anaesthetic, and as a consequence 
broke down under the excessive load.1 And lastly, as evidence going 
1 An analogous instance of a medicine apparently acting out of proportion to the 
dose is illustrated in the incipient stage of typhoid fever, where, on account of an 
irritative condition of the bowels, an ordinary cathartic dose will produce hyperca- 
tharsis. 6 
tOAvards proving that Sims’s case was due to bromine-poisoning, and in cor- 
roboration of Squibb’s assertion, I quote from experiments made by Nun nelly 
(loc. cit., 327) with a similar compound, the Ethylene Bibromide, as well 
as with the Ethyl Iodide (loc. cit., p. 324), in which similar results fol- 
lowed, in so far that the animals appeared perfectly well after the experi- 
ments, but all of them, after some hours, perished from blood-poisoning 
(see, also, Ethyl Iodide, Methyl Iodide, Iodoform). 
Methyl Iodide, which was introduced some years ago, has never come 
into general use because of its being considered unsafe by both Richardson 
and Simpson. The former observer (Med. Times and Gazette, ii. 1870, 
p. 470) found it to cause great excitement of the heart and circulation, 
which was evidently a sign of cardiac depression, if what he thought was 
true, that the iodine was the efficient cause of the phenomena which lie 
outside of the narcotism. He further certifies that the Amyl Iodide and 
Chloride act similarly to the Methyl compound. 
Chloral Hydrate, although not an anaesthetic in a therapeutic sense, 
has, like chloroform, and ethyl bromide, given us painful instances of 
its acting at times altogether out of proportion to the dose. Fuller (Lan- 
cet, March, 1871) quotes a case where thirty grains caused death in a 
young lady. Schwaighofer (Irish Hospital Gaz., 1873) reports another 
of a drunkard, in which a drachm produced death ; and three other cases 
(Reynolds, Practitioner, March, 1870; Watam, Med. and Surgical Re- 
porter, Jan. 1871 ; Fuller, loc. cit.), in which forty-five, eighty, and thirty 
grains respectively caused alarming symptoms, and from the large dose 
death nearly ensued. Death has resulted from a dose of ten grains (Amer- 
ican Dispensatory, 1880, p. 396). Other deaths have been reported (Med- 
ical Times and Gaz., 1871, pp. 131, 672; Norris, Lancet, 1871, i. p.226, 
and Browne, ibid. p. 574), and in some of these cases indisputable evidences 
of its power of weakening the heart were present. Did chloral hydrate 
become decomposed in the system into formic acid and chloroform (Per- 
sonne, Journ. de Pharm. et Chimie, 1870; and Pellogio, Schmidt's Jahr- 
bucher, bd. cli. p. 89 ; Liebreich Wiener Med. Wochensch., Aug. 1860), we 
could readily account for its acting at times in a manner wholly dispro- 
portionate to the dose, and for its being a cardiac depressant; but as recent 
investigations disprove this theory (Ilammertin, Schmidt's Jahrbiicher, 
bd. cli.; Rajursky, Ibid., bd. cli.; Amory, N. Y. Med. Journ., 1870; 
Djurburg, Schmidt's Jahr., bd. cli.; Leurison, Archiv Anat. u. Phys., 
1870), we must look elsewhere for this toxic principle. 
Hydriodic Ether or Ethyl Iodide, also used by Nunnelly (Joe. cit., p. 
324), was found to be so dangerous as to entirely preclude its use in medi- 
cine for anesthetic purposes; and he states that whatever anaesthetic prop- 
erty it might possess (and this is not insignificant) it never could be 
employed in practice, as its action is so very deleterious; for out of the 
four animals experimented upon, three of which were rendered insensible, 7 
all died, and the fourth had not sufficient of the vapour to render it in the 
least insensible, and yet for two or three days it was doubtful whether it 
would recover. Like the bromide of olefiant gas (ethylene bromide), its 
immediate effects were not so dangerous as the consequences of inhalation 
were in a few hours; even when not enough to produce insensibility had 
been used, and when the animal to all appearances had been perfectly 
well, death would supervene. In one case the odour of the ether was dis- 
tinctly perceptible in the brain t-welve hours after death, and Kunnelly 
thinks that death was caused by blood-poisoning. Therapeutically it has 
been used in recent years “ by inhalation to bi'ing the system speedily 
under the influence of iodine.” (National Dispensatory, 1880, p. 114.) 
Bromide of Olefiant Gas or Ethylene Bromide was also condemned by 
Nunnelly (Joe. cit., p. 327), who stated that, although it produced insen- 
sibility, it caused the respiration to become laborious, and although the 
appearances of distress speedily disappeared when the animals were re- 
leased, yet in a few hours they all, without exception, died. He further 
remarks that in this respect it differs from other (?) anaesthetics, because 
of the animals appearing well immediately following the experiments, but 
soon dying. He attributes this effect to blood-poisoning. 
Iodoform was not sufficiently volatile to cause anaesthesia (Nunnelly), 
but, from what we know of its use, when given per stomach or used locally, 
it possesses powerful anaesthetic (analgesic) properties. Unfortunately it 
has not been used sufficiently internally, nor have physiological experi- 
ments been pursued to such an extent as to give us an accurate knowledge 
of its action on the economy; yet we do know that it diminishes the pulse- 
rate, produces muscular and nervous debility, and is decomposed in the 
body, and that, when applied to mucous, serous, or abraded surfaces, it 
becomes decomposed by the fat, and the iodine is eliminated from the body 
in the form of soluble iodides. If iodine is liberated in the system, no 
further comment is needed. 
Carbon Dichloride or Chloric Ether has been used to a sufficient extent 
to indicate that it produces distinct cardiac depression. 
Bromoform, which possesses undoubted anaesthetic properties, was found 
in experiments of my own to powerfully depress the heart, and in one ex- 
periment on a small dog the intravenous injection of thirty minims of the 
preparation caused immediate cardiac arrest. Consequently, it was con- 
sidered useless to pursue any further investigation in this line. 
Tetrachloride of Carbon (CC14) was used by Laffont (American Dis- 
pensatory, 1880, p. 354), who found that it caused great debility of the 
heart, and lowering of the vascular tension. Simpson (Medical Gazette, 
1865, ii. p. 651) previously used it under the name of Bichloride of Car- 
bon, or Chlorocarbon, and more recently the same compound has been 
used by Smith (Lancet, 1867, i. pp. 575, 660). The latter observer found, 
in the post-mortem examinations of the animals experimented on, that 8 
the auricles were much distended Avith blood, and especially on the right 
side. He noticed that the heart did not beat after the cessation of respi- 
ration, and that the pulse Avas decidedly lowered. In conclusion, it is 
stated that “ when pushed to extremes it seems to destroy life by causing 
an arrest of the circulation of the blood tln-ough the lungs, a distended 
condition of the right side of the heart, an insufficient supply of blood to 
the left side of the heart, and consequently diminished systemic circu- 
lation.” 
Chloride of Ethydene, or Ethylidene or Ethidene, was first used by Snow 
(Ancesthetics), and more recently by Liebreich (Med. dimes and Gazette, 
1870, i. p. 642) ; the British Medical Association Committee (Action of 
Anaesthetics, British Medical Journal, 1879) ; Bird (Medical Times and 
Gazette, 1879, i. pp. 62) ; and Reeve (Neio Remedies, Nov. 1880, p. 
334—quoted from Chicago Med. and Surg. Examiner, June, 1880). 
Liebreich considers it somewhat safer than chloroform ; the British Com- 
mittee found an enormous diminution in the arterial pressure, and that 
the heart-beats became so infrequent as to be virtually ineffectual in sup- 
plying the respiratory centres with blood. Bird esteems it a powerful 
cardiac stimulant, and states that all the patients under its influence pre- 
sented the appearance of a strong cardiac stimulant, but that he would 
not like to keep a patient long under its influence for fear of a reaction in 
the opposite direction. Ilis investigations were not carried far enough to 
justify this conclusion of its cardiac action, and, as his conjecture is con- 
trary to the results of all other investigators, it must be rejected as unten- 
able. Reeve found a diminution of blood pressure, which differed from 
that caused by chloroform, because it did not advance to complete extinc- 
tion, nor exhibit such wide variations in its effects at different times in 
the same animal. A death from its use in Berlin has been reported by 
Kappeler (loc. cit.). Steffer (Binz’s Evidences of Therapeutics, p. 69) 
says that it resembles chloroform in ultimate action, yet is not so dan- 
gerous. 
Ethylene or Ethene Bichloride, or Dutch Liquid, was used by Nun- 
nelly (loc. cit.), who speaks of it in a decidedly laudable way, stating that 
just as small a quantity will produce anaesthesia as chloroform, but that 
a much larger quantity is required to destroy life. Simpson (Edinburgh 
Medical Journal, 1848, vol. viii. p. 740) also made some investigations 
with it, and found that when its vapour was inhaled, it caused so much 
irritation in the throat that but few persons could endure inhaling it until 
anaesthesia was produced, and that the condition of anaesthesia was not 
attended with any excitement of the pulse. On himself it produced such 
a degree of irritation in the throat that it did not disappear for many 
hours. Recently, the British Committee (loc. cit.) used it, and report 
that no anaesthesia was produced up to the commencement of convulsions. 
The results of a series of experiments (Phila. Med. Times, May 7, 1881) 9 
made by the writer with this compound indicate that it is a powerful 
anesthetic, and that it fulfils considei*able that Nunnelly claimed for 
it. It is undoubtedly a direct cardiac depressant. Why the British Com- 
mittee got such anomalous results is rather curious. 
Butyl Chloride (British Committee) caused the cardiac pulsation to 
become weaker, and finally extinguished; while Methyl Chloride only 
effected drowsiness. Isobutyl Chloride was not noticed as regarding any 
cardiac action. 
Notwithstanding the fact that the above array affords indubitable 
proof to warrant the assertion that probably all chlorinated, brominated, 
or iodated anaesthetics do act as cardiac depressants, and goes to sustain 
Squibb’s belief of their molecular condition, and as it likewise shows that 
unexceptionally, where used to any extent whatever, they have pro- 
duced death by doses wholly disproportionate to ordinarily cause such a 
result, yet it is but a little venture to further assert that were any of these 
compounds, of which either of the above facts has not been proven 
to be true, to be investigated thoroughly by experimentation in the lower 
animals, doubt would no longer exist of the correctness of this belief. 
A most interesting question here arises as to the modus operandi by 
which anaesthetics produce death, and one, indeed, which has constantly 
been in the minds of those particularly interested in these compounds, and 
consequently, as Reeve writes regarding chloroform, ‘‘we have had expla- 
nations without number, hypotheses the most untenable, and theories the 
most fantastical; ingenuity has been taxed to the utmost in the formation 
of some of them, and logic torn to tatters.” Thus we have had theories 
depending upon mechanical, chemical, and physiological effects ; stoppages 
of the air-passages with mucus, or by the falling back of the tongue ; im- 
purity of the compound used; idiosyncrasies of the patient; abnormal con- 
dition of the system; degree of concentration of the vapour; emotion or 
peculiar mental condition of the patient, such as fear of the possible con- 
sequences of the inhalation ; improper methods of administration ; the 
greater impressionability of the heart at times than at others, etc. And, 
as to the cause of death, about as many theories and as diverse have been 
advanced. But, without entering into all this distressing detail, it is only 
necessary to state that it is conceded that whatever may be the conditions 
favouring death, it does occur practically from either asphyxia or syncope, 
and that the latter condition may be the result of either a direct action on 
the heart, or by the inhibition of the heart through a stimulation of the 
inhibitory apparatus. But doubt can no longer exist that death in man 
in a vast majority of cases is the result of a paralysis of the heart itself 
by a direct local action, and not of a reflex nature by acting on the inhi- 
bitory nerves. The former has been proven; the latter not. It is also 
equally certain, except in cases where the vapour has been administered 
for a prolonged period in very dilute form, that death very seldom is the 10 
result of asphyxia, so that, pi’actically, sudden deaths are due to cardiac 
paralysis. 
Just why it is that the heart appears to be more impressionable at some 
times than at others, and why a person maybe safely anaesthetized several 
times with chloroform, and on a subsequent occasion and under similar cir- 
cumstances perish during its administration, is a question which has called 
forth many answers, some of which are as fanciful as the processes advanced 
to account for the deaths themselves. The whole answer practically can be 
simply and satisfactorily contained in the single word—dosage. It is one 
thing, as we all know, to give a man a grain of morphia in divided doses 
and spread out over several hours, and another to give him the whole at a 
single dose ; and just as true is it, that it is one thing to give a drachm or 
two of chloroform in a few inhalations, or to give it slowly during a period 
of some minutes. And while it is one thing to give a medicine hypodermi- 
cally or by the stomach, it is yet another (in effect) if given intravenously ; 
and especially so, in regard to medicines affecting the heart or nervous 
centres; and any one who has watched the blood-pressure of animals under 
the influence of chloroform must have been struck with the remarkable 
variations and the diminution of heart-beats which occur after each fresh 
administration, and of the sudden deaths often occurring immediately after, 
while, if the drug has been given by the stomach or hypodermically, these 
remarkable phenomena are comparatively absent. The drug when given 
by inhalation is absorbed so rapidly that practically it acts as an intrave- 
nous injection, and reaches the heart in a state of concentration almost as 
great; where, on the other hand, it must be slowly absorbed from the 
stomach or subcutaneous tissue, the drug reaches the heart in sucli a 
dilute condition as to be unable to make such a decided impression, and as 
a consequence when death ensues it-is from asphyxia, the same as when 
the vapour of chloroform is given very dilute and for a prolonged period, 
lleeve (Am. Jour, of Med. Sci., p. 199, July, 1880) says, that “we find 
no such idiosyncrasies in regard to’other medicines,” and that “opium, 
strychnia, and arsenic never cause death when administered in ordinary 
doses.” Although this is not by any means a parallel case, because neither 
of these medicines is ever administered either by inhalation or by intra- 
venous injection, nor are they decided cardiac depressants, yet deaths have 
occurred from the use of morphia in ordinary doses, when given hypoder- 
mically; for a death ensued in one case from an injection of one-sixth of a 
grain. Just now I recall a better instance, and in connection with apomor- 
phia; a drug which promised to be the most valuable emetic of the Pharma- 
copoeia, but which has been almost entirely abandoned for therapeutic 
purposes. This drug was asserted by some of the early investigators not 
to affect the heart or arterial pressure, but more recently the reverse has 
been found true (and conclusively proven by my own experimentation). 
In clinical medicine such alarming symptoms of a syncopal condition 11 
and threatening collapse were induced by u very small doses” (ordinary 
doses), that it is never used in this country as an emetic except in cases of ex- 
treme emergency. 
Doubtless, if time permitted such a laborious research in the lite- 
rature before me, similar instances could be found where other cardiac 
depressants acted in this way,1 and scarcely anything could be more 
safely predicted than that, if it were the custom and practicable to give 
this class of remedies by inhalation or by intravenous injection, deaths 
from them would be proportionately as great as from the popular anaesthetics 
under consideration ; and there likewise can be no doubt that the reason 
they are looked upon as being safe is simply because they are never 
given by the above method, or in such doses as to produce such a profound 
impression on the system as is necessary to produce in anesthetization; 
and hence they are absorbed relatively so slowly as to reach the heart in 
an exceedingly dilute condition, as already stated. An example illustrating 
the difference in the effects of intravenous and subcutaneous administra- 
tion of the same amounts, I quote from my experiments with apomorphia 
(Phil. Med. Times, Dec. 1879) on animals in which the heart was sepa- 
1 Since the above was put in type, the writer is enabled to cite several instances in 
corroboration of this belief, and which are only the more valuable because of their illus- 
trating the truth of it in three of our principal cardiac depressants. The first is a 
death which occurred in an adult in three hours from five grains of the fresh extract 
of aconite (Pareyra and Perrin, in Buchner’s Report fur die Pharm., No. 68, p. 199, 
and Med. Chir. Rev., Oct. 1839, p. 544; quoted by Tucker, N. Y.Journ.of Med., 
1854, i. p. 230). Two others took the same amount and received the same antidotal 
treatment and recovered. Tucker does not state what extract it was, whether of the 
root or leaves, but as it was probably the latter, and as the usual therapeutic dose is 
one or two grains, and twenty grains or more have been used during the day, it appears 
to be an interesting case for us. It will also be remembered that three drops of the 
saturated tincture of the root caused alarming symptoms (Rational Dispensatory, 
1880, p. 97). This tincture (Flemings’s) being two-thirds the strength of a fluid ex- 
tract gives the amount of the drug in the dose taken as equivalent to one grain of the 
pure drug, or equal in a physiological point of view to from four to six grains of the 
leaves, or from a half to three-fourths of a grain of the extract of the leaves of the 
British Pharmacopoeia. If the first case is not altogether a fair one as an illustration, 
because of the uncertainty of the preparation used, yet it will be admitted that the 
last one is. Headland (La?icet, July, 1856) gives an instance where fifteen drops of 
the tincture nearly proved fatal. A case is reported of a medical student (Andral’s 
Clinique Medic ale, Spillan, 1836, p. 698; quoted by Taylor, Guy’s Hospital Reports, 
1857, p. 415) who died in four hours from the effects of two grains of tartar emetic. 
Another is given by Richelot (Ibid.) of death in a child of four years from one-third 
of a grain. Moreover, Noble states (Guy’s IIosp. Rep., 1857, p. 415) that prostration 
and collapse followed in four cases of infants from ordinary doses. I have not yet 
seen his original paper. Stille quotes a case of a woman in whom alarming symptoms 
were caused by half a grain. Nunnelly, from the results of a series of experiments on 
animals with hydrocyanic acid (Med. Gaz., xl. 1837, p. 508), apprehends that the same 
creature is “ liable to be seriously affected by a dose which at another time would 
produce but little effect.” I will take occasion to resume a discussion of this subject 
at an early day. 12 
rated from any central nervous influence, and so practically isolated, 
where after a subcutaneous injection no effect on the arterial tension was 
apparent, yet after an intravenous injection of the same amount, the arte- 
rial pressure was decidedly reduced, showing that although in both cases 
the dose was the same apparently, yet practically it was vastly different, 
and while it was evident that repeated subcutaneous injections could be 
borne with relative freedom from danger, on the other hand, regarding in- 
travenous injections, it must be obvious that the reverse is true. That 
this argument is equally applicable to anesthetics needs no further com- 
ment. 
Moreover, there can be no doubt that the heart and other parts of the 
system, but especially the former, are more readily influenced at times by 
impressions, both intrinsic and extrinsic, than at others, and particularly 
so in those persons possessing a nervous temperament; and it is not an 
uncommon thing for such individuals to experience, on some occasions, a 
palpitation, or some vague or indefinable sensation about the heart, while at 
others, under similar circumstances, they would appreciate nothing of the 
sort. If, therefore, the heart and other vital parts are at times more suscep- 
tible, and more readily influenced by mental or other intrinsic impressions at 
certain but indefinite periods, why is it not probable that they are more sus- 
ceptible at these periods to extrinsic influences, such as medicines ? If this 
is so, and we probably have good illustrations of the truth of it in the in- 
stances already given, it is not difficult to conceive how the same dose, 
under apparently similar circumstances, may have double the effect it 
Avould have had on other occasions. As, for instance, let us illustrate the 
resistance of the heart to a given drug as being 10: if, now, the resistance 
is reduced to 5 by causes which we do not as yet understand, it is readily 
understood how the same dose will produce a given effect in the first in- 
stance, and double the effect in the second. If wre now superadd to this 
changeableness of the impressionability of the heart a second factor, as 
shown in the very excessive variability of the degree of concentration of 
the vapour inhaled, the subject is made still more comprehensible, and it 
certainly requires no stretch of the imagination, when the many surround- 
ing and modifying conditions are considered, to understand how it is that 
some inhalations may contain a very large percentage of the anaesthetic, and 
others relatively less, and, as a consequence, how a comparatively larger 
quantity may thus reach the heart at one time than at others. For it must 
be obvious, when we consider these conditions attending the administration 
'of an anaesthetic, that the drug does not reach the heart in a steady supply, 
but gaining entrance into the pulmonary acini in an ever-varying degree 
of concentration, sometimes in large, and at others in small quantities, it 
must be certain that it reaches the blood in similarly varying proportions, 
because it finds its way into the circulation immediately, and, as a conse- 
quence, its action on the organism must .then be analogous to repeated 13 
intravenous injections of similarly varying amounts. For the sake of 
illustration, let us assume that when a given anaesthetic is administered 
the depressant effect on the heart is 10, and that now, as a result of the 
modifying conditions, the average degree of concentration of the vapour is 
doubled, is it not evident that the depressant action on the heart will be 
doubly felt? And now let us suppose we have a condition of the system 
when the heart’s resistance is only half the normal, and we have the aver- 
age degree of the concentration of the vapour considerably increased, it 
is readily conceivable as to how death may supervene. 
To reiterate : it therefore must be apparent that we have here two im- 
portant and self-evident factors, representing, respectively, two modes by 
which dosage is materially affected, and in accounting, in part at least, 
for the capriciousness in the action of chloroform and other cardiac de- 
pressants at different times under apparently similar circumstances, and a 
satisfactory explanation of the reason of their acting on such occasions 
altogether out of proportion to the dose used, and of the occurrence of 
death from ordinary anaesthetic doses. 
Further, when we have a compound acting on the heart as a depressant, 
of a probable loosely molecular combination, which is liable to under- 
go under favourable conditions a decomposition in the blood, and of a 
composition which contains an element which, in a free state, is even more 
deleterious to the heart than the preparation itself, we certainly have 
added still another dangerous property. 
It seems opportune in this connection to say a word in reference to the 
action on the nervous system, for we also have instances of the capricious- 
ness of the action of anaesthetics, and of deaths as a result of shock, which 
are attributed to a sudden overwhelming of the nervous centres, and are, 
therefore, but other instances illustrating what was stated with particular 
reference to the heart in a previous paragraph. But the nervous system 
appears to be more strongly fortified against these sudden paretic im- 
pressions than the heart, and, as a consequence, death so seldom results 
from this cause, and as without exception probably every antestlietic is 
capable of causing such an effect, it is obviously one of the dangers we 
must anticipate in the use of these compounds, but which we cannot 
guard against or expunge in our choice of preparations. 
Therefore, the dangerous properties of anassthetics, i. e., those proper- 
ties which we can avoid in our selection of a compound, resolve themselves, 
practically into decided depressant effects on the heart and on their con- 
taining toxic elements in their composition which may further, and possi- 
bly more powerfully, deleteriously affect the system by becoming liberated; 
and just such properties we find possessed by the group of preparations 
under consideration. It is taken for granted, of course, that compounds 
having such dangerous properties as some possess by causing an intense 
degree of irritation in the lungs and air-passages, etc., would undoubtedly 14 
be avoided if for no other reason than the impracticability of administering 
them. 
It may be said, however, that beneath the truth the writer is burying 
the truth, in so far that many other anesthetics have been used not be- 
longing to the above group, of which nothing has been said, and which 
also act as cardiac depressants, hence, that it must follow that this prop- 
erty of depressing the heart is not one peculiar to any class of anesthetics, 
but a very general one. Admitting that other anesthetics may induce 
cardiac paralysis before asphyxia is produced,—and it must be acknowl- 
edged that certain of them have a special tendency in this direction, such 
as hydrocyanic acid and creasote, the same as certain of the chlorinated 
compounds, such as the ethylidene and ethylene chlorides show a more 
decided tendency to the respiratory centres, but which is readily explained 
when we consider that the heart is so depressed as to be ineffectual in sup- 
plying the respiratory centres with blood,—yet the rule appears to hold 
good, and, to facilitate a comparison of these two classes of compounds, 
they are here placed in parallel columns :— 
Chlorinated, Brominated, and Iodated 
Anaesthetics. 
Chloroform, CHC13. 
Chloral hydrate, C2HC130H20. 
Carbon dichloride, C2H4. 
Carbon tetrachloride (chlorocarbon) 
CC14. 
Bromoform, CHBr. 
Ethyl chloride (chloric ether), C2H5C1. 
Ethyl iodide, C2H6I. 
Ethyl bromide, C2H5Br. 
Ethylene bichloride (Dutch liquid), 
C2H4C12. 
Ethylidene bichloride (ethydene chlo- 
ride), C2H4C12. 
Iodoform, CHI,. 
Ethylene bromide, C2H4Br2. 
Methylene bichloride, CH20l2. 
Butyl chloride, C4II9C1. 
Methyl chloride, CII3C1. 
Isobutvl chloride, C5H9C1. 
Methyl iodide, CH31. 
Amyl iodidfe, C10H10I. 
Amyl chloride, C101I10C1. 
Miscellaneous Anaesthetics. 
Aldehyde, C2H40. 
Benzole, C6II6. 
Coal gas. 
Creasote, C6II60. 
Carbonous oxide, CO. 
Carbon bisulphide, CS2. 
Ethyl oxide (ethei’), C4II10O, or 
(C,H5)20. 
Ethyl, acetate, C2H:!02C2H5. 
Ethyl, methylate, C,,HfiO (CHA.O. 
Ethyl, nitrate, C2H5ONO. 
Ethyl, formate, CI10?C,II5. 
Acid, hydrocyanic, C2N2H. 
Hydrogen sulphide, SH... 
Naphtha. 
Nitrous oxide gas, N202. 
Olefiant gas, C2H4. 
Essential oils, C10H16. 
Pyrrol, C4H.N. 
Acetone, C3H60. 
Amylene, C5Ii10. 
While these two classes represent the halogen and miscellaneous com- 
pounds respectively, yet were two other classes formed from them as 
representing syncopal and asphyxiating anesthetics, or those having a de- 
cided tendency to depress the heart and those Avhose tendencies are to 
compromise the respiratory function, scarcely much change would be made, 
and with but few exceptions the above division would stand as it is. And 
while it is to be seriously regretted that our knowledge of the physio- 
logical actions of these compounds is so grievously inadequate, and that of 15 
sucli a small percentage of the whole number we have scarcely sufficient 
information to be able to assert positively what their action is, yet we do 
know that every one of the halogen anaesthetics which have been in- 
vestigated in reference to their action on the arterial pressure and as to 
their mode of producing death, have been found to both diminish the 
blood-pressure and paralyze the heart; and that probably at least sixty 
per cent, of the deaths from chloroform have been due to arrest of the 
heart; while in regard to the miscellaneous anaesthetics, it is undoubted 
that some of them do diminish the arterial tension and depress the heart, 
and will cause death by cardiac paralysis; yet, there seems to exist that 
unmistakable predominant tendency to produce death by asphyxia and 
not by sudden cardiac arrest, although with those which possess to any 
marked degree a cardiac depressant action,- a sudden failure of the heart 
is likely to occur, as with the lialogenated compounds. Every anaesthetic 
has a decided tendency to cause death by asphyxia, and the reason of this 
is very apparent when we consider how greatly all the functions of animal 
life are diminished, but particularly those of the nervous system, whose 
excito-motor functions especially must always be very decidedly lessened in 
anaesthesia ; and when we have such a serious interference with the trans- 
mission, reception, and origination of impulses, as is invariably present in 
complete narcosis, it is not difficult to understand how it is that any anaes- 
thetic possessing this powerful depressant power may, if given in exces- 
sive doses (a too concentrated condition of the vapour inhaled), or in states 
of the system when these centres are in an abnormally impressionable 
condition, cause a sudden paralysis, such as has followed the use of ether, 
which, as is generally admitted, is beyond doubt, with but one exception, 
the safest of all anaesthetics in general use, and the least liable to cause 
death without a warning such as the merest novice must appreciate. Yet 
because it must follow that every anajsthetic may and will cause death 
by asphyxia, the same universal rule does not apply to them in regard to 
their effects on the circulatory system, and instead of its being the rule to 
decidedly depress the heart and blood-pressure, excluding the chlorinated, 
brominated, and iodated compounds, it is probably the exception ; there- 
fore, it must be evident that while in the anaesthetic compounds such as 
creasote and hydrocyanic acid, their decided depressant action on the 
heart is an accidental concomitant associated Avith their other physiological 
properties, on the other hand, in the halogen preparations the action ap- 
pears to be so universally existent as to suggest that there must be some 
inherent toxic principle or principles which enter into the composition of 
each, and is common to all of them, and which endows them with this 
one dangererous property. 
That this toxic principle is not to be found in tlie radicles forming the 
bases of these compounds, but in the negative elements, is obvious for 
several reasons, and some years ago Richardson reached a similar con- 16 
elusion regarding one of these particular divisions, and stated that he deemed 
all chlorinated compounds dangerous. More recently, Squibb has warned 
us to be careful in the use of ethyl bromide, for fear of inducing brominism; 
and we know that by giving the ethyl iodide by inhalation, the system is 
rapidly brought under the influence of iodine. Now, for instance, let us 
take ether,, an oxide of ethyl, and substitute for the oxygen bromine, and 
what is the result? The ether, which was before a cardiac stimulant, 
and would almost without exception cause death by asphyxia, has now 
become excessively increased in power, and the half drachm of the com- 
pound will produce an effect more intense than ten or twenty or more 
times the original amount, and, instead of a cardiac stimulant, we have a 
decided depressant, and instead of having deaths following from slowly 
induced asphyxia, we have deaths occurring from cardiac arrest, and sud- 
den, overwhelming, and unanticipated results following its use. Further, 
take olefiant gas, and we find that when inhaled it possesses but feeble 
anaesthetic powers and causes death by asphyxia; but add bromine or 
chlorine to it, and we have powerful anaesthetics and undoubted cardiac 
depressants. 
Considering all these things, there can be but little doubt that the dan- 
gerous properties, if not the degrees of potency, of anaesthetics, are de- 
cidedly enhanced by the addition of either of the halogens, and it is not 
at all improbable that these ethers are mostly loosely molecular compounds, 
some of which are more readily decomposed in the system than others, and 
that their degree of dangerousness, cceteris paribus, depends upon the rela- 
tive amount and relative physiological power of either of these halogen 
principles which enter into the composition of any one of them, and upon 
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