According to Bernstein, want of oxygen appears to stimulate the inspiratory and the presence of carbonic acid to stimulate the expiratory centre.1

As the blood becomes venous the activity of the respiratory centre increases, the respirations becoming quicker and deeper, and the accessory respiratory muscles are thrown into action. This condition is called dyspnoea. Finally the excitement extends to all the muscles of the body and we get general convulsions, which have usually an opisthotonic character. The eyeballs very often protrude during these convulsions, and the blood-pressure rises greatly from stimulation of sympathetic and vasomotor centres in the medulla.

After the convulsions cease, the animal usually lies motionless, and the heart as a rule continues to beat for a short time after the respirations have ceased.

The excessive venosity of the blood in this condition has paralysed the nerve-centres, but if artificial respiration be now commenced and the blood becomes gradually aerated, the conditions just described are again passed through in the reverse order : convulsions first reappearing, then dyspnoea, next normal breathing, and, if the respiration be pushed far enough, apnoea.

Asphyxial convulsions only occur in warm-blooded animals, and not in frogs, and when we find that any drug produces convulsions in mammals and not in frogs we usually assume that the convulsions are due to asphyxia produced by the action of the drug on the respiration or circulation, and not to a direct irritant action upon the motor centres. If, on the other hand, we find that the convulsions occur in frogs as well as in mammals, the presumption is in favour of their being due to the direct irritant action of the drug on motor centres.

1 Bernstein, op. cit. p. 324.

Blood becomes venous when the external respiration or interchange of gases between it and the external air is arrested while internal respiration continues.

Internal respiration or interchange of gases occurs between the blood and the tissues outside the vessels which are consuming oxygen and deriving it from the blood. But the blood although fluid is itself a tissue and likewise consumes oxygen, so that it will become venous if left to itself in a thoroughly-stoppered glass bottle.

External respiration may be arrested or diminished by (1) Interfering with the access of air to the blood; or

(2) ,, ,, ,, ,, ,, blood to the air; or

(3) ,, ,, „ power of the blood to take up and give off oxygen. The access of air to the blood may be prevented by obstruction to the air-passages or alteration in the structure of the lung; thus anaesthetics may obstruct respiration by allowing vomited matters to enter the trachea and plug it mechanically. Apomorphine may lead to obstruction of the bronchi by profuse secretion from the mucous membrane, and large doses of antimony may cause consolidation of the lung.

Air may be prevented from reaching the blood by any obstruction in the respiratory passages.

The respiratory passages may be obstructed by spasmodic closure of the glottis or of the nostrils in rabbits when an irritating vapour is inspired. This source of obstruction is easily avoided by putting a cannula into the trachea and allowing the vapour to be inspired through it. Another source of obstruction is the formation of plugs of mucus or clots of blood in the trachea or in the cannula, which has been introduced into it. Occasionally a plug of mucus, and sometimes a clot of blood, forms in the tracheal cannula and seriously impedes the respiration, whether natural or artificial, without being perceived by the experimenter. In order to be sure that such an occurrence has not taken place and vitiated the results, it is always advisable, on removing the cannula from the trachea at the end of an experiment, to blow through it and see that its lumen is perfectly unobstructed.

Access of air to the blood may be prevented also by paralysis of the muscles of respiration; thus curare will produce it by paralysing the ends of the motor nerves, hydrocyanic acid by paralysing the respiratory centre, and snake poison by paralysing both.

The blood may be prevented from reaching the lungs by arrest of the circulation either local or general, and may thus become venous, either locally or generally.

The venosity of the blood circulating in the medulla may be altered locally without any change in the rest of the body. Thus if the carotid and vertebral arteries are tied, the blood stagnates in the vessels of the medulla, and there becoming venous causes dyspnoea and convulsions, which again disappear when the ligatures are loosened and the circulation re-established.

Dyspnoea and convulsions are likewise produced by alteration in the general circulation, e.g. by loss of blood, as is seen when an animal is bled to death, or when the supply of blood in the arteries is greatly diminished by ligature of the portal vein, which causes the blood to accumulate and stagnate in the capacious veins of the intestine.

Stoppage of the heart, either by ligature directly applied to it or by the action of drugs upon it, causes asphyxia and convulsions.

Arrested circulation through the pulmonary vessels by emboli has a similar action. This sometimes leads to error in regard to the action of drugs when these are injected, as is often done, into the jugular vein.

If they contain solid particles, these may give rise to embolism in the pulmonary arteries and lead to the belief that the drug has a tetanising action, when, as a matter of fact, it has nothing of the kind. Thus, in making an experiment on condurango, I injected an infusion into the jugular vein of a rabbit, and it rapidly died with symptoms resembling those of strychnine-poisoning. The cause of this, however, was simply embolism of the pulmonary vessels, due to undissolved particles in the infusion, and when this was avoided by injecting the drug into the peritoneal cavity, no symptom whatever was produced. Gianuzzi, in his experiments on this drug, appears to have fallen into the same error as I did at first.

Altered condition of the blood also gives rise to dyspnoea, as is seen in the breathlessness of anaemia, where the blood is unable to take up the quantity of oxygen necessary for any exertion, and the patient pants violently after any quick movement, such as going up stairs.

Dyspnoea and even convulsions are also caused by nitrites, e.g. nitrite of amyl or sodium, which lessen the power of the blood to give off oxygen, and by carbonic oxide, which replaces the oxygen in the blood.

It must be remembered, however, that, whatever may be the remote cause of dyspnoea, its direct cause is the condition of the nerve-cells in the medulla, and if these are unable to take up oxygen, and give off carbonic acid to the blood, dyspnoea may occur, although the blood itself circulating in the medulla contains abundance of oxygen.

In the case of carbonic-oxide poisoning the blood cannot take up oxygen from the lungs, although there is abundance of oxygen present; and in a similar way the nerve-cells of the medulla may possibly be rendered by certain drugs unable to take up oxygen from the blood circulating through the medulla.

In simple suffocation the internal respiration of the nerve-cells in the medulla is arrested by the general venous condition of the blood; in carbonic-oxide poisoning by the oxygen being absent from the haemoglobin; in nitrite poisoning by the oxygen being locked up in methaemoglobin. In all those cases the condition of the blood is betrayed to the eye by the appearance of the mucous membranes, which in suffocation and in nitrite poisoning become dark and livid, and in carbonic-oxide poisoning of a cherry-red colour. Perhaps the change is most conveniently seen in the comb of a cock poisoned by these substances; in it the alteration in the colour of the blood produced by artificial respiration is readily observed. The dependence of convulsions upon the blood is also easily observed : the convulsions appearing as the comb becomes livid, and again disappearing when artificial respiration has been employed, and the colour of the comb becomes bright. In poisoning by hydrocyanic acid, however, I have observed that convulsions come on while the mucous membranes are still of a bright colour, so that we may conclude that they are not due to a venous condition of the blood, as in ordinary suffocation. They might be due to the formation of a compound between the hydrocyanic acid and the blood, as in poisoning by nitrites or carbonic oxide; but accurate analyses have shown that hydrocyanic acid does not displace the oxygen in haemoglobin like carbonic acid, nor lock it up in the form of methaemoglobin like the nitrites. We are therefore obliged to consider the possibility that the dyspnoea and convulsions produced by hydrocyanic acid are not due so much to its effect upon the blood circulating in the medulla as to an action on the cells of the medulla itself, by which it prevents the ordinary internal respiration taking place in them.