Arthur D. Hirschfelder

Inhibition of Experimental Auricular Fibrillation by Procaine and Other Substances.

Summary At least three local anesthetics, procaine, pontocaine and nupercaine can inhibit experimental auricular fibrillation in dogs.

Clinical Manifestations of Variations in Blood Magnesium-- Hypomagnesaemia and Hypermagnesaemia.

Serles and one of us reported 1 , 2 that, contrary to the usual conceptions, a large part of the magnesium ingested orally as magnesium sulphate is absorbed from the intestine and in normal animals and normal human beings about 40% of the ingested magnesium passes out in the urine in 24 hours, without causing any significant rise in plasma magnesium. The determinations of magnesium were facilitated by the introduction of a modification of Kolthoffs colorimetric method 3 for determining the magnesium in the oxalated Ca-free plasma and in oxalated Ca-free urine, after precipitation of the phosphate by uranyl acetate. We then found that in nephrectomized or nephrotic animals, oral administration of magnesium sulphate caused the plasma magnesium to rise significantly, a single dose bringing it to about 10 mg. per 100 cc. plasma, larger doses to above the coma producing level (which is about 17 mg. per 100 cc.). Extending these studies to human beings we have obtained similar results. 1. High blood magnesium. This was found especially in nephritics after the administration of Epsom salts. In normal individuals 20-30 gm. MgSO4, 7 H2O by mouth does not significantly raise the blood magnesium and about 40% is excreted in the urine in 24 hours. In nephritics less of the ingested Mg is excreted in the urine, and the blood magnesium rises. 20-30 gm. MgSO4, 7 H2O administered to 9 patients with acute and chronic glomerulo nephritis raised blood magnesium from near normal to 9.8-11.3 mg. All these patients were definitely more drowsy when at these levels. Two nephritics with blood magnesium 8.9-9.0 without administration of MgSO4 were definitely drowsy and unresponsive. Coma is induced in animals when the blood magnesium approaches 17 mg. Mg per 100 cc. Elevation of blood magnesium to about two thirds of the coma-producing level thus seems to be accompanied by a tendency to somnolence.

Effect of Nephrectomy on Duration of Action of Barbitals

Fitch and Tatum 1 have divided the barbitals into 2 groups based upon the duration of their action and upon the manner in which they cause death. They found that the longer acting barbitals (especially phenobarbital and barbital, ethyl-n-butyl barbital (neonal), isoamyl barbital (amytal), ethyl iso-propyl barbital (barbituric acid of ipral), and also iso-propyl bromallyl barbital (noctal) cause death from pulmonary oedema, while the other barbitals, which they group as the short acting barbitals, when injected intraperitoneally in toxic doses cause death from depression. Our finding that there is a marked difference in action of magnesium sulphate when administered to normal and to nephrectomized rabbits and to nephritic patients 1 , 2 , 3 led us to try this method of testing barbital action. Nephrectomy in etherized rabbits was done through a lumbar incision and was greatly accelerated by the use of a specially devised kidney fork. This was made from an ordinary table fork the first and third tynes of which were sawed off completely, the second and fourth being sharpened and bent around to form a semicircle of 3 cm. diameter. This was inserted through the lumbar incision so as to grasp the kidney, the renal pedicle passing through the space left by removal of the third tyne of the fork. A plate of spring phosphor bronze 7 cm. long and 2 cm. wide, sliding on a collar surrounding the handle of the fork was then pressed down so as to grasp the kidney completely, the kidney was drawn up through the incision and the renal pedical ligated. The incision was then sutured. The operation requires 15 to 20 minutes. The animals were allowed to recover completely from the ether anesthetic and the barbital was injected subcutaneously on the following day.

Bloodless Method for Recording Respiration and Quantitative Determination of Alterations of Sensation in Small Animals

Schmitz and Loevenhart 1 published a method for judging the onset and duration of anesthesia in the sciatic nerve of rabbits by the disappearance of changes in respiration when the distal portion of the nerve was stimulated. They recorded the respiration with a tambour attached to a cannula introduced into the trachea. In order to study anesthesia (general, local and spinal) analgesia and hyperalgesia in small laboratory animals, without performing surgical operations, we have devised the apparatus shown in Fig. 1. The respiration is recorded using a modified blood pressure cuff which is laced around the chest and abdomen and connected with a tambour in the manner described below. Ordinary platinum electrodes are applied to the shaved skin (moistened with 0.9% NaCl) over the area to be tested. The stimulus is furnished by induction shocks from a Harvard induction coil, either faradic or break shocks being used. The coil distance is noted, so as to furnish a fairly quantitative measure of the stimulus. For purposes of comparison, the threshhold of sensation can be taken as the minimal stimulus which causes a definite change in amplitude or rate of respiration. The elastic sac of the respiration cuff for rabbits consists of a small toy balloon 18 cm. in diameter, covered with a linen sac (Fig. 1). The sac is placed inside of an ordinary tire boot through which a hole is made for the tube leading to the recording apparatus. The tire boot bears lacings and is applied to the animals chest and abdomen. The rubber sac is connected by a rubber tubing and a T tube whose one branch inflates a rubber condom enclosed in a glass bulb. The other branch of the T tube is connected with a pressure bottle in which the pressure is kept constant by a slow stream of compressed air provided with a water valve maintaining about 15 cm. H2O pressure as shown in the figure.

Further observations on relation of glomerular function to phenolsulphonephthalein excretion in frog's kidney.

Summary When a dye solution is run into the frogs kidney in such a way that, in the lower portion of the kidney, it runs into tubular capillaries and into a large number of glomerular capillaries, while in the upper portion of the kidney it runs into tubular capillaries, and into only a few glomerular capillaries, the amount of dye excreted follows the number of active glomeruli receiving dye solution, although both halves of the kidney are producing urine.

Some Observations Upon Blood Glucose in Epilepsy

Pigott 1 has recently reported low blood sugar in epileptic convulsions and regards hypoglycemia as a possible etiological factor. In our series of 25 cases in which 3 or more determinations have been made in each case we do not confirm this view. The blood glucose was determined by the method of Gibson. 2 Determinations were made before, during and after seizures and in each case the blood glucose was within normal limits (90 to 110 mg. per 100 cc. blood) before convulsions, and rose during the convulsions. The rise of blood sugar was roughly proportional to the severity of the seizure, and after termination of the convulsion the blood sugar returned to normal in two to four hours. In 4 cases of status epilepticus the blood sugar value before seizure was 95.0 to 100.0 mg. per 100 cc. blood. After about one hour of status the values rose to 139.0 to 190 mg. per 100 cc. and after three hours of status the values were 150 to 240 mg. per 100 cc. In 21 cases having moderate to very severe isolated seizures the blood sugar rose from the average of 92.5 mg. per 100 cc. blood before seizures to 168.0 mg. per 100 cc. during convulsions. In 7 cases the elevation of blood sugar was above 185 mg. per 100 cc. during the height of the convulsions. In no instance was hypoglycemia found either before or during the convulsions.

Variations in Plasma Magnesium and Potassium in Epilepsy

McCollum and his collaborators, 1 , 2 and also Greenberg and Tufts 3 have produced hyperirritability and convulsions in rats fed on a diet deficient in magnesium. Since we have found neuromuscular twitchings and convulsions in cases of clinical hypomagnesaemia, 4 since McQuarrie 5 believes that in epilepsy there is a “leakage of potassium” through the cell membrane, and since Hirschfelder 6 has shown that potassium salts can antagonize the narcotic action of magnesium, we have investigated the plasma magnesium and potassium in clinical epilepsy. We determined magnesium by the method of Hirschfelder, Serles and Haury 7 † and potassium and calcium by those of Kramer and Tisdall. 8 , 9 Total magnesium 1.7 mg. Mg or below 100 cc. plasma and ultrafiltrable Mg 0.7 or below were regarded as low; K above 30 mg. was regarded as high. In epileptics whose plasma was collected during or just before convulsions we found the following deviations from normal: In 5 cases of status epileptics low magnesium (1.2 to 1.7 mg.) occurred in 4, high potassium (35 to 68.5 mg.) occurred in 5, high potassium/magnesium ratio occurred in 5. In 13 epileptics with very severe convulsions, low magnesium (1.3 to 1.7 mg.) occurred in 9, high potassium (31.7 to 63.6 mg.) occurred in 6, high potassium/magnesium ratio occurred in 13. In 12 moderately severe epileptics low magnesium (1.6 to 1.7 mg.) occurred in 3, high potassium (31.6 to 52.8 mg.) occurred in 8, high potassium/magnesium ratio occurred in 11. In 5 epileptics with mild convulsions, low magnesium (1.6 to 1.7 mg.) occurred in 2, high potassium (31.7 to 40.2) occurred in 3, high potassium/magnesium ratio occurred in 4.

Enhanced Action of Morphine in Experimental Nephrosis after Oral Ingestion of Magnesium Sulphate

We have shown 1 , 2 , 3 that the oral administration of magnesium sulphate raises the plasma magnesium of animals and men with damaged kidneys, but not that of normal individuals. In view of the old-time clinical teaching that one should exercise caution in the administration of morphine to severe nephritics and to old persons, we have tested the effects of morphine sulphate injections on rabbits whose kidneys were injured by the subcutaneous administration of 10 mg. HgCl2/K. The plasma magnesium of these animals ranged from 1.89 to 2.17 mg. Mg. per 100 cc. and rose to 6.90 to 8.98 mg. Mg. Two hours after the oral administration of 2 gm. per kg. MgSO4, 7H2O, 30 mg. morphine sulphate per kilo was administered subcutaneously to 8 of these nephrotic rabbits. In 3 of these narcosis lasted 9 to 11 hours (av. 9 2/3 hours) and 5 animals died in deep narcosis in 1/2 to 5 hours after the injection. The 4 control animals receiving the same dose recovered from the narcosis after 3 to 4 hours. The narcosis of the controls was less intense than that of the nephrotic animals. These results indicate that animals, whose plasma magnesium is only moderately elevated (7.0 to 8.70 mg. per 100 cc.) (as in the case in nephrotic patients who have received a single purgative oral dose of Epsom salts), are much more sensitive to morphine than are normal animals. These results are in striking contrast to the results obtained by MacKay and MacKay, 4 who found that “uraemic” (nephrectomized) rats are less sensitive to morphine than are normal rats. The level of the plasma magnesium is most probably the determining factor.

Ultramicroscopic Studies Upon Colloidal State of Antiseptics and Arsenicals in Relation to Their Actions.

As Voegtlin 1 and others have shown that the action and toxicity of arsphenamine is closely related to their viscosity and colloidality, and as the action of antiseptics is greatly diminished by the presence of protein and of lipoids (Hirschfelder and Decherd 2 ) we have studied the appearance of solutions of a number of these substances under the Szigmondy slit ultramicroscope. Solutions of arsphenamine and neoarsphenamine show the soap-bubble-like appearance of hydrated lyophillic colloids, the micellae being smallest between pH 7 and 9, and again from 11 to 13. In the presence of proteins they aggregate to form stellate, highly refractive micellae. Rivanol is fluorescent, lyophillic, soap-bubble-like and aggregates with proteins. Triphenyl methane dyes are crystalloidal, but aggregate with proteins. Quinine and the hydrocuprein series (optochin, eucupin and vuzin) are fluorescent, crystalloid and aggregate with proteins. Metaphen is crystalloid and produces little change in the proteins. Mercurochrome and acriflavine show fluorescence, but no visible particles; the micellae formed by mercurochrome and protein appear to be quite small; with acriflavine the protein aggregates are somewhat larger. These colloidal phenomena are probably associated with the toxicity and pharmacological action of the drugs, especially in intravenous injection.

The effect of quinidine on interauricular conduction and irritability in the terrapin's heart.

Numerous investigators have demonstrated that quinidine decreases the irritability of the heart muscle and the auriculo ventricular conduction. We have recorded the contractions of both auricles in the terrapin, and find that, although much stronger stimuli (rhythmic make-and-break shocks) are required to cause extrasystolic responses after intraventricular injections of 1-2 mg. quinidine sulphate than before, there is no marked disturbance of conduction of spontaneous contractions or of rapid rhythmic extrasystoles from right auricle to left auricle. This indicates that quinidine depresses irritability more than it depresses intrand inter-auricular conductivity; and renders it probable that in auricular fibrillation it rather suppresses the genesis of ectopic impulses than that it blocks the conduction of circus movements when once generated. Our results are in accord with the investigations of Hirschfelder 1 in 1908, which indicated that increased irritability of the heart muscle is one of the important factors in the genesis of auricular fibrillation.