Hiram E. Essex

Experiments with calculated therapeutic and toxic doses of digitalis: I. Effects on the myocardial cellular structure

No microscopic pathologic changes were found in the myocardiums or coronary arteries of the control animals. No evidence of histologic changes was found in the myocardiums of the experimental animals after the administration of calculated therapeutic amounts of digitalis (30 per cent of minimal lethal dose) in single or divided doses, given over a period of forty-eight hours. The histologic studies were made after a minimum of six days and a maximum of fifty-six days. Myocardial lesions were not produced in our experimental animals when they were digitalized rapidly with a calculated therapeutic dose of digitalis, and were then given daily maintenance doses of the drug which were estimated to correspond to either 1 or 2 cat units for a man weighing 70 kg. The histologic studies were made after a minimum of nineteen days and a maximum of sixty days. In our experiments, 60 per cent of the minimal lethal dose was the smallest amount of digitalis which, when given as a single dose, produced definite evidence of myocardial lesions. This dose of digitalis is in the toxic range. The frequency with which myocardial lesions occurred increased as the size of the single dose of digitalis was increased to 80 per cent of the minimal lethal dose. Myocardial lesions were not found until five or more days after the single toxic doses of digitalis had been administered. Histologic changes were not observed in the hearts of all the animals which had received toxic amounts of digitalis, even when the quantity of the drug was 80 per cent of the minimal lethal dose. Histologic changes were produced in the myocardium when the animals were digitalized rapidly with a calculated therapeutic dose of digitalis, and were then given daily quantities of the drug which were estimated to correspond to 3, 4, 5.5, or 6 cat units for a man weighing 70 kg. The equivalent of 3 cat units daily of parenterally administered digitoxin caused myocardial lesions within five days in one animal, whereas the same amount of orally administered tincture of digitalis produced myocardial lesions within eleven days in another animal. The digitalized animals in this group which received daily doses of digitalis in the toxic range had their myocardiums examined microscopically after a minimum of five days and a maximum of thirty days. Histologic changes in the heart were produced by digitalis whole leaf or by crystalline products of digitalis (digitoxin, lanatoside A, lanatoside B, and lanatoside C). The sequence of pathologic changes in the myocardium after the administration of toxic doses of digitalis was studied. The observations of Levitski1 and Bu¨chner3 were confirmed. The myocardial lesions were focal in distribution, and were more frequent in the papillary muscles and in the left ventricular wall than in other regions. This also confirmed the observations of Levitski and Bu¨chner. Animals which survived the toxic doses of digitalis recovered completely in three or more weeks. Animals which had myocardial scars produced by digitalis (healed lesions) appcared entirely normal after three to four or more weeks. Myocardial lesions were more prone to develop in old animals after the administration of digitalis than in young ones. This difference in sensitivity to the drug was not related to arteriosclerosis, for no evidence of this disease was found in the cardiac arteries or arterioles of any of the cats. Experimental hyperthyroidism increased the sensitivity of the animals to digitalis. Myocardial lesions were found after the administration of calculated therapeutic doses of digitalis to hyperthyroid cats. No evidence of anatomic changes was seen in the skeletal musculature or the smooth musculature of any of the animals which had received digitalis in therapeutic or toxic quantities.

Certain effects of positive pressure respiration on the circulatory and respiratory systems.

Abstract Experimental studies were carried out on dogs anesthetized with pentobarbital sodium to determine the effect of long periods of pressure breathing alone and when combined with acute hemorrhage or trauma of the hind limbs. The following results were obtained: 1. 1. Continuous positive pressure respiration with a pressure of 20 cm. of water. 2. a. Five of nine animals survived three hours of continuous positive pressure respiration, but, in the case of the other four, fatal apnea developed. 3. b. The apnea caused by a continuous positive respiratory pressure of 20 cm. of water was not affected by large doses of atropine but was abolished by bilateral vagotomy. 4. c. Continuous positive pressure respiration had a variable effect on the femoral arterial pressure and on the heart rate. It slowed and deepened the respirations. It elevated the jugular venous pressure, the renal venous pressure, the pulmonary arterial pressure, and the pulmonary venous pressure. It decreased the diameter of the heart and thoracic inferior vena cava but increased the diameter of the abdominal vena cava. It dilated the tracheobronchial tree. 5. d. Three of eight animals survived two hours of continuous positive pressure respiration after a hemorrhage of 30 c.c. per kilogram of body weight in five minutes, but in the case of the other five animals either apnea or circulatory failures developed. 6. e. Three hours of continuous positive pressure respiration did not cause either pneumothorax or mediastinal emphysema in a single case, but in all of a group of five animals acute parenchymal and subpleural emphysema developed. 7. 2. Intermittent positive pressure respiration with a pressure of 20 cm. of water. 8. a. All of a group of five animals withstood three hours of intermittent positive pressure respiration without difficulty. 9. b. Intermittent positive pressure respiration produced considerable fluctuation of the femoral arterial pressure with a decrease of the mean pressure. It elevated the jugular venous pressure, the pulmonary venous pressure, the renal venous pressure, and the pulmonary arterial pressure. It decreased the diameter of the heart and thoracic inferior vena cava but increased the diameter of the abdominal vena cava and the tracheobronchial tree. It slowed and deepened the respirations but had no consistent effect on the heart rate. 10. c. Three of five animals survived, without difficulty, two and a half hours of intermittent positive pressure respiration following a hemorrhage of 30 c.c. per kilogram of body weight in five minutes. In the case of the other two, eirculatory failure developed and the animals were given 10 c.c. of blood per kilogram of body weight with such improvement that they were then able to complete the experiment. 11. d. Splenectomized animals were unable to withstaud even a small hemorrhage (10 to 20 c.c. per kilogram of body weight) during intermittent positive pressure respiration. 12. e. Trauma to the hind limbs during intermittent positive pressure respiration proved fatal to all four animals. It was demonstrated that the pressure breathing was a definite factor in hastening their death. 13. f. Three hours of intermittent positive pressure respiration with a pressure of 15 cm. of water did not cause either pneumothorax or mediastinal emphysema in a single case, but in all of a group of three animals acute parenchymal and subpleural emphysema developed.

A study of the movements of heart valves and of heart sounds.

Excerpt For years there have been many theories and explanations given for the causes of the heart sounds. There is still considerable variance of opinion, controversy and debate among investigator...

Certain cardiovascular effects of vasopressin (Pitressin).

Abstract Pitressin was administered intravenously in doses of 0.1 to 1 unit per kilogram of body weight either at once or during a period of thirty minutes to dogs which were anesthetized with pentobarbital sodium. Cardiac output was determined by application of the Fick principle. Systolic and diastolic blood pressures at various points in the heart or pulmonary vessels were recorded by means of strain gauges connected to cardiac catheters. Another strain gauge recorded the blood pressure from a needle inserted into the femoral artery. The blood flow was recorded in heparinized animals from one or both femoral arteries by use of bubble flowmeters. Administration of Pitressin produced definite reduction in cardiac rate, consumption of oxygen, venous content of oxygen and cardiac output. Sometimes the heart became arrhythmic, and extrasystoles appeared soon after injection of Pitressin. Initially, transient increases were noted in both systolic and diastolic blood pressures in the femoral artery. This was soon followed by increases in the systolic and diastolic pressures in the pulmonary artery, in the wedge pressure in the small pulmonary vessels, and in pressures in the left atrium, while pressures in the femoral artery decreased to less than control values and the pulse pressure was much reduced. Administration of Pitressin produced great reduction in femoral blood flow.

The effects of whole bile and bile salts on the innervated and the denervated heart

Abstract The effects of the intravenous administration of whole bile and bile salts on the blood pressure and the electrocardiogram were studied in a series of acute experiments, under pentobarbital sodium (nembutal) anesthesia, on normal dogs and on dogs with denervated hearts; the same methods and technical procedures were employed in both cases. Similar observations were made over a period of several weeks on normal, trained dogs, and on one trained dog with a denervated heart; this permitted us to make repeated observations which could not have been influenced by anesthesia, operative trauma, or an accumulative effect of successive injections of bile. There were no detectable electrocardiographic differences between the effects of whole bile and bile salts on the innervated and the denervated heart; the irregularities and slowing of the rate of the heart were similar. During the period of gradual recovery from the hypotensive effect brought about by the first injections of bile constituents, the blood pressure of the dogs with denervated hearts usually did not return to its previous level, but the blood pressure of the dogs with innervated hearts, usually tended to do so. In both the normal animals and those with denervated hearts, approximately the same, gradual, hypotensive effect was produced by the intravenous administration of repeated doses of whole bile or bile salts. The injections finally led to failure of the heart, fall of blood pressure, and death of the animal. Our observations on the innervated heart differed so slightly from those on the denervated hearts of otherwise intact dogs to which whole bile or bile salts were administered intravenously, that it appears justifiable to conclude that whole bile and bile salts can produce practically the same hypotensive effect and cardiac changes, such as bradycardia and disturbances in rhythm, in the absence, as well as in the presence, of the cardiac autonomic nerves.

Experiments with calculated therapeutic and toxic doses of digitalis: V. Comparative effects of toxic doses of digitalis and of pitressin on the electrocardiogram, heart, and brain

Abstract Histologic changes were observed in the myocardium after the repeated injection of large doses of pitressin. The myocardial lesions resembled those which occurred after the administration of toxic doses of digitalis. They were focal in distribution and were most prominent in the subendocardial layer of the left ventricular musculature. The following is a summary of the changes in the RS-T segment and T wave after large doses of pitressin: (1) decrease or increase of the height of the T wave; (2) elevation of the RS-T segment (not of the plateau type) in one or more leads; (3) simple inversion of the T wave in one or more leads; (4) depression of the RS-T segment in one or more leads; (5) cove-plane, negative T 2 and T 3 ; and (6) cove-plane, negative T 1 and T 2 . Cellular degeneration was observed in the cerebral cortex after the repeated injection of large doses of pitressin. Myocardial and cerebral lesions were not observed in all the animals which received large doses of pitressin. Myocardial lesions were produced in the older, but not the younger, animals. Gastric lesions were observed after the injection of large doses of pitressin. This confirms the observation of Dodds and his associates.

The effects of whole bile and bile salts on the perfused heart

Abstract A series of experiments were performed on the isolated perfused heart of the rabbit. The changes in cardiac activity were observed, and graphic records were taken to portray the disturbances produced by whole bile and commercial preparations of sodium taurocholate and sodium glycocholate on the amplitude, rate, and rhythm of the contractions of the perfused heart. Definite and uniform effects were produced. Commercial preparations of bile salts and whole bile from the gall bladders of humans, dogs, and rabbits produced a slowing of the rate of the perfused heart, a diminution in the amplitude of its contractions, and a variety of irregularities in its rhythm, such as ventricular alternation, extrasystoles, and, finally, ventricular fibrillation, ending in complete cardiac failure.

Experiments with calculated therapeutic and toxic doses of digitalis: VI. Comparative effects of toxic doses of digitalis and of prolonged deprivation of oxygen on the electrocardiogram, heart, and brain

Abstract Histologic changes were observed in the myocardiums of animals which were subjected to prolonged systemic deprivation of oxygen over periods of three or more days. An endeavor was made to keep the concentration of oxygen near 4 to 5 per cent. One animal, which died one and a half hours after the inhalation of low percentages of oxygen, did not show any evidence of anatomic changes in the myocardium. The myocardial lesions produced by deprivation of oxygen resembled those found in the heart after the administration of toxic doses of digitalis. They were focal in distribution and were most prominent in the papillary muscle and in the left ventricular wall. The following is a summary of the prominent changes in the RS-T segment and the T wave after prolonged systemic deprivation of oxygen: (1) decrease or increase in the height of the T waves in one or more leads, (2) simple inversion of the T waves in one or more leads, (3) depression of the RS-T segment in one or more leads, (4) cove-plane, negative T2 and T3, and (5) negative T1 and positive T3. The electrocardiographic changes, as a rule, disappeared when atmospheric air was introduced into the chamber. Cellular changes were observed in the central nervous system after prolonged deprivation of oxygen. The changes were similar to those described by others after anoxia and to those observed after the administration of toxic doses of digitalis. Old animals were more sensitive to deprivation of oxygen than young ones.

Bartonellosis : a Cause of Severe Anemia in Splenectomized Dogs.

SummaryAfter splenectomy had been performed on a dog severe anemia developed and stained smears of the blood revealed organisms that had the morphologic characteristics of Bartonella canis. The dis...Summary After splenectomy had been performed on a dog severe anemia developed and stained smears of the blood revealed organisms that had the morphologic characteristics of Bartonella canis. The disease was transmitted to two other dogs, confirming the diagnosis of bartonellosis.

Experiments with calculated therapeutic and toxic doses of digitalis: IV. Effects on the cellular structure of the central nervous system☆

Abstract No significant cellular changes were observed in the brain and spinal cord after the administration of calculated therapeutic amounts of digitalis (30 per cent of the minimal lethal dose) in single or in divided doses. The histologic studies were made after a minimum of six days and a maximum of fifty-six days. No cellular changes were produced in our experimental animals when they were digitalized rapidly with a calculated therapeutic dose of digitalis and then were given maintenance doses of the drug which were estimated to correspond to either 1 or 2 cat units for a man weighing 70 kg. The histologic studies were made after a minimum of nineteen days and a maximum of sixty days. In our experiments, 60 per cent of the minimal lethal dose was the smallest amount which, when given as a single dose, produced definite evidence of cellular degeneration in the cerebral cortex. This dose of digitalis was in the toxic range. The frequency with which lesions of the central nervous system occurred increased as the size of the single dose of digitalis was increased to 80 per cent of the minimal lethal dose. Cerebral lesions were not observed until six or more days after single toxic doses of digitalis had been administered. Histologic changes were not observed in the central nervous systems of all of the animals which had received toxic amounts of digitalis, even when the quantity of the drug was 80 per cent of the minimal lethal dose. Degenerative changes were produced in the central nervous system when the animals were digitalized rapidly with a calculated therapeutic dose of digitalis and then were given daily quantities of the drug which were estimated to correspond to 3, 4, 5.5 or 6 cat units for a man weighing 70 kg. The equivalent of 3 cat units daily of parenterally administered digitoxin caused lesions in the brain and spinal cord within five days in one animal, and a corresponding daily dose of orally administered tincture of digitalis produced cellular changes in the central nervous system within eleven days in one animal. The central nervous systems of the digitalized animals in the group which had received daily doses of digitalis in the toxic range were examined microscopically after a minimum of five days and a maximum of thirty days. The cellular changes in the brain after the administration of digitalis were not specific. The following cellular alterations were observed in the large and small pyramidal cells of the cerebral cortex: swelling of the cell body; vacuolization of the cytoplasm; varying grades of cytoplasmic and nuclear degeneration, up to complete liquefaction of the cell; pyknosis of the cells; and cellular degeneration plus satellitosis. The cerebral changes often occurred in localized zones, with normal cortical cells in the surrounding tissue. The lesions were at times diffuse when large doses of digitalis had been administered. Old animals were more prone than young ones to manifest cerebral lesions after the administration of digitalis. This difference of sensitivity to the drug was not related to arteriosclerosis; at least no evidence of this disease was observed in any of the arteries or the arterioles of the central nervous system. Drowsiness and spastic reflexes were observed in the animals which were markedly intoxicated with digitalis. Animals which survived the administration of the toxic doses of digitalis recovered completely in three to four weeks.