Search

Early and adequate transfusion, prevention of infection and improved supportive measures are responsible for the survival of an untold number of casualties whose injuries would formerly have been rapidly fatal. But the very survival of persons seriously injured raises new problems in traumatotherapy, among which anuria assumes increasing significance. This report summarizes clinically relevant observations made during an experimental study of post-traumatic renal injury. The effects of trauma on renal function vary widely, according to the nature, severity and duration of the injury. Hemorrhage which does not cause prolonged hypotension usually results in temporary anuria, which is corrected by transfusion and which has no more significant sequel than the transitory appearance in the urine of casts, protein and red blood cells. Prolonged shock from hemorrhage or skeletal trauma may be followed by oliguria or anuria which does not respond to transfusion and culminates in uremia, although no specific renal lesion

Traumatic shock is thought of as an acute state from which no threatening residues persist. As regards recovery ofrenal function, doubt was cast on this view by reports from the scene of the Messina earthquake and by detailed studies of cases of post-traumatic uremia occurring in the German Army in World War I. 1 Crush syndrome was rediscovered, named and studied on a wider scale during the London blitz. 2 Similar cases have been reported from the accidents of civilian life. 3 Many others, civil and military, have probably gone undiagnosed because fatal shock and sepsis have probably overshadowed the defect of renal function. Typically, the syndrome is initiated by crush of a limb or occlusion of its arterial supply for several hours. Release from debris or restoration of blood flow is followed by swelling, with whealing at the sites of compression. The limb becomes hard, paralyzed and anesthetic. Loss

1. Isolated dogs' kidneys have been perfused with defibrinated blood under hemodynamic conditions similar to those in the body. Under these circumstances blood flow, urine secretion, and oxygen consumption are well maintained, but urea clearance is low. Renal venous blood collected initially and at the end of 3 or more hours of perfusion exhibited no difference in vasoconstriction properties when perfused along with renin or renin-activator through an isolated rabbit's ear. 2. Reduction of pulse pressure by constricting the renal artery may be performed without reducing mean pressure significantly. Impairment of urea clearance and rate of urine secretion follow, and oxygen consumption is slightly reduced. 3. After an hour or more of perfusion with reduced pulse pressure, gradual rise in mean renal arterial pressure distal to the clamp and reduction of blood flow occur. 4. Renal venous blood collected after about one hour of perfusion with reduced pulse pressure differs from that collected before reduction of pulse pressure in that it causes intense vasoconstriction when perfused with renin-activator through an isolated rabbit's ear. 5. Perfusion of a dog's hind leg under similar circumstances does not cause this change in the venous blood to occur.

1. Extracts of human blood plasma, ascitic and cerebrospinal fluids have been shown to contain a substance or substances which have a prolonged and powerful pressor action when injected into test animals. 2. The chemical properties of the substance suggest those of an organic base. It is extracted with alcohol, soluble in water and acetone, extracted from water by chloroform, and probably is but slightly heat-stable. The plasma colloids seem to hold the substance in a bound state since it does not appear in the ultrafiltrate and is liberated on coagulation of the colloids by alcohol. Coagulation alone of the blood does not cause the substance to be formed. 3. Its action suggests that its pressor effect is brought about by mediation of the central nervous system. This inference was drawn from the following observations. (a) The functional intactness of the central nervous system is essential in order that pressor responses be obtained. Unanesthetized animals exhibit greater vascular responses than do anesthetized. (b) Pithing animals completely abolishes the response. Progressive ablation of the brain to the level of the hind brain does not alter the response, but below this level, injury abolishes the activity of the extract. (c) Some substance in the extract sensitizes the mechanism responsible for the carotid sinus reflex. (d) There is no parallelism between the response to peripherally acting drugs and pressor extracts. (e) Removal of the adrenal glands does not affect its character. 4. The rise in blood pressure appears to be due especially to constriction of the arteries in the splanchnic region. 5. Assay of the pressor extracts is made difficult because of the dependence of the vascular response on the functional state of the central nervous system. The carotid sinus reflex and stimulation with carbon dioxide-air mixtures have proved most useful means for the estimation of this functional state. It has been pointed out that the vascular responses to extract, stimulation of the carotid sinus, and inhalation of carbon dioxide-air vary greatly during the course of an experiment on anesthetized animals. This natural history of the vascular responses has been described. 6. No evidence has been produced by the method employed that the amount of this pressor substance is increased in the blood or spinal fluid of patients with hypertension of varied pathogenesis (nephritic hypertension, essential hypertension, malignant hypertension, eclampsia, and pituitary basophilism).

Excerpt To the Editor:Part 2 of The American College of Physicians' Ethics Manual (1) is first-rate throughout. Even I cannot find fault with it. I come from the school where a researcher was large...

It may well be asked, What difference does it make in the long run who discovered what and when? My answer reflects my own deep biases and experiences with particular discoveries, in this case, serotonin. I believe that science is best taught and remembered when it is humanized and thereby related to the people involved. This is simply good pedagogy, part fact and often part poetic license. How much of each history will judge. A firsthand, eyewitness report could provide the substance for debate. This has always been the way of science, and I hope it always will be. But there are other reasons as well.

The combined effect of clofibrate and a fat-modified diet was determined in 17 hyperlipidemic patients: 7 type IIA, 7 type IV, 2 type VI(IIB), and 1 type III. Control serum lipid levels and lipoprotein patterns and their alteration with a fat-modified diet had been determined previously 1/2 to 2 years for 3 patients, and 6 to 10 years for 14 patients. Two grams of clofibrate a day (0.5 gm four times daily) was taken along with the fat-modified diet for 2 to 6 months by 5 patients and for 2 years by 13 patients. The effect of clofibrate and a fat-controlled diet was also determined in 10 normolipidemic men who were subjects of an 18-day test in which the polyunsaturated fat diet was quantitatively prepared and eaten along with 2 gm clofibrate a day (0.5 gm four times daily). The effect of clofibrate on serum cholesterol levels was a further mean reduction in type IIA patients by 19 %, in type III by 23%, in type IV by 12%, in type VI by 7%, and in normolipidemic subjects by 8%. The extent of the additional serum cholesterol reduction with clofibrate in individual hyperlipidemic patients varied from +10% to minus 44% and was not related directly to the type of hyperlipidemia. The extent of reduction appeared related directly to the level of minus S 40-70 (similar to Sf 12-20) lipoprotein fraction in the control serum sample. Serum triglyceride levels were unaffected in type IIA and normolipidemic subjects. Serum triglyceride levels did not change consistently in the 2 type VI patients, rising by 11% in 1 and dropping by 31% in the other. Serum triglyceride levels were significantly (p = 0.001) and consistently reduced by 39% only in type IV patients.

A 48 year old male patient presented with xanthomatosis, hyperbeta lipoproteinemia and hyper-IgA globulinemia; these two serum components occurred as a "complex." The patient has subsequently been studied for 22 years (1952 to 1974). His serum cholesterol and triglyceride levels have been consistently and excessively high despite efforts to regulate them by means of diet or diet and drugs. Serum immunoglobulin A (IgA) concentration ranged from 1,400 to 3,400 mg/dl compared with a normal value of 156 plus or minus 92 mg/dl. The metabolism of lipoproteins, judged by vitamin A turnover studies was slow. Peripheral atherosclerosis became evident 15 years after beginning the study whereas cinecoronary arteriography concurrently demonstrated only minimum changes. Xanthomas exhibited marked regression only during the last 6 years, after 16 years of diet and the addition of clofibrate for 7 years. Beta lipoprotein and IgA globulin determined by immunofluorescent and immunoelectrophoretic technics were demonstrated in the atherosclerotic material obtained from the patient's arterial wall. They were also found in the plasma cells of the bone marrow. The IgA globulin-beta lipoprotein complex in the serum was broken with difficulty. The patient's isolated IgA globulin, free of lipoprotein, formed a firm complex when mixed with beta lipoprotein prepared from normal human serum. Initially, IgA globulin studies showed presence of both kappa and lambda light chains in normal proportion. But after 18 years, the IgA globulin has become monoclonal, type lambda. The plasma cells of the bone marrow have become progressively more atypical and immature. No clinical indications of multiple myeloma have been found. It is concluded that association of lipoproteins with IgA globulin in the serum of this patient with hyperlipidemia, hyper-IgA globulinemia did not prevent the development of atherosclerotic lesions and the deposition of lipids and lipoproteins in the plaques. It is possible that the lipoprotein-immunoglobulin association may have retarded the process, since it became manifest only after many years of known hyperlipidemia.

The treatment of hypertension was discovered long before the mechanisms of the disease became known. Only recently has it been appreciated that blood pressure is controlled physiologically in many ways. Hypertension has suddenly achieved celebrity status. It is now recognized as the second leading cause of death in the United States. New programs have made the public aware of it and have prompted many individuals to have their blood pressure checked. Office diagnostic measures usually suffice to determine the presence of the disease. Treatment should generally be initiated with a slow-acting diuretic or with propranolol; other drugs may be added later. Treatment is a lifelong undertaking, and engaging the patient as a partner in the venture by means of home blood pressure measurements and an educational program contributes to its success. Treatment of hypertension is the first step in the prophylaxis of atherosclerosis.

The following editorial is a reprint of an article inLegacies in the Study of Behavior: The Wisdom and Experience of Many (edited by Joseph Warren Cullen and published by Charles C Thomas (1975) Springfield, Illinois) by Irvine H. Page, born 1901, a graduate of Cornell Medical College, and editor of “Modern Medicine.” The life of Dr. Page has been an enviable one and extremely colorful, reminiscent of the more comprehensive, less technically oriented careers of a bygone era. Beginning as Director of the Chemical Division of the Kaiser Wilhelm Institute in Munich from 1928 to 1931, later Director of the Research Division of the Cleveland Clinic Foundation (1945–1966), he pioneered in the mechanism of arteriosclerosis and hypertension, the isolation of serotonin, and in the research on angiotensin. Having been a successful experimental investigator as well as an eminent clinician, he speaks with a direction and brevity from a long experience. Because of the great value of his counsel, his article is reprinted here with his permission and that of the editor, J. W. Cullen, and the publisher Payne Thomas.

(1978). Science, intuition, and medical practice. Postgraduate Medicine: Vol. 64, No. 5, pp. 217-221.

Arterial pressure, cardiac output, stroke volume, heart rate, and peripheral resistance have been recorded daily in eight trained, healthy dogs with implanted aortic flow probes and aortic catheters. After suitable control periods angiotensin II was infused for periods of from 2 to 29 days. The effects observed were considered under four categories: 1) The immediate effects consisted of rise of arterial pressure, decrease of cardiac output and heart rate, rise of peripheral resistance and increased pulse pressure. Within five days all values tended to return to control levels unless the infusion rate of angiotensin was increased. 2) A chronic phase followed and, during this period, cardiac output was normal while arterial pressure and peripheral resistance were elevated. 3) After infusions were stopped pressure and peripheral resistance rapidly declined to be low normal, while cardiac output and heart rate rose to above normal. 4) A transient "malignant" phase was elicited by very large increases in the rate of angiotensin infusion, during which cardiac output and stroke volume were diminished while arterial pressure and peripheral resistance were increased greatly. The hemodynamic changes resulting from prolonged angiotensin infusion were similar in some respects to those found by us during the onset of hypertension due to renal artery constriction in dogs. They differed, however, in that doses of angiotensin, which were great enough to induce arterial pressure elevations similar to those of chronic experimental renal hypertension, reduced stroke volume, and these higher pressures could not be maintained for more than a few days. Hypertension did not persist after discontinuing angiotensin even after 28 days of almost continuous infusion. There was a distinct tendency for the pressor response to diminish with passage of time; more angiotensin was required to maintain similar elevations of arterial pressure.

SummaryIn rats made hypertensive by clipping a renal artery or subcutaneous renin injections, removal of the clipped kidney or cessation of renin administration were followed by an abrupt fall in arterial pressure, which stabilized at a level higher than the control value. This was associated with healing of mesenteric arteritis, while hyaline lesions remained unaffected. The functional and pathologic changes caused by removal of the clip were prevented by administration of renin. These experiments provide additional evidence that renal and renin-induced hypertension may have the same pathogenesis.

Coronary disease is rare among the Navajo Indians. Their plasma proteins and lipids differ from those of the population of Cleveland in that albumin is low normal and α- and γ-globulin elevated; total cholesterol was much lower. Since the diet and living habits are not strikingly different from those of the control group, it is suggested that heredity, in this case, is the most likely explanation for the low incidence of coronary disease and low level of cholesterol. Neither in the control nor Navajo group did mean serum total cholesterol rise with age.

1. (1) A useful method for perfusing a dog's tail is described. 2. (2) Purified renin, which produces a marked rise in arterial pressure when injected into intact animals, has little or no constrictor action on the vessels of a dog's tail perfused with Ringer-Lockeacacia solution. The addition of small amounts of whole blood, plasma, laked erythrocytes, or plasma colloids to purified renin causes intense vasoconstriction in the perfused tail. 3. (3) Partially purified extracts of kidneys contain heart-stable and dialyzable substances that cause constriction of the blood vessels of the dog's tail. 4. (4) The injection of sufficient cocaine to make the blood vessels nonresponsive to tyramine does not inhibit the action of renin-plasma mixture. 5. (5) Plasma from dogs after bilateral nephrectomy and hypophysectomy activates renin. 6. (6) Experimental hypertension produced in dogs by clamping the renal arteries or applying cellophane to the renal parenchyma appears to increase the ability of plasma to activate renin. There is no strict parallelism between the mean arterial pressure of the hypertensive animals and activator content of the blood.

1. 1. Nicotine has been isolated as crystalline oxalate and picrate from the urine of persons who smoke. Its pharmacologic properties are the same as those of pure nicotine. 2. 2. Most of the nicotine disappears from the urine within three to four days after smoking has been discontinued. 3. 3. Nicotine appears to be the substance responsible for the marked pressor action of many urine specimens. Unless tobacco has been eliminated as a source of pressor substance in urine, conclusions relating urinary pressor substances to arterial disease may not justifiably be drawn.

A new substance, Benzmalacene, was tested to determine whether it had hypocholesteremic effect in normotensive, hypertensive and hypercholesteremic patients. It proved effective. But after 4 months' treatment liver function began to deteriorate. It is strongly urged that drugs which interfere with cholesterol synthesis in the body be studied most carefully for long periods before widespread clinical trials to prevent atherosclerosis are attempted.

The hemodynamic changes accompanying experimental neurogenic hypertension due to sinoaortic denervation were measured in unanesthetized dogs for 3 weeks with chronically implanted arterial catheters and aortic flow transducers. Hypertension was modest, the average increase in mean arterial pressure being 31 ± 5 (SE) mm Hg. In about half of the dogs it was due predominantly to increase in cardiac output and in the others to increase in peripheral resistance; one factor or the other tended to maintain the hypertension in each dog throughout the experiments. Arterial pressure became extremely labile during the first few days after denervation and remained so during the entire experiment. This lability was closely correlated with environmental stimuli; rather minor distractions caused a sharp fall in pressure due variably to decrease in both cardiac output and peripheral resistance; greater distractions or physical activity caused a rise in pressure due usually to increase in peripheral resistance. Mean arterial pressures were higher when measured by transcutaneous puncture of a femoral artery, presumably because of the necessity of restraint and the discomfort associated with passage of a needle. Before sinoaortic denervation, arterial pressures fell to basal levels during sleep. After denervation, unexpectedly and for an undetermined cause, pressures rose to very high levels during sleep; the rises were consistently due to increase in peripheral resistance. Awakening was accompanied by a sharp fall in pressure and peripheral resistance.

Oral administration of chlorothiazide depresses glomerular filtration, increases blood urea, maintains sodium output in the face of decreased filtered sodium load, and paradoxically for a diuretic, in these and in tests done shortly after intravenous administration, increases the efficiency of water reabsorption.

Hypertension was induced in rats by constricting the aorta between the origins of the renal arteries. The left kidney, which became ischemic and atrophic ("endocrine kidney"), caused a malignant type of hypertension associated with weight loss, cardiac hypertrophy, hypertension, cardiac necrosis, nephrosclerosis of the right kidney, and arteritis. Amounts of pressor substances were increased in the left kidney and decreased in the right as compared with those in kidneys of normal rats. Aqueous extracts of ischemic kidneys, of kidneys contralateral to ischemic kidneys and of normal kidneys were prepared and the supernatant solutions were injected subcutaneously into test rats which had been uninephrectomized a few hours previously. Extracts of ischemic kidneys caused hypertension, cardiac hypertrophy, weight loss, and renal and vascular lesions mimicking the signs which result from renal ischemia. The extracts from the other kidneys were inactive. Administration of renin in doses roughly equivalent in pressor activity to the extracts of ischemic kidneys caused a rise in pressure, diuresis, and proteinuria but no lesions when given subcutaneously. It is proposed as a working hypothesis that renal hypertensive disease results not only from increased secretion of renin and formation of angiotensin but from simultaneous release from kidneys with reduced perfusion pressure of a substance which augments the enzymatic formation of angiotensin. This substance is presumably absent from normal kidneys and from semipurified renin preparations.

1. Extracts of kidneys have been prepared containing a substance which lowers arterial blood pressure for prolonged periods in patients with essential and malignant hypertension, and in hypertensive dogs and rats. 2. Several different chemical procedures are proposed for the preparation of the extract. The best one has not been decided upon. 3. The quantity of original fresh whole kidney required to yield enough extract to lower blood pressure from hypertensive levels (200 mm. Hg mean pressure) to normal levels is roughly 600 to 900 gm. in dogs within 4 to 8 days. In hypertensive patients the yield from 700 to 1000 gm. daily for several weeks may be necessary. 4. Lowering of the blood pressure too rapidly in animals results in a shock syndrome which may be fatal. If overdosage is avoided, no appreciable rise in blood urea nitrogen occurs, nor do other signs of toxicity appear. 5. Lowering of blood pressure to nearly normal levels has been accomplished in 60 hypertensive dogs, and in some of these it has been allowed to rise and was again reduced as many as five times. Similar results have been obtained with hypertensive rats. 6. Six patients with essential hypertension have been treated resulting in prolonged reduction of blood pressure. Clinically the patients appear improved. 7. Five patients with malignant hypertension have been treated, with reduction of the blood pressure in all instances. One patient was treated despite urea clearance of 5 per cent of normal. His blood pressure was sharply reduced, but death in uremia occurred. The second patient also exhibited sharp reduction of pressure and died after treatment was discontinued. The other three are much improved after treatment, as indicated by increase in vision and mental activity, loss of dyspnea, improvement in the electrocardiogram, etc. 8. The length of time the blood pressure remains lowered varies greatly in both animals and man. The trend is usually upwards after discontinuing treatment for 4 to 6 days. 9. Increasing experience with this treatment suggests that it is of value in the management of hypertension, but it is yet in the experimental stage.

1. Fur normale und atherosklerotische Aorten wurde in einer Versuchsreihe gleichzeitig der Gehalt an Gesamteisen und an organisch gebundenom Phosphor, in einer zweiten Reihe der Gehalt an locker gebundenem Eisen bestimmt. 2. Der Gehalt an organisch gebundenem Phosphor steigt ubereinstimmend mit bisherigen Untersuchungen mit der Verkalkung. 3. Eine Parallelitat zwischen Eisengehalt (sowohl gesamt-als auch locker gebundenem) und Grad der Verkalkung besteht nicht, was mit alteren, histologischen Untersuchungen in Einklang steht.

The synthetic octapeptide angiotonin evoked systolic and diastolic pressure responses in anesthetized and unanesthetized dogs identical with those due to a natural, largely decapeptide, angiotonin, and responses to both angiotonins were modified in the same manner by a variety of procedures. Infusion of synthetic angiotonin caused hypertension sustained for the durations of the infusions and tachyphylaxis was not observed. Induced tachyphylaxis to a crude renin preparation was accompanied by loss of response to both synthetic and natural angiotonin but not to norepinephrine.

The aortae of dogs may be constricted or occluded at the arch without the development of arterial hypertension proximal to the occlusion. Hypotension of moderate to marked degree occurs distal to the occlusion, and is usually more marked a few hours after clamping than later. the return toward normal of the pressure distal to the clamp was attributed, among other causes, chiefly to the development of collateral circulation and acute and chronic thining of the vessel walls within the clamp. After several days the pressure in the femoral artery may fall progressively, without simultaneous reduction of carotid pressure. The oxygen content of the blood does not appear to be reduced significantly until a great reduction of femoral pressure has occurred. The failure to produce, in dogs, hypertension proximal to a clamp constricting the aorta at or near the site where aortic coarctation occurs in human beings is attributed to the ready development in dogs of an extensive collateral circulation. Hypertension of renal origin occurs when the aorta is closed a few centimeters below the origin of the renal vessels, and, in addition, constricted or closed in the thorax at a level corresponding to the dome of the diaphragm. Removal of the kidneys reduces or abolishes this hypertension. The hemodynamic changes are sufficiently similar to suggest the possibility that the hypertension of human coarctation is of renal origin, and that the manner in which collateral circulation develops differentiates the response to constriction of the aorta in dogs and men.