Desperate diseases, desperate measures: Tackling malignant hypertension in the 1950s

Desperate diseases, desperate measures: Tackling malignant hypertension in the 1950s

Curriculum in Cardiology Desperate diseases, desperate measures: Tackling malignant hypertension in the 1950s Hector O. Ventura, MD,a Mandeep R. Mehr...

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Curriculum in Cardiology

Desperate diseases, desperate measures: Tackling malignant hypertension in the 1950s Hector O. Ventura, MD,a Mandeep R. Mehra, MD,a and Franz H. Messerli, MDb New Orleans, La

Background The conquest of malignant hypertension is one of the most important medical achievements of the second half of the 20th century. As we enter the new millennium, it is critical to examine the efforts that have led to our ability to treat this once incurable disease.

Methods Review was performed of the literature from 1900 to the 1950s regarding the etiology, clinical evaluation, and treatment of hypertension, focusing on malignant hypertension.

Results Fifty years ago, in a time of sparse treatment options, the occurrence of malignant hypertension was a dreaded event that taxed the aptitude of the clinician. Confronted with an “extreme disease,” physicians chose to use “extreme methods of cure” in conformity with the teaching of Hippocrates. In the 1950s malignant hypertension was treated with such drastic measures as rice diet, sympathectomy, and intravenous pyrogens. Conclusions In the practice of medicine today, while work is being done to reassert biomolecular mechanisms, we still face patients who have reached the end stages of failure and manifest devastating morbidity. These patients are subjected to “extreme therapies” reminiscent of those that surrounded malignant hypertension in the past. In an era when adequate treatment of hypertension has become a reality for so many patients, it is appropriate to give credit to those who paved the way to such great progress. (Am Heart J 2001;142:197-203.) The conquest of malignant hypertension must be considered as one of the most important medical achievements of the last half century. In the midcentury, hypertensive cardiovascular disease started to be understood, although the development of malignant hypertension was still a dreaded disorder that taxed the clinician. Once malignant hypertension was established, drastic treatment was in order. There was no time to temporize. Thus confronted with an “extreme disease,” investigators sometimes chose to devise “extreme methods of cure” in conformity with the teaching of Hippocrates: “For extreme diseases, extreme methods of cure are most suitable.”1 Physicians in the 1950s treated malignant hypertension with such drastic measures as a rice diet, sympathectomy, and intravenous pyrogens. As we practice with the comfort zone provided by the current clinical arsenal for the treatment of hypertension, it is critical to re-examine the efforts of the past. The trials and tribulations of yesterday’s clinical investigators are important to understand and give us greater insight into today’s practice. In the current article we sought to report a historical overview of the treatment of hyperFrom the aDepartment of Cardiology, and the bSection of Hypertension, Department of Medicine, Ochsner Medical Institutions, New Orleans, La. Submitted October 30, 2000; accepted April 13, 2001. Reprint requests: Hector O. Ventura, MD, Ochsner Medical Institutions, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/116480 doi:10.1067/mhj.2001.116480

tension in the 1950s and thus render homage to those physicians, because they paved the way to an era, in which primary and secondary prevention of hypertension had become a reality.

Malignant hypertension: A view from the past In 1957, the Medical Advisory Board of the Council for High Blood Pressure of the American Heart Association2 defined malignant hypertension as follows, “A clinical phase, rarely occurring de novo, more often appearing after a primary or secondary hypertension, characterised by diastolic hypertension and by accelerated and progressive renal damage, usually (but not necessarily) accompanied by papilledema, often by retinal hemorrhages and exudate, and giving rise to early death from uremia unless the course is terminated along the way by complicating brain or heart damage.” Histologically, the characteristic feature of the accelerated or malignant form of hypertension was changes of a widespread endarteritis and necrotizing arteriolitis. In this context it is important to briefly summarize some of the classic studies related to the understanding of both hypertension and, more specifically, malignant hypertension. Already in 1827 Bright3 had recognized that many patients with renal disease had diffuse vascular disease, kidney disease, and cardiac hypertrophy more than a half a century before a blood pressure measuring device

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was constructed to measure blood pressure and thus diagnose hypertension. By the turn of the century, Allbutt4 and Janeway5 had reported cases of patients having what they called benign hypertension or hyperpiesia. They followed the course of these patients for several years and showed that many lived comfortably to old age and that the function of the heart, kidneys, brain, and retina remained adequate. But it was in 1914 that Volhard and Fahr6 reported their clinicopathologic investigation of hypertension and divided arterial hypertension into 2 types. The first group of patients (red hypertension) showed no evidence of generalized arterial contraction or renal or retinal abnormalities, and appeared to be in the best of health. The second group of patients (pale hypertension) had chronic nephritis and generalized arterial contraction with associated renal and retinal abnormalities (“angiospatic retinitis,” a serious prognostic risk factor). These patients were ill and apathetic. Histologic analysis of the kidneys demonstrated severe thickening of the arterioles and small arteries, which led to ischemia and changes in the parenchyma of this organ. These microscopic changes in the kidneys were called “malignant sclerosis” or “bösartige hypertenie.” In 1928 Keith et al7 used the term “malignant hypertension” for the first time in the English literature. They reported a series of patients in whom they observed the presence of retinitis, marked hypertension, and fairly adequate renal function. They pointed out that this syndrome was slightly different from chronic nephritis and emphasized that the presence of retinitis was a bad prognostic sign. They argued that the application of the term “malignant hypertension” was correct because this clinical condition was rapidly fatal. In all 14 cases death occurred within 1 to 44 months. Subsequently, Keith et al8 described the course and prognosis of patients with hypertension according to the degree of retinopathy. The patients were divided into 4 groups (I-IV): patients in group I (only mild narrowing or sclerosis of retinal arterioles) had a survival of 70% at 7 years; conversely, group IV (cotton-wool exudates, hemorrhages, edema of the optic discs) had a 90% mortality at 1.5 years. Thus the phrase “malignant hypertension” has remained in use in clinical medicine since then. What was different throughout the subsequent years compared with before was that something could be done for some patients with severely high diastolic blood pressure who were not azotemic.

Management of malignant hypertension The relationship of elevated blood pressure to the disease of hypertension itself was not well understood. Many excellent clinicians believed that lowering blood pressure would play no advantageous therapeutic role

for the underlying vascular disease that they believed was primary and immutable. Thus in the first edition of his excellent treatise in cardiology, White9 wrote, “. . . for aught we know hypertension might an important compensatory mechanism, which we should not tampered with even if we know how to control it.” In patients with malignant hypertension several treatment modalities were proposed with varied results in reducing blood pressure and regressing target organ damage. These included, among others, operations on the sympathetic nervous system, rice and low-sodium diets, bed rest, and intramuscular injections of kidney extracts. Certainly, the determination of the therapeutic effectiveness of a new approach could be made with less difficulty in cases with malignant hypertension because had they worked they would have been life saving. The spectrum of these clinical options required skillful judgment on the part of the physician to define the best possible cohesion between patient selection and the singular treatment option likely to be of benefit. Thus the science of the day demanded an artistic execution on the part of the clinician to optimize the benefits of treatment strategies targeted to an individual.10

Medical therapeutic modalities Medical approaches were largely focused on amelioration of malignant hypertension, and the therapeutic paradigm was weighted toward a balancing act of risk and benefit. Because malignant hypertension was usually lethal, clinicians determined that more extreme measures were justified. Thus “Once malignant hypertension appears, every possible effort should be directed toward the lowering of blood pressure even at the risk of treatment toxicity or surgical incapacitation.”11 We will summarize some of these medical therapies.

Low-salt and rice diets The restriction of the dietary intake of sodium chloride in the therapeutic management of patients with hypertension was advocated periodically throughout the current century. Ambard and Beaujard12 in 1904 recommended the exclusion of salt from the diet of hypertensive patients. Subsequently, in 1922 Allen and Sherrill13 advocated the use of a low-sodium diet as a means to lower blood pressure, and this procedure was adopted and widely used in Europe but received little attention in the United States. Most of the earlier observers believed that the beneficial effects of a lowsalt diet were related to chloride restriction. Moreover, because little was known of the role of sodium in the body metabolism, there was no rationale for the procedure, and most of the clinicians did not consider it worthwhile. Although many patients were often instructed to avoid salty foods and not to add excessive quantities of salt to their food, there was no objection

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to its use in sufficient amounts to render it palatable. Efficient dietetic treatment for hypertension received a new stimulus when Kempner14 reintroduced this concept in 1944. Kempner’s fruit-rice diet consisted essentially of fruit in any form, fruit juices, rice sugar, and a little milk. It contained approximately 2000 calories, 20 g of protein, 5 g of fat, and 200 mg of chloride and 150 mg of sodium.14 Lean meat, fish, and nonleguminous vegetables without salt and fat could be added only after the blood pressure was controlled. In 1949 Kempner15 reported 777 cases of severe or malignant hypertension treated with the rice diet and demonstrated its effectiveness. He described an improvement in 66% of the patients who persisted with the diet for an average of 3 to 4 months. The clinical benefits included a marked decrease in the systolic and diastolic blood pressures (up to 40 mm Hg), a disappearance of papilledema and retinal hemorrhages and exudates, restoration of an upright T wave in lead I (50% of cases), and an appreciable reduction in the transverse diameter of the heart.15 Although the reasons the diet was effective were unclear, it remained a very important therapy in patients with malignant hypertension who could faithfully follow the diet. In addition, the diet was also helpful when added to other medical or surgical measures. The clinical application of this approach evoked considerable debate with protagonists supporting the diet while skeptics felt that the salutary effects on end organ damage were not clearly explainable. Kempner attributed the effect of this diet to factors such as lower protein content and enzymatic effects. He did not consider the low salt content as a contributing factor in the effectiveness of the diet. Subsequently, Grollman and Harrison16 studied the effects of various diets, including the rice diet, on the blood pressure and survival on hypertensive rats and demonstrated that sodium restriction was in fact the motive by which blood pressure decreased. This was associated with an improved survival of the animals. Subsequently, these data were confirmed in humans, suggesting that the rice diet was just a drastic salt-depleted diet and that the majority of patients with hypertension would be unable to tolerate such dietary restrictions.17 Pickering18 pointedly commented, “The rice-diet [was] introduced by Kempner who arrived at this diet as the result of experiments on kidney slices, using mental processes that are not accessible to me.” He added, “It is insipid, unappetizing and monotonous and demands great care in its preparation. Even its deadly monotony tends to make the diet intolerable unless the physician can infuse into the patient some of the aestheticism of the religious zealot.” Regardless of the mechanism and the foul taste of this therapeutic measure, the rice diet and the work of Kempner is very significant because he demonstrated

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that blood pressure can be lowered effectively and that the target organ damage can be resolved in patients with malignant hypertension. Perhaps Kempner’s observations had stood the passing of time. Certainly, diet is today a significant component in the treatment of hypertension.

Intravenous pyrogens In the 1940s investigators from the Cleveland Clinic studied the use of injections of kidney extracts in patients with malignant hypertension with good results. Because fever was in most cases part of the reaction, they also administered agents designed to produce fever in some patients. Although at the time it was known that pyrogens given over short periods of time lowered blood pressure only temporarily, the prolonged use of this strategy had not been studied. In one particular report Page and Taylor19 used a soluble bacterial pyrogen (Pyromen) as an intravenous injection. Living nonpathogenic bacilli, killed staphylococci, streptococci, and tubercle bacilli as well as stock typhoid vaccine were used previously but discarded in favor of Pyromen, which did not evoke excessive and uncontrollable clinical reactions. Pyromen was given as a single dose 5 to 6 days weekly in amounts needed to raise the temperature to 103°F to 104°F each day. The first dose was 0.5 mL of a solution containing 50 gamma of solid per milliliter. Duration of the treatment depended on individual response but often extended over 3 to 6 months. The investigators noted poor clinical outcome in patients with azotemia, and best results occurred in those with preserved renal function. Page and Taylor also demonstrated what was the sequence of improvement of target organ damage after the use of pyrogens. First to improve were the retinal changes, with papilledema disappearing in all properly treated patients. Hematuria and proteinuria resolved within the first 2 months of treatment, whereas signs of hypertensive heart disease were the last to improve. The few patients (5) who elected to discontinue treatment before all signs of target organ damage were corrected had great morbidity, with 3 having cerebral hemorrhage within 3 months, 1 succumbing during the second stage of lumbodorsal sympathectomy, 1 alive and with no further signs of malignant hypertension, and the other lost to follow-up at the time of this report. Of the remaining 14 patients treated, 9 lived for an average of 32 months (range 15-45 months) and were leading fulfilling lives. The remaining 5 died of cerebral hemorrhage, 1 with recurrence of malignant hypertension 9 months after treatment. The authors concluded, “. . . the malignant phase of hypertension may be reversed by repeated injections of bacterial pyrogens provided that renal function is adequate.19 McMichael10 remarked, “This [pyrogens] is harsh treatment but malignant hypertension is more than harsh; it is lethal.”

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Table I. Rationale for the use of sympathectomy Lowering of basal blood pressure: two thirds of patients have decreased basal blood pressure, associated with an interruption of the vasomotor tone Abolition of the sudden elevations of blood pressure: associated with the removal of vasoconstriction from the denervated area and with a decrease in the release of catecholamines from the adrenal gland Alterations in renal blood flow and function: the use of sympathectomy confirmed that the reduction of blood pressure was associated with the delay on the progression of renal disease Production of norepinephrine in sympathetic tissue: the demonstration that the depletion of norepinephrine was responsible for the beneficial effects of sympathectomy. The following observations were made: Electrocardiographic abnormalities identical to those seen in hypertensive heart disease can be produced experimentally by the administration of sympathomimetic amines apart from any consistent hypertensive effects The heart in many hypertensive patients contains abnormally large amounts of chromogenic catecholamines The concentration of catecholamines in the myocardium of sympathectomized animals is greatly reduced

Autonomic blocking agents Veratrum viride and hexametonium. Studies

demonstrated that veratrum10 and its derivatives were useful in around 15% to 20% of the patients with hypertension. In addition, hexametonium10 was given subcutaneously in patients with malignant hypertension because of the irregular absorption in the gastrointestinal tract. It is important to point out that both drugs had a very small therapeutic window, that is to say that the margin between the effective dose and the toxic effects was very little. Reserpine. In severe or malignant hypertension reserpine was used parenterally in the hospital setting, 2 to 4 mg given intramuscularly every 4 to 12 hours depending on the response of the blood pressure. When the blood pressure was reduced adequately, the oral form of reserpine was used at a dose of 0.25 mg once or twice daily.20 After its clinical introduction, reserpine became a useful agent for the treatment of essential hypertension. The most common side effects of the drug were depression, drowsiness, lethargy, and nasal congestion.

Surgical therapeutic modalities In the quest to achieve a “cure” for malignant hypertension, clinicians looked to various surgical procedures to lower blood pressure. Approaches targeted to removing kidney tissue were attempted. As an example, decortication of the kidneys was proved to be ineffective, and unilateral nephrectomy of a diseased kidney (cystic or pyelonephritis) with the other kidney fairly normal cured hypertension in a few cases.10,11 Unilateral nephrectomy lent credence, albeit partially, to the animal data, which demonstrated that clamping the renal artery produced hypertension. Extensive bilateral thoracic and lumbar rhizotomy, although reported to be effective, was too serious and dangerous an operation.10,11 In addition to the procedures described above, 2 surgical strategies, sympathectomy and in a lesser degree adrenalectomy, became the most com-

monly used techniques for the treatment of hypertension. We will discuss the clinical experience with sympathectomy.

Sympathectomy Historical background. Rowntree and Adson21 in 1925 performed a bilateral lumbar sympathectomy in a patient with malignant hypertension. Immediately it was evident that this technique was inadequate, and during the succeeding 20 years increasingly radical interruptions and excisions of the sympathetic nerves were performed in an effort to control the progressive forms of hypertension. Thus Peet22 reported the subdiaphragmatic splanchnicectomy, Smithwick23 reported the thoracolumbar splanchnicectomy and sympathectomy, and, finally, Grimson24 reported the total sympathectomy. Physiologic considerations. The rationale for the use of sympathectomy is summarized in Table I. The experimental and clinical observations suggested that the beneficial effect of sympathectomy in some patients may in part be due to depression of the production of norepinephrine in the adrenal medulla and in the sympathetic ganglia.25,26 Furthermore, some authors believed that these beneficial effects on the heart after sympathectomy were the reasons some hypertensive patients improved despite not having changes in basal blood pressure.25,26 Clinical experience with sympathectomy. Among the work performed in the field of sympathectomy, we will discuss the work of Smithwick.27,28 He performed denervation above and below the diaphragm. Smithwick stated, “removal of virtually the entire great splanchnic nerve with division of all of its aortic branches coupled with interruption of the communicating rami of D9, D10, D11, D12, and L1, together with excision of the sympathetic trunk over this area, is the minimal procedure found consistently to produce a blood pressure change which is characteristic of a through interruption of the nerve supply to the splanchnic bed.” Smithwick27,28 reported 256 patients

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with essential hypertension, including malignant, in which patients underwent splanchnicectomy from 1938 to 1943 and were followed up for 5 to 9 years. The total mortality rate was 31.2%, distinctly less than the expected rate for similar patients not treated. In addition, 90% of the survivors improved symptomatically: the eye grounds improved in 41%, the electrocardiograms were better in 42%, and the blood pressure was lower in 47%. During the first 5-year follow-up, 80% of the cases showed a definite decrease in blood pressure; however, a considerable number of these patients showed a gradual increase in blood pressure toward the preoperative levels during the 5 to 9 years of follow-up. Subsequently, Smithwick27,28 introduced in 1950 new criteria to categorize patients who might benefit from sympathectomy. This was a score system in which adverse points were given according to several cardiac and renal findings. For example, an abnormal electrocardiogram was one adverse point, x-ray evidence of cardiac enlargement another, age of 50 years another, and so on. Abnormal renal function was a very serious adverse prognostic finding and, in general, was a contraindication for the operation. Patients who had a score of 4 or less were more suitable for splanchnicectomy. By use of this selection, Smithwick reported his experience of 1862 cases comparing splanchnicectomy with medical treatment. At 10 years of follow-up, patients who were classified in the Smithwick group III had a mortality of 89% (males) and 58% (females) if they were treated medically. However, patients in this group who underwent splanchnicectomy had a mortality rate of 56% if they were male and 37% if they were female. In relation, patients included in the Smithwick group IV, the ones who received medical treatment and were male had a mortality of 100% and if they were female had a mortality of 90%. Patients in the same group who underwent splanchnicectomy had a mortality rate of 74% and 71% if they were male or female, respectively. The side effects associated with the use of sympathectomy ranged from increased vasoconstriction and sweating in the arms, postural hypotension, increasing motility of the colon, failure of ejaculation in the male, and impaired perception of pain arising from the abdominal viscera. The indications for sympathectomy can be summarized as follows: failure to respond to adequate medical therapy, diastolic pressures of 120 mm Hg or higher, and evidence of progressive damage to the heart, eyes, brain, or kidneys. Moreover, the contraindications were as follows: age >55 years, myocardial infarction or cerebral vascular accident <6 months before the operation, blood urea nitrogen >20 mg/dL, and lack of emotional maturity or reliability. Another study worth mentioning is the one by White.29 The author reported experience with sympathectomy (most of the operations performed by Smith-

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wick) in 100 patients with hypertensive heart disease and added several important conclusions. First, the fact that 5 patients with severe cardiovascular disease were perfectly well with normal blood pressure after 3 years of follow-up and 15 patients were distinctly improved proved that hypertensive cardiovascular disease was reversible. Up to that time sympathectomy had achieved the greatest therapeutic success in that respect. Second, conversely, sympathectomy was a serious major operative procedure in itself, it was followed by a tedious, often uncomfortable convalescence, and it was not suitable for the majority of the patients with hypertension. Finally, White29 concluded that Smithwick’s work represented a notable advance in the control of hypertension but that he hoped that in the future some simpler therapy or preventive measure would eventually replace sympathectomy.

Conclusion of the surgical treatment of hypertension According to Page,30 there was a great deal of controversy regarding this procedure. For some it seemed an extreme measure with unacceptable side effects, and to others it seemed beneficial in improving the prognosis of the disease. From Page’s point of view, sympathectomy occupied an important therapeutic position but was not the ultimate answer for the patient with hypertension. Although the long-term results of the surgical treatment of hypertension were mediocre, its historical value should not be underestimated. Despite having side effects, sympathectomy proved that the blood pressure in essential hypertension could be permanently lowered, occasionally even to normal, and that lowering the blood pressure abolished the progression to malignant hypertension, improved the patient’s health, and prolonged life. In 1950, Wood31 commented about the importance of sympathectomy, stating, “blood pressure in essential hypertension could be permanently lowered . . . thereby disproving the illfounded theoretical objection that to lower the blood pressure in essential hypertension without dealing with the disease itself (whatever that was supposed to mean) was unphysiological.” In addition, he stated, “Surgical sympathectomy thus opened the way to medical sympathectomy and encouraged pharmacological research into blood pressure lowering of all kinds.”

Lessons from the past The path to discovery is often perilous, yet the principles of keen observation and persistence to challenge the standard knowledge lead to advances in medical therapy. As it relates to cardiovascular diseases, the conquest of malignant hypertension is one of the most important medical achievements of the last half of the century. Fifty years ago the occurrence of malignant hyperten-

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sion was an “extreme disease” that required prompt treatment. Among other therapies, the treatment of malignant hypertension consisted of such drastic measures as rice diet, sympathectomy, and intravenous pyrogens. Although these treatments were drastic, the use of these measures demonstrated that physicians were not powerless to help people with severe hypertension. Several decades of intensive investigations in different areas of hypertension leading to the 1950s culminated in the development of medications such as reserpine, hexametonium, hydralazine, chlorothiazide, α-methyldopa, and others that made those previous therapies obsolete and led to our ability in reducing the onslaught of an enormous killer. Compared with the testing and approval of therapies used today in the form of placebo-controlled clinical trials, the clinical evaluation of therapies before World War II relied on 3 aspects.32 First, perhaps the oldest method to evaluate a medicine was the experiential or empirical method. Second, a method also used to assess medical therapy relied on authority, either sound or unsound. Finally, the third method is the experimental, a more scientific approach that appeared in the 18th century. The latter was the one used to evaluate the treatment of malignant hypertension; because it was a lethal disease, lowering blood pressure was the key to reducing mortality. It is important to point out that, even when the first randomized trial designed by Hill was performed studying the benefits of streptomycin in tuberculosis, the Medical Research Council in England approved the use of this drug in patients with either miliary tuberculosis or tuberculous meningitis because it was life saving.33 This action by the Council might also be viewed as the approval of a medicine for an “extreme” disease, similar to the ones used for malignant hypertension. Therapeutic trial and research are the key to the progress of medicine. A concept was well summarized by Page30 in 1951, when he wrote, “. . . while no simple cure for most types of hypertension is at hand, still there are now several procedures which aid greatly in some patients but not in others. Unfortunately, at the present time, no method is known of deciding who will benefit, so we perforce must go our blundering way by trial and error. But significant advances have been made in understanding the disease and the advances are much more rapid today than six years ago. It almost seems that the indifference and lethargy of the past is being discarded and the research will prevail. If this is so, and I think it is, the future of the hypertensive is bright, even though present treatment must seem pedestrian, complicated and unsure.” The historical relevance of the therapies for malignant hypertension in the 1950s can be explained as it relates to today’s clinical practice. In the practice of medicine today, while work is being done to reassert biomolecular mechanisms, we still face patients who

have reached the end stages of failure and manifest devastating morbidity. These patients are subjected to “extreme therapies,” such as heart transplantation, left ventricular reduction surgery, artificial hearts, or inotropic agents, reminiscent of those that surrounded malignant hypertension in the past. In an era when adequate treatment of hypertension has become a reality for so many patients, it is appropriate to give credit to those who paved the way to such great progress. We thank Mark Silverman, MD, for a critical review of the manuscript.

References 1. Jacques J. Hippocrates. Baltimore: Johns Hopkins University Press; 1999. 2. Medical Advisory Board of the Council for High Blood Pressure of the American Heart Association. Circulation 1957;16:697-9. 3. Bright R. Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine. Guy’s Hosp Rep 1836;1:338-400. 4. Allbutt TC. An address on arteriosclerosis of the kidneys. BMJ 1911;1:853-922. 5. Janeway TC. Nephritic hypertension: clinical and experimental studies. Am J Med Sci 1913;145:625-35. 6. Volhard F, Fahr T. Die Brightsche Nierenkrankheit: Klinik, Pathologie und Atlas. Berlin: Julius Springer; 1914. 7. Keith NM, Wagener HP, Kernohan JW. The syndrome of malignant hypertension. Arch Intern Med 1928;41:141-88. 8. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939;197:332-9. 9. White PD. Hypertensive heart disease. In: Hypotension in heart disease. New York: Macmillan; 1932. p. 391-409. 10. McMichael J. The management of hypertension. BMJ 1952;1:933-98. 11. Proger S. An approach to the treatment of essential hypertension. Modern Concepts Cardiovasc Dis 1953;22:194-6. 12. Ambard L, Beaujard E. Causes de l’hypertension artérielle. Arch Gen Med 1904;1:520-33. 13. Allen FM, Sherrill JW. Treatment of arterial hypertension. J Metab Res 1922;2:337-434. 14. Kempner W. Treatment of kidney disease and hypertensive vascular disease with rice diet. N C Med J 1944;5:125-7. 15. Kempner W. Treatment of heart and kidney disease and of hypertensive and arteriosclerotic vascular disease with the rice diet. Ann Intern Med 1949;31:821-6. 16. Grollman A, Harrison TR. Effect of rigid sodium restriction on blood pressure and survival of hypertensive rats. Proc Soc Exp Biol Med 1945;60:52-5. 17. Grollman A. Sodium restriction in diet for hypertension. JAMA 1945;129:533-7. 18. Pickering G. High blood pressure. 2nd ed. London: Churchill; 1968. 19. Page IH, Taylor RD. Pyrogens in the treatment of malignant hypertension. Mod Concepts Cardiovasc Dis 1949;18:51-2. 20. Wilkins RW, Judson WE. The use of rauwolfia serpentina in hypertensive patients. N Engl J Med 1953;248:48-53. 21. Rowntree LG, Adson AW. Bilateral lumbar sympathetic neurectomy in the treatment of malignant hypertension. JAMA 1925;85:959-61. 22. Peet MM. Splanchnic section for hypertension: a preliminary report. Univ Hosp Bull 1935;1:17-8.

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23. Smithwick RH. A technique for splanchnic resection for hypertension. Surgery 1940;7:1-8. 24. Grimson KS. Total thoracic and partial to total lumbar sympathectomy and celiac gangliectomy in treatment of hypertension. Ann Surg 1941;114:753-75. 25. Raab W, Lepeschkin E. Biochemical versus hemodynamic factors in the origin of hypertensive heart disease. Acta Med Scand 1950;138:81-93. 26. Allen EV, Adson AW. The treatment of hypertension: medical versus surgical. Ann Intern Med 1940;14:228-307. 27. Smithwick RH. Hypertension as viewed from its surgical treatment. Mod Concepts Cardiovasc Dis 1944;13:50-6. 28. Smithwick RH. Splanchnicectomy in the treatment of essential

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hypertension. In Moyer JH, editor. Hypertension: the first Hahnemann symposium of hypertensive disease. Philadelphia: WB Saunders; 1959. p. 681-90. White PD. Hypertensive heart disease. In: Heart disease. New York: Macmillan; 1951. p. 486-8. Page IH. Hypertension. 6th ed. Springfield (IL): Charles C Thomas; 1951. Wood P. Diseases of the heart and circulation. London: Eyre and Spottiswoode; 1950. Green FHK. The clinical evaluation of remedies. Lancet 1954;2: 1085-91. Hill AB. The clinical trial. N Engl J Med 1952;76:64-5.

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