Pheochromocytoma and the abnormal electrocardiogram

PHEOCHROMOCYTOMA AND THE ELECTROCARDIOGRAM

ABNORMAL

WILLIAM J. SAYER, CAPTAIN, MC, USA,* MARVIN MOSER, AND THOMAS W. MATTINGLY,~OLONEL, MC,USA*

M.D.,**

D. C.

WASHINGTON,

P

HEOCHROMOCYTOMA with surgical cure is no longer a medical rarity.’ Nevertheless, since this tumor is still occasionally diagnosed only on the autopsy table,2 there remains a constant need for appropriate clinical suspicion based upon a sound familiarity with all the characteristics of this disease. The clinical features, the laboratory and metabolic abnormalities, and the medical and surgical management of patients with a pheochromocytoma have been extensively discussed.3-7 Several chemodiagnostic tests have been devised and the utility as well as the pitfalls of these procedures have been adequately reviewed.3~6~8-*2a*b There has been, however, no recent emphasis of the fact that electrocardiographic abnormalities are frequently noted in the presence of a functioning chromaffin cell tumor. In order to direct attention to this feature of the clinical syndrome, the electrocardiographic changes encountered in two patients with surgically cured pheochromocytoma are presented, the pertinent literature reviewed, and the pathologic physiology of these abnormalities discussed. CASE REPORTS CASE 1.-A 29-year-old white woman was seen by a physician during the twenty-eighth week of her first pregnancy for treatment of “sinus headaches.” Histamine base, 0.05 mg., administered subcutaneously, caused an immediate flush without reproduction of her typical headache. Thirty minutes later, generalized pallor and marked nervousness were observed. The administration of bacterial vaccine resulted in the disappearance of the headaches, and she remained asymptomatic with normal blood pressure and urinalyses until the thirty-sixth week of her pregnancy. At this time she noted the onset of paroxysmal “attacks” consisting of marked tremor of the extremities followed immediately by’palpitation in the epigastric, precordial, and substernal areas. A severe, generalized throbbing headache immediately ensued, followed by extreme apprehension, The duration of an “attack” was marked coolness of all extremities and occasional parasthesias. never more than one or two minutes, but the frequency of occurrence increased as her pregnancy progressed. In infant.

March, 1951, Immediately

using saddle-block anesthesia, postpartum, a state of severe

she was delivered of a full-term normal shock with pulmonary edema intervened.

Received for publication Dec. 27, 1953. *Cardiology Section, Medical Service. Walter Reed Army Hospital, Washington, D. C!. **Present address: Thornycrofts Apts.. Scarsdale, New York: Formerly OfUcer in Charge, lar Clinic, Walter Reed Army Hospital. Washington, D. C. 42

Vascu-

SAYEK

ET

AI..:

PHEOCHROMOCYTOMA

AND

ABNORMAL

ECG

43

This did not respond to plasma, whole blood, oxygen, or ephedrine sulfate. There was no evidence of hemorrhage. After 12 hours of vasomotor collapse, she responded spontaneously with all vital signs becoming normal. At the time of her discharge from this hospital, the physical examination, chest x-ray, complete blood count, and urinalysis were normal. One week later the “attacks” recurred with increasing frequency and severity. Three weeks postpartum her blood pressure, recorded during an attack, was 160/110 mm. Hg in contrast to her usual blood pressure of 110/70 mm. Hg and she was rehospitalized. i\ histamine test was positive and the patient was transferred to Walter Reed Army Hospital with the presumptive diagnosis of pheochromocytoma. Physical ~xa~~ination: On May 1, 1951, an nourished white woman of stable disposition with Attacks could not no abnormal physical findings. palpation; postural tachycardia and hypotension dominal masses or bruits.

examination revealed a well-developed, poorly a blood pressure reading of 100/64 mm. Hg and be produced by change of position or abdominal were not demonstrable and there were no ab-

Laboratory data: Repeated complete blood counts, urinalyses, serologic tests for syphilis, complete serum electrolyte determinations, blood urea nitrogen, serum proteins, and 24-hour urinary excretion of 17 ketosteroids were all within normal limits. Repeated basal metabolic rates were consistently low-normal. The glucose tolerance curve was abnormally high, and persistent fasting hyperglycemia without glycosuria was confirmed. The chest x-ray was within normal limits, but excretory and retrograde urograms and abdominal laminography revealed lateral displacement and nonvisualization of the upper pole of the left kidney. Hospital course: Preoperatively, blood pressure determinations varied between 80/40 to 240/110 mm. Hg, and a cold pressor test produced a rise of from 110/74 to 150/110 mm. Hg. For 36 hours after an exceptionally severe series of “attacks,” postural hypotension and tachycardia were demonstrable. The day before surgery a left abdominal mass was palpable, and a bruit was heard in this area. Exploratory laparotomy, utilizing a transverse epiga&ric incision, revealed a cystic tumor in the left adrenal area. Manipulation of the tumor resulted+ a:precipitous rise in blood pressure which was reduced by 1.5 mg. of intravenous Regitine. Sho&ly thereafter, the tumor ruptured into the peritoneal cavity and the blood pressure fell to ‘shock levels. Constant intravenous administration of norepinephrine, 4 mg. per 1,000 cc. of normal saline, was necessary until 36 hours after surgery for the maintenance of normal blood pressure. During this period the patient also received whole adrenal cortical extract, parenteral fluids, whole blood transfusions, and antibiotics. The convalescent period was uneventful and re-examination one year later which included a repeat histamine test, revealed the patient to be completely well. Electrocardiographic description: The first electrocardiogram was taken after the episode of .A tracing postpartum shock and revealed only sinus tachycardia and generalized low voltage. obtained following an exceptionally severe series of “attacks” recorded a wandering pacemaker within the sinoatrial node, Q-T interval of 0.44 sec. with rate of 98 per minute and inverted ‘T waves in Leads I, II, aVr,, aVr, and Vz through V6. Diphasic T waves were noted in Leads III and VZ (Fig. 1,A). These changes persisted becoming somewhat less marked during the preoperative period. At operation, during manipulation of the tumor, an intermittent wandering pacemaker between the atrioventricular and sinoauricular nodes and occasional nodal premature contractions were noted on the cnrdioacope. The nest significant change occurred postoperatively during norepirtephrine infusion (Fig. 1,R) when high-peaked I’ \vaves, right-axis deviation, and upright conliguration of some of the previously inverted ‘I‘ waves occurred. Immediately following cessation of the norepinephrine infusion, the elcctrocardiograIn resumed the preoperative contiguration (Fig. 1 ,A). TWO weeks after removal of the tumor (Fig. 1,C) the T waves were isoelectric in Lead I, Gradual reversion inverted in a\‘,., Vr through V6 and of low amplitude in Leads II and a\:r. to a normal electrocardiogram (Fig. 1,D) was observed within six weeks of the operation.

44

AMERICAN

P

HEART

JOURNAL

SAYER

ET AL.:

PHEOCHROMOCYTOMA

AND

ABNORMAL

ECG

45

CASE Z.--A 30-year-old white woman was in excellent health until the eighth month of her At that time she developed hypertension, first pregnancy five years prior to the present admission. ankle edema, and 3-plus albuminuria which disappeared after delivery. During another pregnancy, one year later, identical findings recurred and again disappeared after delivery. Two years prior to the present admission, during her third pregnancy, hypertension was again noted. This and profuse sweating” was accompanied by severe occipital headaches and episodes of “tenseness related to emotional stress. Following an uneventful delivery a sustained hypertension was recorded varying between 180/120 and 220/140 mm. Hg with a transient fall to a base line blood pressure of 120/90 when she was treated with bed rest and sedation. During the six months preceding the present admission, the hypertension and symptoms described above persisted with occasional nocturia, and one brief episode of precordial pain. concomitant severe “impatience,” Thorough studies at several hospitals revealed minimal electrocardiographic evidence of left ventricular hypertrophy, and Grade 2 retinopathy, with no other evidence of disease except the elevated blood pressure. She was transferred to Walter Reed Army Hospital for observation and treatment. Physicul pressure of exudates.

examination: 180/120 mm.

Abnormal physical findings on admission were limited to Hg, excessive perspiration, papilledema, retinal hemorrhages,

blood and

Complete blood count, serologic test for syphilis, phenolsulfonphthalein Laboratory data: excretion, and Fishberg concentration test were all within normal limits. Repeated urinalyses revealed only an occasional trace of glycosuria and persistent l-plus albuminuria. A fasting hyperglycemia and an abnormally high glucose tolerance curve were noted. Repeated basal metabolic rates were moderately elevated and the total eosinophil count was 2.5. Chest retrograde

x-ray and pyelography

cardiac fluoroscopy showed minimal

suggested downward

minimal left ventricular and lateral displacement

hypertrophy, of the left

and kidney.

Nospitat course: With bed rest the patient was asymptomatic except for excessive perspiration and blood pressure determinations which varied between 170/115 mm. Hg and 200/130. Following the intravenous injection of 40 mg. of hexamethonium, the patient’s blood pressure in the sitting position fell from 180/130 mm. Hg to 90/60. 0 n resuming the reclining position a rise to 270/160 mm. Hg occurred.* Since this reaction so closely paralleled that of patients with pheochromocytoma who are given intravenous tetraethyl ammonium chloride, the following tests were performed: (a) benzodioxane, 1.5 mg., intravenously, resulted in a fall of blood pressure within 5 minutes to 100/70 mm. Hg from a resting level of 200/130; (b) a blood pressure fall to 90/70 mm. Hg from 200/130 followed the intravenous injection of 30 mg. of Dibenzyline; (c) eighteen hours after this injection, when it was felt that the patient was still under partial adrenergic blockade, 0.025 mg. of histamine base was administered intravenously resulting in a rise of the blood pressure from 150/100 mm. Hg to 210/130; (d) oral Regitine; 60 mg. resulted in a lowering of the blood pressure to 100/70 mm. Hg from 200/124 within one hour of administration. These observations will be reported in detail elsewhere.r*b With the provisional diagnosis of pheochromocytoma of the left adrenal area, the patient was given oral Dibenzyline, 10 mg. three times daily, for one week until 24 hours prior to surgery with resultant maintenance of base line blood pressure determinations at 140/90 mm. Hg to 150/100. ,At operation a pheochromocytoma of the left adrenal area was removed, and an immediate blood pressure fall ensued. This necessitated the constant intravenous administration of norThe postoperative course was epinephrine for a period of 7 hours after completion of surgery. uneventful. Blood pressure levels were stabilized at 120/80 mm. Hg to 130/85; fundoscopic abnormalities cleared gradually; and blood sugar levels, eosinophil count, and the basal metabolic Following a negative histamine test the patient was discharged rate all returned to normal levels. and has remained asymptomatic for ten months following surgery.

this

*Since hexamethonium is now being widely used in the study unusual response should be looked for as a possible indication

and therapy of essential of a pheochromocytoma.

hypertension,

46

AMERICAN

HEART

JOURNAL

SAYER

ET

AL.

:

PHEOCHROMOCYTOMA

AND

ABNORMAL

ECG

47

Electrocardiographic description: Unusual electrocardiographic hndings were noted preoperatively in this patient, during the administration of adrenolytic agents, and postoperatively. Initial tracings (Fig. 2,A) revealed deep S waves in Leads VI and \‘z as well as tall K waves in Leads V, and Vg. S-T segment depression and diphasic or inverted ‘1‘ waves were present in Leads I, II, III, aVL, ~VF and VI to Va. S-T segment elevation with terminal inversion of the T wave was noted in Lead VI. These changes were interpreted as representing diffuse myocardial ischemia as well as probable left ventricular hypertrophy and, in order to ascertain to what extent the abnormalities might be secondary to circulating pressor amines, all chemodiagnostic tests were performed with simultaneous recording of the electrocardiogram. Following intravenous administration of benzodioxane, and on another occasion Dibenzyline, reduction of blood pressure resulted and the following changes were noted in the electrocardiogram (Fig. 3 and Fig. 4): (a) a shift to a more vertical position of the heart; (b) clockwise rotation of the heart; (c) a change of the inverted or diphasic T waves in Leads I, II, aVL, a\‘F, and VI to a more nearly upright configuration; and (d) a definite prolongation of the Q-T interval from 0.30 to 0.36 sec. following the use of Dibenzyline (Fig. 3,B) despite the increase in cardiac rate from 75 to 136 (Q-T, 0.35 prolonged to Q-T, 0.52 sec.). All leads to hypertensive administration

returned to the previous appearance (Fig. 2,A) with the return of the blood pressure levels. The blood pressure elevation following hexamethonium and histamine did not produce significant changes in the electrocardiogram.

Preoperative tracings prior to administration of oral Dibenzyline, compared to during the period of effective adrenergic blockade, revealed a definite shift towards heart with clockwise rotation (Figs. 2,A and 2,B). In addition, the previously inversion over the right precordium was no longer present. This may have been change of electrical position.

those obtained a more vertical noted T-wave related to the

After removal of the tumor, similar diminution of the T-wave abnormalities was immediately noted (Fig. 2,C) and six months later (Fig. 2,D) further reversion was noted with the T waves The tracing had not, in Leads I, II, aVL, V+ VE,, and VS at that time being diphasic or isoelectric. however, returned to normal. REVIEW

OF

LITERATURE

Electrocardiographic abnormalities were presented in the first case report of a surgically cured pheochromocytoma by Shipley.13 As subsequent case reports appeared, additional electrocardiographic abnormalities were described and properly attributed to the coexistent chromaffin cell tumors.14J5 Until 1946, occasional review articleP-ls appeared in which even more abnormalities were reported and appropriate emphasis was placed on the observation that the presence of a pheochromocytoma could, not infrequently, account for certain abnormal electrocardiograms. A review of sixty-three case reports of pheochromocytoma16-52 occurring in the literature since 1946 reveals, however, that the electrocardiogram was not mentioned in thirty-two instances and a normal electrocardiogram was described for only nine patients. Of more significance is the fact that those electrocardiographic changes reported were frequently presented without indication or implication that these abnormalities were related to the pheochromocytoma. Nonetheless, it is quite apparent from the previous reviews and certain case reports that many different electrocardiographic abnormalities have been recorded which were due to a functioning chromaffin ceil tumor. Following the suggestion of MacKeith,16 these may be categorized as abnormalities of rhythm or abnormalities which suggest myocardial ischemia, damage, or “strain.”

48

AMERICAN

HEART

JOURNAL

SAYEK

ET

AI,.

:

PHEOCHKOMOCYTOMA

AND

.IHNOKM.\L

49

E CG

B.

D.

Fig. 4.-Case 2. The effects of intravenous Benzodioxane upon the abnormal electrocardicg of pheochromocytoma. A, Control blood pressure 204/130 mm. Hg. 13. Eight minutes after C, Twenty minutes later, blood pressure 210/130 Benzodioxane, blood pressure 120/60 mm. Hg. Hg. D. Eighty minutes later, blood pressure 210/130 mm. Hg.

16 I

The abnormalities of rhythm that have been reported are wandering pacemaker,lR sinoauricular dissociation,” auricular tachycardia’,i5 auricular premature contractions,14s17,44 auricular flutter,” auricular fibrillation,17 nodal tachycardia,21 ventricular premature contractions,‘7J5Js,43 and ventricular tachycardia.13.35*43 These arrhythmias have occurred most frequently during paroxysms of hypertension16-18~45 and may persist after the blood pressure has returned to normal levels.17,43 All reported arrhythmias have disappeared following removal of the tumor. Tetraethylammonium chloride administration has induced cardiac arrhythmia43 in one patient with a pheochromocytoma, and it would seem possible that electrocardiographic observation of provocative tests for pheochromocytoma might reveal data of value when interpretation of such tests is questionable. The reported abnormalities suggestive of myocardial damage include 2)) left-axis deviation,l4’16,22.23,25 ,28.44S0352 abright-axis deviation46 (C ases 1 and normally high or peaked P waves, 3~1*~Z1,42,45 low-amplitude or inverted T waves,‘4-16,?3,24,34,35,42,4P46,52 S-T segment deviation,21q4Z*46 (Case 1)) and prolongation of Q-T interva130s52 (Case 1). These changes have occurred transiently during,‘$ or between paroxysms of hypertension21j4s (Case 1) and persistently with sustained hypertension35J6 (Case 2). Disappearance of these abnormalities prior to the removal of the tumor has occurred spontaneously,i4B16 during hypertensive paroxysms,21 and during a low-sodium regimen.43 Partial or complete reversal of this group of changes to normal following removal of the tumor is reported3s45*53 and well illustrated by our cases. A characteristic of this group, warranting especial emphasis, is the diffuse distribution of the T-wave abnormalities; e.g., inverted T waves in Leads I, I I, I II, aVL, aVF, V 1 through V 6 in our cases and others.31,3ss53 Undoubtedly the most significant feature of the electrocardiographic abnormalities described above is that demonstrable etiologic factors are most often absent and for this reason clinical suspicion should be directed toward the possibility of a pheochromocytoma. DISCUSSION

The electrocardiographic abnormalities associated with a pheochromocytoma have previously been attributed to hyperepinephrinemia.16-1* It is well established that arrhythmias and even cardiac arrest may result from excessive epineThis has been attributed to the direct stimulation of phrine administration.54 the myocardium as well as that stimulation mediated via the conduction tissue.55 That the arrhythmias arising as a result of epinephrine sensitization can be prevented by adrenergic blockade has also been well documented.56 There is no evidence, however, that norepinephrine can produce arrhythmias by direct action in the intact normal heart, although elevation of blood pressure alone by this agent may produce sudden changes in cardiac rate and rhythm.57n58 Other factors which may contribute to the electrocardiographic changes noted in an adrenalin-secreting tumor may be related to (1) the marked increase in pulmonary artery pressure often produced by epinephrine or norepinephrine6g; (2) the relatively disproportionate increase in right ventricular work that is

SAYER

ET

AL.

:

PHEOCHROMOCYTOMA

AND

ABNORMAL

DCG

51

produced by these agenMg (producing patterns similar to those noted in acute car pulmonale); (3) the elevation of serum potassium by norepinephrine and lowering by epinephrine.60*61 Factors other than hyperepinephrinemia must occasionally be invoked to explain the persistence of diffuse T-wave inversions (Case 2) long after removal of a pheochromocytoma. The reported cases of myocardial infarction23*3* and autopsy findings of other myocardial pathology36 attest to the role of organic myocardial damage in the production of some of the abnormal electrocardiographic findings in pheochromocytoma. These persistent changes after tumor removal are uncommon in the reported cases covered by this review. Organic damage may be differentiated from electrocardiographic abnormalities which are produced by excess circulating pressor amine by the administration of adrenolytic drugs as shown in our experience with Case 2. It is evident from the foregoing discussion that the pathogenesis of the abnormal electrocardiogram produced by a pheochromocytoma is a complex interplay of the relative amounts of epinephrine and norepinephrine secreted by the tumor, the duration of the secretion, whether intermittent or sustained, and the net effects of these pressor amines upon the cardiac rate, rhythm, output, oxygen demand and supply, as well as the coronary circulation, pulmonary and peripheral arterial resistance, and perhaps the body electrolyte distribution. Evaluation of the changes apparent in our cases would suggest that in Case 1 the S-T segment deviation, prolonged Q-T interval, and diffusely abnormal T waves (Fig. l,A) were the result of reversible myocardial injury. This seems more logical when one considers the brief periods of hypertension and the complete return to a normal tracing after tumor removal. The marked right-axis deviation which occurred during norepinephrine infusion (Fig. l,B) may have been a manifestation of the sudden increase of right ventricular work discussed previously since systemic hypertension did not accompany the infusion. The high P waves may have resulted from increased auricular pressure. Serum electrolytes were not determined, but this factor could possibly have influenced the reversion of previously inverted T waves by the norepinephrine infusion. In Case 2 the sustained hypertension, as well as excessive circulating pressor substances, may have been the responsible factors underlying the diffuse S-T segment deviation and T-wave inversion (Fig. 2,A). Undoubtedly this combinaThis is suption resuited in reversible as well as irreversible myocardia1 injury. ported by the diminution in extent of these abnormalities which followed the administration of the adrenolytic drugs, as well as the observation after operation that the same changes affected by these agents were the ones which disappeared following the removal of the tumor. The changes (Fig. 2,D) which persisted for 6 months must be attributed to diffuse myocardial damage which has been shown at autopsy to have occurred in patients with pheochromocytoma and sustained hypertension.3B SUMMARY

1. Two patients with pheochromocytoma and abnormal electrocardiograms due to the presence-of this tumor are reported. Serial tracings illustrating the effects of surgery, as well as the administration of adrenolytic agents, are presented.

52

AMERICAN

HEART

JOURNAI.

2. Pertinent literature is reviewed, and it is observed that the association of pheochromocytoma and electrocardiographic abnormalities has been previously noted though recently neglected. 3. The reported abnormalities are either arrhythmias or changes suggesting myocardial damage, ischemia, or “strain.” A singularly striking feature of the latter group is the diffuse distribution of the S-T segment and T-wave changes. 4. The role of cscessive circulating epinephrine and,‘or norepinephrine in the production of these changes is discussed. 5. It is emphasized that in the absence of known etiology certain electrocardiographic abnormalities may indicate the presence of a pheochromocytoma. REPEKENCES 1.

2. I1

4. 5.

6.

8. 9. 10. 11.

Editorial: Hypertension’ and Pheochromocytoma, J.A.M.A. 138:514, 1948. Berkheiser, S. W., and Rappoport. A. E.: Unsuspected Pheochromocytoma of the Adrenal; Report of Five Cases, Am. J. Clin. Path. 21:657, 1951. Cahill, G. F., and Monteith, J. C.: The LTse of Dibenamine and Norepinephrine in the Operative Treatment of Pheochromocytoma; Report of Two Cases, New England J. Med. 244:657, 19.51. Cahill, G. F.: Pheochromocytoma, J.A.M.A. 138:180, 1948. Calkins. E., and Dana, G. W.: Current Methods of Diagnosis of Pheochromocvtoma, J:;\.M..%. 145:880, 1951. L1ranow, H., Jr.: The Differential Diagnosis of Pheochromocytoma, M. Clin. North America

34:757, 1950. Smithwick, B. H., Greer, iv:. E. R., Kobertson, C. W., and Wilkin, B. W.: Discussion of Symptoms, Signs and Procedures of Diagnostic Value, New England J. Med. 242:2.52, 1B.50. Goldenberg,. M.! and Aranow, Ii., Jr. : Diagnosis of Pheochromocytoma by the Adrenergic Blockmg Action of Benzodlosan, J.A.M.A. 143:1139, 1950. ITntoward Reactions to Tests for EpinephrineBierman, H. K., and Partridge, J. W.: sec.ret& Tumors IPheochromocvtoma). New England I. Med. 244:.582. 1951. ConleT:, J. E., and Junkeiman, C. L.: -Lack ‘if Specificiyy of Piperoxan Hydr&hloride Test ‘for Adrenal Medullary ‘rumors, J.I1.M.A. 147:921, 1951. Koth, G. M., and Vale, 1%:. F.: Tentative Test for Pheochromocytoma, Am. J. M. SC.

210:653, 194.5. 12. (a)

Gitford, Rav W., Jr., Koth, Grace M., and Kvale, Walter F.: Evaluation of a New ;1drenoI$tic Drug as Test for Pheochromocytoma, J.A.M.A. 149:1628, 1952. (1~) i\Ioscr, M., Walch, \V. F’., Kyle, L., and Mattingly, T. W.: Evaluation of the Present11 Available Chemical Teats for Pheochromocytoma, (In press). Shipley. ;\. M.: Paroxysmal Hypertension Associated With Tumor of the Suprarenal, 1B. . _ .inn. Surg. 90:731, 1929. E.: Paroxysmal Hypertension Associated With Ganglioneuroma of the Suprarenal 14. Rogers, Medulla, AM. HErlRT J. 8:269, 1932. 15. Caller, F. A., Field, H., Jr,, and Durant, T. M.: Chromaffin Cell Tumor Causing Hypertension, Kelieved by Operation, Arch. Surg. 28:1136, 1934. 16. MacKeith, R.: Adrenal Sympathetic Syndrome, Brit. Heart J. 6:1, 1944. Changes in Paroxysmal Hypertension 17. Espersen, ‘1‘., and Jorgensen, J.: Electrocardiographic I)ue to Chromaffin Adrenal Tumor, Acta med. Scandinav. 127:494, 1947. Sympathetic Syndrome With 18. Burgess, 21. M., Waterman, G. W.: and Butts, F. B.: adrenal llnusual Variations in Cardiac Rhythm, Arch. Int. Med. 58:433, 1936. 1946. 19. Green, D. M.: Pheochromocytoma and Chronic Hypertension, J.A.M.A. 131:1260, 20. Snvder. C. H.. and Vick. E. H.: HvDertension in Children Caused by Pheochromocytoma, Am. J. i)is. Child.‘73:581, 194?. W. S., Shafar, J,, and Symington, T.: Phaeo21. Blacklock, J. iv. S., Ferguson, J. W., Mack, chromocytoma, Brit. J. Surg. 35:179, 1947. 22. Ferraro. L. R.. and Angle, R. G.: Pheochromocytoma With Symptoms of Epinephrine Shock; lieport of aCase, Arch. Int. Med. 81:799, 1948. M. : Pheochromocytoma With Diabetes 23. I)eVrics, !\., Rachmilewitz, M., and Schument, and Hypertension; Report of Two Cases Cured by Operation, Am. J. Med. 6:51, 1949. 2.4. Laham, A. J., and Schrock, J. B.: Pheochromocytoma, With Persistent Hypertension, and Thor&olumbar Sympathectomy, Surgery 27:93.5, lY50. of Pheochromocytoma, Brit. Heart J. 12:232, 1950. 2.5. Cole, L.: The Early Diagnosis 26. Goldenberg, M., Aranow, H., Jr., Smith, ‘4. A., and Faber, M.: Pheochromocytoma and Essential Hypertensil-e Vascular Disease, Arch. Int. Med. 86:823, 1950.

SAYER

27. 28. 29.

ET

AL.:

PHEXXHROMOCYTOMA

AND

ABNORMAL

EOG

53

Koffler,

I., Buck, G., Wingard, C., Hitchcock, P., Guthrie, R., and Teaque, R. S.: A Case of Pheochromocytoma; Diagnosis by the Benzodiozane Test, Urinary Hormone Studies, and Norepinephrine Assay of the Tumor, J. Clin. Endocrinol. 10:897, 1950. McFarland, G. E., Jr., and Bliss, W. R.: Hemorrhage From Spontaneous Rupture of the Right Adrenal Gland, Ann. Surg. 133:404, 1951. Craig, A. B., Jr., and Schilling, J. A.: Pheochromocytoma; a Case Report With Details of the Medical and Surgical Management and Experimental Study, Surgery 29:596, 1951. _, _-.

and PhysioA. P., Baker, H. M., Hoffman, M. S., and Ferris, E. B.: Pharmacologic logic Studies of a Case of Pheochromocytoma, Am. J. Med. lO:llS, 1951. L. T., Henderson, H. W., and Derr, J. W.: Use of Adrenolytic Drug, Regitine, in Pheochromocytoma, AM. HEART J. 42:129, 1951. H. C.: Intrathoracic Pheochromocytoma With Hypertension, Ann. Surg. 130:1059,

30.

Shapiro,

31.

Iseri,

32.

Maier,

33.

Intrathoracic Pheochromocytorna; R. H., Ramsey, B. H., and Meissner, W. A.: Case, Dis. Chest 17:55, 1950. Wilkins, R. W., Greer, W. E. R., Culbertson, J. W., Halperin, M. H., Litter, J., Rurnett, C. H., Smithwick. R. H.: Extensive Laboratorv Studies of a Patient With Phenchromocytoma B&fore and After Successful Operation With a Note on the Triai~of Piperidylmethyl Benzodioxine to Differentiate Such Conditions From Essential Hypertensive Vascular Disease, Arch. Int. Med. 86:51, 1950. Kyle, L. H.: Personal communication. Moser, M., Sheehan, G., and Schwinger, H.: Pheochromocytoma With Calcification Simulating Cholelithiasis, Radiology 55:855, 1950. Crede, Robert H., and Kerr, William J.: Pheochromocytoma: Report of a Case With Symptoms Simulating Acute Anxiety Attacks, Post-Grad. M. J. 11:288, 1952. Woolsey, John Homer, and Person, Woodring: Extra-adrenal Abdominal Pheochromocytoma, Arch. Surg. 65~779, 1952. Cope, Oliver, Labbe, J. P., Raker, J. W., and Bland, E. F.: Pheochromocytoma and Adrenal Cortical Adenoma, J. Clin. Endocrinol. 12:875, 1952. Gendel, B. R., and Ende, M.: Pheochromocytoma: Report of Unusual Case With Gastrointestinal Bleeding, Gastroenterology 19:344, 1951. Decker, H. C., McDowell, Fletcher W:, and Trimble, I. Ridgeway: Case Report \l;ith Discussion of Differential Diagnosis and Surgical Treatment, J.A.M.A. 147:642, 1951. Lumb, George: Chromaffin Tumour With Chronic Hypertension, Brit. M. J. 2:936, 1951. Pyle, F. J.: Pheochromocytoma: Report of a Malignant Case, J. Urol. 66:153, 1951. Kosltchek, R. J., and Rabwin, M. H.: Pheochromocytoma Successfully Removed With the Aid of Piperoxan Hydrochloride (Benodain), J.A.M.A. 144:826, 1950. McCoy, G. E., and Bridgeman, M. L.: Use of Drugs in the Diagnosis and Treatment of Pheochromocytoma; Case Report, Pediatrics 6:286, 1950. McFarland, G. E., Jr., and Bliss, W. R.: Hemorrhage From Spontaneous Rupture of a Pheochromocytoma of the Right Adrenal Gland; a Case Report, Ann. Surg. 133:404, 1951. Craig, A. G., Jr., and Schilling, J. A.: Pheochromocytoma, a Case Report With Details of the Medical and Surgical Management and Experimental Study, Surgery 29:596, 1951. Richards, V., and Hatch, F. N.: Surgical Experiences With Pheochromocytoma, Ann. Surg. 134:1, 1951. Fernando, P. B., Cooray, G. H., Thana-Balasundram, R. S.: Adrenal Pheochromocytoma y2i;h ly;;roblastomatous Elements; Report of a Case With Autopsy, ;\rch. Path.

1 OAO A,

34.

35. 36. 37. 38. 39. 40. 41. 44. E: 47. 48. 49. 50. 51. 52. 53. 54.

58. 59. 60. 61.

L,.

Overholt,

Medullary Tumor of the Adrenal Glands, With Hypertension and Juvenile ‘D: N.: Arteriosclerosis, Arch. Int. Med. 57:1001, 1936. Mitchell, R. E.: Armed Forces M. J., (In press). The Pharmacological Activity of Epinephrine and Related Dihydrosyphenyl Lands, A. M.: Alkylamines, Pharmacol. Rev. 1:279, 1949. Goodman, L., and Gilman, A.: The Pharmacologic Basis of Therapeutics, New York, 1941, The Macmillan Company. Nickerson, Mark: The Pharmacology of Adrenergic Blockade. Pharmacol. Rev, 1:27, 1949. Moe, Gordon F., Malton, S. Donald, Rennick, B., Freyburger, W.: The Role of Arterial Pressute m the Induction of Idioventricular Rhythms Under Cyclopropane Anesthesia, J. Pharmacol. & Exper. Therap. 94:319, 1948. Rothberger! C. J., and Winterberg, H.: Article quoted by Moe, reference 62, Arch. f. d. ges. Physlol. 132:233, 1910. Witham, A. C., and Fleming, J. W.: The Effect of Epinephrine on the Pulmonary Circulation in Man, J. Clin. Investigation 30:707, 1951. Pullman, T. N., and McClure, W. M.: The Effect of L-noradrenaline on Electrolyte Escretion in Normal Man, J. Lab. & Clin. Med. 39:711, 1952. Jacobson, W. E., Hammarsten, J. F., and Heller, B. I.: The Effects of Adrenaline Upon Renal Function and Electrolyte Excretion, J. Clin. Investigation 30:1503, 1951. Kremer,