Primary Ventricular Fibrillation* Some Unusual Features David S. Sheps, M.D.; Cesar A. Conde, M.D.; Alvaro Mayorga-Cortes, M.D.; Stephen M. Mallon, M.D.; Ruey ]. Sung, M.D.; Agustin Castellanos, M.D., F.C.C.P.; and Robert]. Myerburg, M.D.
A 47-year-old man experienced ventricular fibrDiation three times during a 31h-year pertod. Eacb episode was preceded by an auditory aura, and no ventricular Irritability was identified between episodes. Tbe results of COI'OII8ry arteriograpbic, hemodynamic, and lntracardiae electropbysiologic: studies were all normal. Hypokalemia and abnormal oxyhemoglobin dissodation were present. The possible relationships of tbese unusual features to tbe patient's disturbances in rbytbm are discussed. is current interest in identifying the factors T here which predispose to the occurrence of ventricular fibrillation. While the majority of individuals who develop this potentially lethal arrhythmia have coronary arterial disease as the underlying structural abnormality,l-8 recent evidence from both clinical studies and experimental studies in animals suggests that the central nervous system may play a role in the pathogenesis of this cardiac arrhythmia. This report presents evidence for a link between the central nervous system and the occurrence of ventricular fibrillation in the absence of identifiable organic heart disease. In addition to this relationship, noncardiac metabolic factors (hypokalemia and abnormal oxyhemoglobin dissociation) were observed in relationship to the disturbance in rhythm. CASE REPoRT
A 47-year-old white man was asymptomatic and in good health until May 1972, when he lost consciousness for the first time subsequent to a "ringing" sensation in his ears while °From the Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Fla. Supported in part from funds provided by National Heart and Lung Institute grant 1-R01-HL-18769-01 and by Florida Heart Association grant AG 424. Reprint requests: Dr. Sheps, Division of Cardiology, PO .Ben
520875,M~i33152
at rest. He was brought to the emergency room of a community hospital, where ventricular fibrillation was documented electrocardiographically. The patient underwent cardioversion to sinus rhythm. Findings from physical examination were within normal limits. There was no history of hypertension, rheumatic fever, diabetes, cardiac clicks or murmurs, chest pain, shortness of breath, or palpitations. Chest x-ray films and serial studies of cardiac enzyme levels were normal. Serial electrocardiograms revealed minor Twave changes in the anterior leads but no evolutionary changes of myocardial infarction. The patient remained in the hospital for three weeks and was treated with procaine amide hydrochloride ( 500 mg every three hours) . He was discharged on this regimen, and his condition remained stable for two months. In July 1972, the patient again noticed a "ringing" sensation in his ears while at rest, quickly followed by loss of consciousness. On arrival at a local hospital's emergency room, the patient was in ventricular fibrillation; he was defibrillated and returned to normal sinus rhythm. The results of cardiovascular examination, serial ECGs, and enzyme levels were normal. The patient was maintained on therapy with procaine amide hydrochloride ( 500 mg every three hours) and diphenylhydantoin ( 100 mg every four hours) . The serum concentration of potassium was 2.8 mEq/L and rose to nonJ)al levels with potassium supplementation. The patient had not been taking any diuretic drugs prior to admission. The urinary pH was 5. The patient was discharged after four weeks and did well until December 1974, when he stopped taking his medications. Two weeks later, while watching television, the patient experienced a "ringing" in his ears, quickly followed by vertigo and loss of consciousness. He was found to have ventricular fibrillation, which spontaneoulsy converted to atrial fibrillation with an irregular ventricular response (Fig 1 ) . The serum level of potassium was 3.4 mEq/L. Findings from physical examination and laboratory studies were unrema.rlcable. After four days of hospitalization, the patient was transferred to Jackson Memorial Hospital for further workup. In January 1975, the patient underwent cardiac catheterization. Findings from hemodynamic and left ventriculographic studies were normal. Selective coronary arteriograms revealed a normal dominant right system. Intracardiac electrophysiologic studies revealed a normal P-R interval ( 170 msec), an atrio-His interval of 105 msec, and His-ventricle interval of 45 msec. Repetitive pacemaker stimuli were applied at 10-msec intervals during diastole (including application during the T wave) at a stimulus strength up to 15 times the diasrolic threshold. Neither ventricular tachycardia
12/21/74 1:45 A.l.
I
.I
TO ;IAL IFI!.
111111
FxcURE 1. One of multiple episodes of ventricular fibrillation. Top, Ventricular fibrillation with spontaneous reversion to atrial fibrillation. Bottom, Ventricular premature contractions did not precede or follow episodes like this.
CHEST, 72: 2, AUGUST, 1977
PRIMARY VENTRICULAR FIBRILLAnON 235
nor ventricular fibrillation was produced. Atrial and ventricular stimulation at varying cycle lengths and coupling intervals produced no arrhythmias. The patient was discharged on a regimen of diphenylhydantoin ( 100 mg four times per day) and propranolol ( 40 mg four times per day) and returned to work. He did well until May 1975, when he again stopped taking his medications. On the night of admission, the patient had had two blackout spells, both preceded by "ringing" in his ears. He was transferred to the emergency room, where he had ventricular tachycardia requiring cardioversion. Again, findings from physical examination and routine laboratory studies were normal. The findings from electroencephalograms with the patient awake and asleep and during otic and photic stimulation were within normal limits. Simultaneous electrocardiographic monitoring failed to reveal cardiac arrhythmias.
Oxyhemoglobin dissociation curves7 and red blood cell levels of 2,3-diphosphoglyceric acidS were determined on two separate occasions. Measurements of the partial pressure of oxygen at which hemoglobin is 50 percent saturated ( PSO) obtained while the patient was clinically stable were 22.5 mm Hg and 23.5 mm Hg, respectively (normal. 27 ± 1 mm Hg), and the level of 2,3-diphosphoglyceric acid was 4.~oVml (normal, 4.8 ± 0.3/illloVml of packed cells). Levels of carbon monoxide were 8 percent and 3.5 percevt, the hemoglobin level was 13 gm/100 mi. and the results of hemoglobin electrophoresis were normal. Several 12-hour ambulatory electrocardiographic recordings revealed no evidence o£ arrhythmia. DiscuSSION
The sequence of events observed in this patient demonstrates several unique and interesting features. The mere survival from multiple episodes of ventricular fibrillation occurring in the patient's home is noteworthy. 9 Other interesting features observed in this patient were an auditory aura preceding the episodes of ventricular fibrillation, the presence of hypokalemia on admission to the hospital in each instance, and an abnormality of oxyhemoglobin dissociation resulting in increased affinity of hemoglobin for oxygen. The most likely underlying causes for ventricular fibrillation in a man of this age are coronary arterial disease or cardiomyopathy. Since this patient had no
angiographic evidence of coronary arterial disease and completely normal hemodynamic and electrophysiologic findings at cardiac catheterization, he falls into the group of patients included in the category of primary ventricular fibrillation. We do not believe that this patient falls into the subgroup of any of the known hereditary syndromes that are reported with prolonged Q-T intervals, with or without hereditary deafness, 10- 13 since the patient's Q-T interval has never been found to be prolonged, even immediately after defibrillation, and his hearing has been demonstrated to be totally intact; however, we believe that there is a neurogenic link in the pathophysiology of the disturbance in rhythm, suggested by the aura of "ringing" in the ears prior to each episode. This aura has never been noted at any other time by the patient. It has been recently postulated that neurogenic mechanisms may play a role in patients with transient nonischemic changes in the T wave (such as those seen in this patient [Fig 2]), even without prolongation of the Q-T interval. Similar changes have been experimentally produced with stimulation of the right stellate ganglion.a The auditory aura is reminiscent of a case report by Wellens et al16 of a young girl in whom ventricular fibrillation was precipitated by the ringing of an alarm clock. That case was successfully treated with administration of propranolol, and because of the similarities to our case, our patient was started on therapy with propranolol. Recently, Lown et al16 have reported a case of recurrent ventricular fibriUation without demonstrable heart disease, which was very similar to ours. They were able to demonstrate an increased frequency of ventricular premature contractions with REM sleep and a decrease with meditation. These investigators hypothesized that instantaneous death might be triggered by neural mechanisms. Our case differs in one important respect, ie, the absence of ventricular premature contractions between episodes of ventricular fibrillation. Another interesting finding is hypokalemia on each admission for ventricular fibrillation. We have no explanation for this. The patient did not have renal tubular
FIGURE 2. Top, ECG obtained following episode of ventricular fibrillation. Note marked T-wave inversion in leads Vt, V2, and V6. Bottom, ECG obtained during asymptomatic period, showing regression of T -wave abnormalities. The Q-T interval is within normal limits in both tracings.
236 SHEPS ET AL
CHEST, 72: 2, AUGUST, 1971
acidosis, was not taking diuretic drugs, and did not have gastrointestinal losses or alkalosis to account for this electrolyte abnormality. In addition, the serum level of potassium was normal on numerous occasions when the patient was clinically stable. Regardless of the cause of the hypokalemia, it affects the transmembrane action potential and predisposes to atrial and ventricular irritability;17 however, without further evidence in this particular patient, this consideration must remain conjec-
tural. Delivery of myocardial oxygen was evaluated by means of oxyhemoglobin dissociation curves. The P50 represents the partial pressure of oxygen at which hemoglobin is 50 percent saturated and thus is a measure of the position of the oxyhemoglobin dissociation curve. An increase in P50 or a shift to the right of the curve will facilitate the delivery of oxygen to tissues; and conversely, a decrease in P50 or a shift to the left of the curve will inhibit release to tissues at a given oxygen pressure. While the possibility exists that a primary abnormality in oxyhemoglobin dissociation was present in this patient, there are other important considerations. Most of the decrease in the measured P50 can be explained by the patient's elevated carbon monoxide levels; however, the patient was also taking propranolol at the time this measurement was made. Propranolol has been shown to elevate P50 in normal subjects and in patients with
~RCENT
Oz Delivery
OXYHEMOGLOBIN
42"
Pso-t&.s(nl) 55%
2
FIGURE 3. Solid line illustrates normal oxyhemoglobin dissociation curve. Broken line represents our patient's curve. Degree of saturation at typical myocardial oxygen pressure of 25 mm Hg, and, thus, oxygen delivery is indicated. Decrease in P50 results in 24-percent decrease in oxygen delivery (55 percent- 42 percent 13 percent; 13/55 24 percent).
=
CHEST, 72: 2, AUGUST, 1977
=
coronary arterial disease who are receiving long-term oral therapy. 18 •19 Thus, our patient's P50 might even have been lower if he were not taking propranolol. The effect of depression of P50 and a leftward shift of the curve, regardless of its mechanism, is potentially deleterious. This degree of depression of P50 could deprive the myocardium of as much as 20 to 30 percent of the oxygen that would be delivered at a normal P50. This mechanism is illustrated in Figure 3. Although there are many factors other than P50 which influence the delivery of oxygen to the myocardium, the potential significance of this finding should not be ignored.
REFERENCES 1 Spain DM, Bradess VA: The relationship of coronary
thrombosis to coronary atherosclerosis and ischemic heart disease: A necropsy study covering a period of 25 years. Am J Med Sci 240:701-710, 1960 2 Spiekerman RE, Brandenburg JT, Achor RWP, et al: The spectrum of coronary heart disease in a community of 30,000: A clinicopathologic study. Circulation 25:57-65, 1962 3 Crawford T, Dexter D, Teare RD: Coronary artery pathology in sudden death from myocardial ischemia. Lancet 1:181-185, 1961 4 Vincent GM, Abildskov JA. Burgess MJ: QT interval syndromes. Prog Cardiovasc Dis 16-6:523-530, 1974 5 Kliks BR, Burgess, MJ, Abildskov JA: The influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Circulation 46 ( Suppl 2) : 115, 1972 (abstract) 6 Kolman BS, Verrier RL, Lown B: The effect of vagus nerve stimulation upon vulnerability of the canine ventricle. Circulation52:578-585, 1975 7 Longmuir IS, Chow J: Rapid method for determining effect of agents on oxyhemoglobin dissociation curves. J Appl Physiol 28:343-345, 1970 8 Keitt AS: Reduced nicotinamide adenine dinucleotidelinked analysis of 2,3 diphosphoglyceric acid: Spectrophotometric and fluorometric procedures. J Lab Clin Med 77:470-475, 1971 9 Cobb LA, Baum RS, Alvarez H III, et al: Resuscitation from out of hospital ventricular fibrillation: Four years followup. Circulation 52 ( suppl3) :223-228, 1975 10 Jervell A, Lange-Nielson F: Congenital deaf-mutism, functional heart disease, with prolongation of the qr interval and sudden death. Am Heart J 54:59-68, 1957 11 Fraser GR, Froggatt P, James TN: Congenital deafness associated with electrocardiographic abnormalities, fainting attacks and sudden death: A recessive syndrome. Q J Med 33:361-385, 1964 12 Barlow JB, Bosman CK, Cochrane JWC: Congenital cardiac arrhythmia. Lancet 2:531, 1964 13 Moss AJ, McDonald J: Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Engl J Med 285:903-904, 1971 14 Abildskov JA: The nervous system and cardiac arrhythmias. Circulation 52 (suppl3):116-119, 1975 15 Wellens HJJ, Vermeulen A, Durrer D: Ventricular fibrillation occurring on arousal from sleep by auditory stimuli. Circulation 46:661-665, 1972 16 Lown B, Temte JV, Reich P, et al: Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management. N Engl J Med 294:623-629, 1976
PRIMARY VENTRICULAR FIBRILLATION 237
17 Surawicz B: Role of electrolytes in etiology and management of cardiac arrhythmias. Prog Cardiovasc Dis 8:364386, 1966 18 Manchester J, Shelburne J, Oslci F, et al: Relationship of antianginal agents to hemoglobin-oxygen affinity. Circulation 45 ( suppl2): 109, 1972 (abstract) 19 Schrumpf JD, Sheps OS, et al: Effects oE propranolol on hemoglobin oxygen affinity in the anginal syndrome. Am J Cardiol33:170, 1974 (abstract)
Disseminated Histoplasmosis Followed by Disseminated Coccidioidomycosis• Peter Kapltm, M.D., F.C.C.P.; John R. Gravblll, M.D.; and Dtmlel Thor, M.D.
A case of dJIIemlnatecl hlltoplaanosll foDowecl later by c:occldfoldomyCOids Is described. 11ae cJin. lc:al IIIDess amd lmmllllOiolk lhldles ........ IIIIJde defecta that may bave alsted aatec:edent to IDfec:tioa 8DCI, thus, provided 1111 opportualty for widespread cU.sendnadoa by these IIOI'IIIally DODOpportualltk . . . Dl&ma. Poor c:orrelatloa ,... DOted betweea tbe c:llaiall c:oane amd in vitro teses of cell-mediated lmmDDity. dlllemfnatecl
A
lthough most patients exposed to fungi handle their infection without serious illness, some develop progressive and, at times, life-threatening disease. Recently, attention has been focused on the immunosuppressed host in whom mycotic and mycobacterial infections frequently occur. 1 · ' Occasionally, mixed fungal and mycobacterial infections occur in the same individual in whom no underlying neoplastic or immunosuppressed condition is apparent.M We report herein an unusual patient in whom disseminated coccicidioidomycosis occurred one year after he was treated for disseminated histoplasmosis. Immunologic evaluation suggested a subtle primary immune deficit that may have predisposed him to both infections.
CASE REPoRT A 35-year-old Caucasian man was previously hOIPitalized
in August 1971, with a three-week history of nonproductive
cough, fever, mya)gias, and headache. Physical enminatioo upon admission revealed a chronically ill man with inspiratory rales over the right anterior' portion of the chest and splenomegaly. On admission the chest ll:-ray 6lm showed a diffuse miliary pattern. Pertinent laboratory data included a white blood cell OOUDt oE 3,700/cu mm, with a normal •From the Department of Pulmonary Disease, United States Air Force Medical Center Scott, Scott Air Force Base, Dlinois; the Departments of Medicine, Nashville Veterans Administration Hospital and Vanderbilt University Hospital, Nashville, Tenn; and the Departments of Microbiology and Pathology, University of Texas Health Science Center, San Antonio. The views expressed herein are those of the authors and do not necessarily reflect the views of the United StateS Air Force or the Department of Defense. Reprint reqfA68ts: Dr. Kapltm, 320 Etue North Aoeooe, PitAburgh 15212
238 KAPLAN, GRAYBIU, THOR
differential count Hepatic function, renal function, the serum glucose level, the results of serum protein electrophoresis, and the findings from examinations of the cerebrospinal fluid were all normal Histoplasma capsulatum was cultured from blood, urine, sputum, bone marrow, and pulmonary aspirate. Therapy with amphotericin B was begun on the fourth day of hospitalization. The patient's condition rapidly improved, and within two weeks, he became asymptomatic and afebrile. Splenomegaly and anemia resolved, and his chest ll:-ray 61m cleared. Tbe patient received a total dose- of 1.5 gm of amphotericin B, with therapy finishing in November 1971. Subsequent fungal cultures were negative. The results of serial fungal serologic studies are summarized in Table 1. After leaving the hospital in March 1972, the patient was transferred to Arizona. In October 1972, he develaped transient cough, fever, mya)gias, and swelling of the left anlcle. The coccidioidin complement-fixation titer increased from 1:2 to 1:64. During November 1972, three cutaneous nodules appeared. The patient was hospitalized in December 1972 and, other than the cutaneous lesions, was totally asymptomatic. Physical examination revealed a healthy appearing man, With the only significant findings being three oval erythematous infiltrative lesions on the right side of his neck, his right uilla, and his badt. These varied from 1 to 2 em in diameter. Biopsy of the axillary lesion revealed granulomas, with Coccidioidu immUV seen on staining with methenamine silver. Cultures were also positive. At that time the patient had a 22-mm reaction to a skin test with a 1: 100 dilution of coccidioidin, as shown in Table 2. The skin test for mumps was positive on multiple occasions; however, the patient had negative results on tests with histoplasmin and Candida. The leukocyte count, results of serum electrophoresis, levels oE immunoglobulins and serum complement, chest ll:ray 61m, findings from a bone survey, and cerebrospinal fluid were all normal. Following a single injection of typhoid vaccine, the serum agglutination titer for Salmonella twho.a 0 antigen rose from less than 1:40 to more than 1:640. In December 1972, therapy with amphotericin B was reinstituted and was continued through June 1973, for a total dose of 3.2 gm. During therapy, gradual healing of the cutaneous lesions occurred, and the patient remained asymptomatic. Concurrent with the therapy with amphotericin B, the migration inhibiting factor converted from the previously negative response to an equivocally positive response one month larer, at a time when transformation response was clearly positive for coccidioidin (Table 2). During this period the patient's clinically mild cutaneous disease regressed. He remained free of clinically active lesions through January 1974. Interestingly, the complement-fixation titer (Table 1) fell to 1 :2 by May 1973, but later began to increase. In July and September 1973, a disturbing depression in transformation to coccidioidin was noted, and two months later, the patient lost his cutaneous reactivity to a 1 :100 dilution of
coocidioidbL
In January 1974, the patient returned, complaining of
diffuse low bade pain. A left paravertebral mass at the level
of Tl0-11 had become apparent radiographically. The cere- . brospinal fluid was normal. Lymphocyte transformation was normal, but response to a skin test with coccidioidin was positive only at the high concentration of 1:10. The complement-hation titer had risen to 1:64 by February. Lymphocyte transformation was selectively depressed to coccidioidin. A presumptive diagnosis of recurrent disseminated coccidioidomycosis was made, and therapy with amphorericin B was reinstituted. In March 1974, after 600 mg of amphotericin B
CHEST, 72: 2, AUGUST, 1977
A 47-year-old man experienced ventricular fibrDiation three times during a 31h-year pertod. Eacb episode was preceded by an auditory aura, and no ventricular Irritability was identified between episodes. Tbe results of COI'OII8ry arteriograpbic, hemodynamic, and lntracardiae electropbysiologic: studies were all normal. Hypokalemia and abnormal oxyhemoglobin dissodation were present. The possible relationships of tbese unusual features to tbe patient's disturbances in rbytbm are discussed. is current interest in identifying the factors T here which predispose to the occurrence of ventricular fibrillation. While the majority of individuals who develop this potentially lethal arrhythmia have coronary arterial disease as the underlying structural abnormality,l-8 recent evidence from both clinical studies and experimental studies in animals suggests that the central nervous system may play a role in the pathogenesis of this cardiac arrhythmia. This report presents evidence for a link between the central nervous system and the occurrence of ventricular fibrillation in the absence of identifiable organic heart disease. In addition to this relationship, noncardiac metabolic factors (hypokalemia and abnormal oxyhemoglobin dissociation) were observed in relationship to the disturbance in rhythm. CASE REPoRT
A 47-year-old white man was asymptomatic and in good health until May 1972, when he lost consciousness for the first time subsequent to a "ringing" sensation in his ears while °From the Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Fla. Supported in part from funds provided by National Heart and Lung Institute grant 1-R01-HL-18769-01 and by Florida Heart Association grant AG 424. Reprint requests: Dr. Sheps, Division of Cardiology, PO .Ben
520875,M~i33152
at rest. He was brought to the emergency room of a community hospital, where ventricular fibrillation was documented electrocardiographically. The patient underwent cardioversion to sinus rhythm. Findings from physical examination were within normal limits. There was no history of hypertension, rheumatic fever, diabetes, cardiac clicks or murmurs, chest pain, shortness of breath, or palpitations. Chest x-ray films and serial studies of cardiac enzyme levels were normal. Serial electrocardiograms revealed minor Twave changes in the anterior leads but no evolutionary changes of myocardial infarction. The patient remained in the hospital for three weeks and was treated with procaine amide hydrochloride ( 500 mg every three hours) . He was discharged on this regimen, and his condition remained stable for two months. In July 1972, the patient again noticed a "ringing" sensation in his ears while at rest, quickly followed by loss of consciousness. On arrival at a local hospital's emergency room, the patient was in ventricular fibrillation; he was defibrillated and returned to normal sinus rhythm. The results of cardiovascular examination, serial ECGs, and enzyme levels were normal. The patient was maintained on therapy with procaine amide hydrochloride ( 500 mg every three hours) and diphenylhydantoin ( 100 mg every four hours) . The serum concentration of potassium was 2.8 mEq/L and rose to nonJ)al levels with potassium supplementation. The patient had not been taking any diuretic drugs prior to admission. The urinary pH was 5. The patient was discharged after four weeks and did well until December 1974, when he stopped taking his medications. Two weeks later, while watching television, the patient experienced a "ringing" in his ears, quickly followed by vertigo and loss of consciousness. He was found to have ventricular fibrillation, which spontaneoulsy converted to atrial fibrillation with an irregular ventricular response (Fig 1 ) . The serum level of potassium was 3.4 mEq/L. Findings from physical examination and laboratory studies were unrema.rlcable. After four days of hospitalization, the patient was transferred to Jackson Memorial Hospital for further workup. In January 1975, the patient underwent cardiac catheterization. Findings from hemodynamic and left ventriculographic studies were normal. Selective coronary arteriograms revealed a normal dominant right system. Intracardiac electrophysiologic studies revealed a normal P-R interval ( 170 msec), an atrio-His interval of 105 msec, and His-ventricle interval of 45 msec. Repetitive pacemaker stimuli were applied at 10-msec intervals during diastole (including application during the T wave) at a stimulus strength up to 15 times the diasrolic threshold. Neither ventricular tachycardia
12/21/74 1:45 A.l.
I
.I
TO ;IAL IFI!.
111111
FxcURE 1. One of multiple episodes of ventricular fibrillation. Top, Ventricular fibrillation with spontaneous reversion to atrial fibrillation. Bottom, Ventricular premature contractions did not precede or follow episodes like this.
CHEST, 72: 2, AUGUST, 1977
PRIMARY VENTRICULAR FIBRILLAnON 235
nor ventricular fibrillation was produced. Atrial and ventricular stimulation at varying cycle lengths and coupling intervals produced no arrhythmias. The patient was discharged on a regimen of diphenylhydantoin ( 100 mg four times per day) and propranolol ( 40 mg four times per day) and returned to work. He did well until May 1975, when he again stopped taking his medications. On the night of admission, the patient had had two blackout spells, both preceded by "ringing" in his ears. He was transferred to the emergency room, where he had ventricular tachycardia requiring cardioversion. Again, findings from physical examination and routine laboratory studies were normal. The findings from electroencephalograms with the patient awake and asleep and during otic and photic stimulation were within normal limits. Simultaneous electrocardiographic monitoring failed to reveal cardiac arrhythmias.
Oxyhemoglobin dissociation curves7 and red blood cell levels of 2,3-diphosphoglyceric acidS were determined on two separate occasions. Measurements of the partial pressure of oxygen at which hemoglobin is 50 percent saturated ( PSO) obtained while the patient was clinically stable were 22.5 mm Hg and 23.5 mm Hg, respectively (normal. 27 ± 1 mm Hg), and the level of 2,3-diphosphoglyceric acid was 4.~oVml (normal, 4.8 ± 0.3/illloVml of packed cells). Levels of carbon monoxide were 8 percent and 3.5 percevt, the hemoglobin level was 13 gm/100 mi. and the results of hemoglobin electrophoresis were normal. Several 12-hour ambulatory electrocardiographic recordings revealed no evidence o£ arrhythmia. DiscuSSION
The sequence of events observed in this patient demonstrates several unique and interesting features. The mere survival from multiple episodes of ventricular fibrillation occurring in the patient's home is noteworthy. 9 Other interesting features observed in this patient were an auditory aura preceding the episodes of ventricular fibrillation, the presence of hypokalemia on admission to the hospital in each instance, and an abnormality of oxyhemoglobin dissociation resulting in increased affinity of hemoglobin for oxygen. The most likely underlying causes for ventricular fibrillation in a man of this age are coronary arterial disease or cardiomyopathy. Since this patient had no
angiographic evidence of coronary arterial disease and completely normal hemodynamic and electrophysiologic findings at cardiac catheterization, he falls into the group of patients included in the category of primary ventricular fibrillation. We do not believe that this patient falls into the subgroup of any of the known hereditary syndromes that are reported with prolonged Q-T intervals, with or without hereditary deafness, 10- 13 since the patient's Q-T interval has never been found to be prolonged, even immediately after defibrillation, and his hearing has been demonstrated to be totally intact; however, we believe that there is a neurogenic link in the pathophysiology of the disturbance in rhythm, suggested by the aura of "ringing" in the ears prior to each episode. This aura has never been noted at any other time by the patient. It has been recently postulated that neurogenic mechanisms may play a role in patients with transient nonischemic changes in the T wave (such as those seen in this patient [Fig 2]), even without prolongation of the Q-T interval. Similar changes have been experimentally produced with stimulation of the right stellate ganglion.a The auditory aura is reminiscent of a case report by Wellens et al16 of a young girl in whom ventricular fibrillation was precipitated by the ringing of an alarm clock. That case was successfully treated with administration of propranolol, and because of the similarities to our case, our patient was started on therapy with propranolol. Recently, Lown et al16 have reported a case of recurrent ventricular fibriUation without demonstrable heart disease, which was very similar to ours. They were able to demonstrate an increased frequency of ventricular premature contractions with REM sleep and a decrease with meditation. These investigators hypothesized that instantaneous death might be triggered by neural mechanisms. Our case differs in one important respect, ie, the absence of ventricular premature contractions between episodes of ventricular fibrillation. Another interesting finding is hypokalemia on each admission for ventricular fibrillation. We have no explanation for this. The patient did not have renal tubular
FIGURE 2. Top, ECG obtained following episode of ventricular fibrillation. Note marked T-wave inversion in leads Vt, V2, and V6. Bottom, ECG obtained during asymptomatic period, showing regression of T -wave abnormalities. The Q-T interval is within normal limits in both tracings.
236 SHEPS ET AL
CHEST, 72: 2, AUGUST, 1971
acidosis, was not taking diuretic drugs, and did not have gastrointestinal losses or alkalosis to account for this electrolyte abnormality. In addition, the serum level of potassium was normal on numerous occasions when the patient was clinically stable. Regardless of the cause of the hypokalemia, it affects the transmembrane action potential and predisposes to atrial and ventricular irritability;17 however, without further evidence in this particular patient, this consideration must remain conjec-
tural. Delivery of myocardial oxygen was evaluated by means of oxyhemoglobin dissociation curves. The P50 represents the partial pressure of oxygen at which hemoglobin is 50 percent saturated and thus is a measure of the position of the oxyhemoglobin dissociation curve. An increase in P50 or a shift to the right of the curve will facilitate the delivery of oxygen to tissues; and conversely, a decrease in P50 or a shift to the left of the curve will inhibit release to tissues at a given oxygen pressure. While the possibility exists that a primary abnormality in oxyhemoglobin dissociation was present in this patient, there are other important considerations. Most of the decrease in the measured P50 can be explained by the patient's elevated carbon monoxide levels; however, the patient was also taking propranolol at the time this measurement was made. Propranolol has been shown to elevate P50 in normal subjects and in patients with
~RCENT
Oz Delivery
OXYHEMOGLOBIN
42"
Pso-t&.s(nl) 55%
2
FIGURE 3. Solid line illustrates normal oxyhemoglobin dissociation curve. Broken line represents our patient's curve. Degree of saturation at typical myocardial oxygen pressure of 25 mm Hg, and, thus, oxygen delivery is indicated. Decrease in P50 results in 24-percent decrease in oxygen delivery (55 percent- 42 percent 13 percent; 13/55 24 percent).
=
CHEST, 72: 2, AUGUST, 1977
=
coronary arterial disease who are receiving long-term oral therapy. 18 •19 Thus, our patient's P50 might even have been lower if he were not taking propranolol. The effect of depression of P50 and a leftward shift of the curve, regardless of its mechanism, is potentially deleterious. This degree of depression of P50 could deprive the myocardium of as much as 20 to 30 percent of the oxygen that would be delivered at a normal P50. This mechanism is illustrated in Figure 3. Although there are many factors other than P50 which influence the delivery of oxygen to the myocardium, the potential significance of this finding should not be ignored.
REFERENCES 1 Spain DM, Bradess VA: The relationship of coronary
thrombosis to coronary atherosclerosis and ischemic heart disease: A necropsy study covering a period of 25 years. Am J Med Sci 240:701-710, 1960 2 Spiekerman RE, Brandenburg JT, Achor RWP, et al: The spectrum of coronary heart disease in a community of 30,000: A clinicopathologic study. Circulation 25:57-65, 1962 3 Crawford T, Dexter D, Teare RD: Coronary artery pathology in sudden death from myocardial ischemia. Lancet 1:181-185, 1961 4 Vincent GM, Abildskov JA. Burgess MJ: QT interval syndromes. Prog Cardiovasc Dis 16-6:523-530, 1974 5 Kliks BR, Burgess, MJ, Abildskov JA: The influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Circulation 46 ( Suppl 2) : 115, 1972 (abstract) 6 Kolman BS, Verrier RL, Lown B: The effect of vagus nerve stimulation upon vulnerability of the canine ventricle. Circulation52:578-585, 1975 7 Longmuir IS, Chow J: Rapid method for determining effect of agents on oxyhemoglobin dissociation curves. J Appl Physiol 28:343-345, 1970 8 Keitt AS: Reduced nicotinamide adenine dinucleotidelinked analysis of 2,3 diphosphoglyceric acid: Spectrophotometric and fluorometric procedures. J Lab Clin Med 77:470-475, 1971 9 Cobb LA, Baum RS, Alvarez H III, et al: Resuscitation from out of hospital ventricular fibrillation: Four years followup. Circulation 52 ( suppl3) :223-228, 1975 10 Jervell A, Lange-Nielson F: Congenital deaf-mutism, functional heart disease, with prolongation of the qr interval and sudden death. Am Heart J 54:59-68, 1957 11 Fraser GR, Froggatt P, James TN: Congenital deafness associated with electrocardiographic abnormalities, fainting attacks and sudden death: A recessive syndrome. Q J Med 33:361-385, 1964 12 Barlow JB, Bosman CK, Cochrane JWC: Congenital cardiac arrhythmia. Lancet 2:531, 1964 13 Moss AJ, McDonald J: Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Engl J Med 285:903-904, 1971 14 Abildskov JA: The nervous system and cardiac arrhythmias. Circulation 52 (suppl3):116-119, 1975 15 Wellens HJJ, Vermeulen A, Durrer D: Ventricular fibrillation occurring on arousal from sleep by auditory stimuli. Circulation 46:661-665, 1972 16 Lown B, Temte JV, Reich P, et al: Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management. N Engl J Med 294:623-629, 1976
PRIMARY VENTRICULAR FIBRILLATION 237
17 Surawicz B: Role of electrolytes in etiology and management of cardiac arrhythmias. Prog Cardiovasc Dis 8:364386, 1966 18 Manchester J, Shelburne J, Oslci F, et al: Relationship of antianginal agents to hemoglobin-oxygen affinity. Circulation 45 ( suppl2): 109, 1972 (abstract) 19 Schrumpf JD, Sheps OS, et al: Effects oE propranolol on hemoglobin oxygen affinity in the anginal syndrome. Am J Cardiol33:170, 1974 (abstract)
Disseminated Histoplasmosis Followed by Disseminated Coccidioidomycosis• Peter Kapltm, M.D., F.C.C.P.; John R. Gravblll, M.D.; and Dtmlel Thor, M.D.
A case of dJIIemlnatecl hlltoplaanosll foDowecl later by c:occldfoldomyCOids Is described. 11ae cJin. lc:al IIIDess amd lmmllllOiolk lhldles ........ IIIIJde defecta that may bave alsted aatec:edent to IDfec:tioa 8DCI, thus, provided 1111 opportualty for widespread cU.sendnadoa by these IIOI'IIIally DODOpportualltk . . . Dl&ma. Poor c:orrelatloa ,... DOted betweea tbe c:llaiall c:oane amd in vitro teses of cell-mediated lmmDDity. dlllemfnatecl
A
lthough most patients exposed to fungi handle their infection without serious illness, some develop progressive and, at times, life-threatening disease. Recently, attention has been focused on the immunosuppressed host in whom mycotic and mycobacterial infections frequently occur. 1 · ' Occasionally, mixed fungal and mycobacterial infections occur in the same individual in whom no underlying neoplastic or immunosuppressed condition is apparent.M We report herein an unusual patient in whom disseminated coccicidioidomycosis occurred one year after he was treated for disseminated histoplasmosis. Immunologic evaluation suggested a subtle primary immune deficit that may have predisposed him to both infections.
CASE REPoRT A 35-year-old Caucasian man was previously hOIPitalized
in August 1971, with a three-week history of nonproductive
cough, fever, mya)gias, and headache. Physical enminatioo upon admission revealed a chronically ill man with inspiratory rales over the right anterior' portion of the chest and splenomegaly. On admission the chest ll:-ray 6lm showed a diffuse miliary pattern. Pertinent laboratory data included a white blood cell OOUDt oE 3,700/cu mm, with a normal •From the Department of Pulmonary Disease, United States Air Force Medical Center Scott, Scott Air Force Base, Dlinois; the Departments of Medicine, Nashville Veterans Administration Hospital and Vanderbilt University Hospital, Nashville, Tenn; and the Departments of Microbiology and Pathology, University of Texas Health Science Center, San Antonio. The views expressed herein are those of the authors and do not necessarily reflect the views of the United StateS Air Force or the Department of Defense. Reprint reqfA68ts: Dr. Kapltm, 320 Etue North Aoeooe, PitAburgh 15212
238 KAPLAN, GRAYBIU, THOR
differential count Hepatic function, renal function, the serum glucose level, the results of serum protein electrophoresis, and the findings from examinations of the cerebrospinal fluid were all normal Histoplasma capsulatum was cultured from blood, urine, sputum, bone marrow, and pulmonary aspirate. Therapy with amphotericin B was begun on the fourth day of hospitalization. The patient's condition rapidly improved, and within two weeks, he became asymptomatic and afebrile. Splenomegaly and anemia resolved, and his chest ll:-ray 61m cleared. Tbe patient received a total dose- of 1.5 gm of amphotericin B, with therapy finishing in November 1971. Subsequent fungal cultures were negative. The results of serial fungal serologic studies are summarized in Table 1. After leaving the hospital in March 1972, the patient was transferred to Arizona. In October 1972, he develaped transient cough, fever, mya)gias, and swelling of the left anlcle. The coccidioidin complement-fixation titer increased from 1:2 to 1:64. During November 1972, three cutaneous nodules appeared. The patient was hospitalized in December 1972 and, other than the cutaneous lesions, was totally asymptomatic. Physical examination revealed a healthy appearing man, With the only significant findings being three oval erythematous infiltrative lesions on the right side of his neck, his right uilla, and his badt. These varied from 1 to 2 em in diameter. Biopsy of the axillary lesion revealed granulomas, with Coccidioidu immUV seen on staining with methenamine silver. Cultures were also positive. At that time the patient had a 22-mm reaction to a skin test with a 1: 100 dilution of coccidioidin, as shown in Table 2. The skin test for mumps was positive on multiple occasions; however, the patient had negative results on tests with histoplasmin and Candida. The leukocyte count, results of serum electrophoresis, levels oE immunoglobulins and serum complement, chest ll:ray 61m, findings from a bone survey, and cerebrospinal fluid were all normal. Following a single injection of typhoid vaccine, the serum agglutination titer for Salmonella twho.a 0 antigen rose from less than 1:40 to more than 1:640. In December 1972, therapy with amphotericin B was reinstituted and was continued through June 1973, for a total dose of 3.2 gm. During therapy, gradual healing of the cutaneous lesions occurred, and the patient remained asymptomatic. Concurrent with the therapy with amphotericin B, the migration inhibiting factor converted from the previously negative response to an equivocally positive response one month larer, at a time when transformation response was clearly positive for coccidioidin (Table 2). During this period the patient's clinically mild cutaneous disease regressed. He remained free of clinically active lesions through January 1974. Interestingly, the complement-fixation titer (Table 1) fell to 1 :2 by May 1973, but later began to increase. In July and September 1973, a disturbing depression in transformation to coccidioidin was noted, and two months later, the patient lost his cutaneous reactivity to a 1 :100 dilution of
coocidioidbL
In January 1974, the patient returned, complaining of
diffuse low bade pain. A left paravertebral mass at the level
of Tl0-11 had become apparent radiographically. The cere- . brospinal fluid was normal. Lymphocyte transformation was normal, but response to a skin test with coccidioidin was positive only at the high concentration of 1:10. The complement-hation titer had risen to 1:64 by February. Lymphocyte transformation was selectively depressed to coccidioidin. A presumptive diagnosis of recurrent disseminated coccidioidomycosis was made, and therapy with amphorericin B was reinstituted. In March 1974, after 600 mg of amphotericin B
CHEST, 72: 2, AUGUST, 1977
