Blood Pressure Response to the Valsalva Maneuver in Pheochromocytoma and Pseudopheochromocytoma
Abstract To elucidate whether a difference in blood pressure reactivity exists between patients with pheochromocytoma (n=8) and pseudopheochromocytoma (n=22), we evaluated blood pressure changes during a Valsalva maneuver and baroreceptor reflex sensitivity. We also examined the effects of propranolol and prazosin on blood pressure reactivity during a Valsalva maneuver in patients with pseudopheochromocytoma. Pseudopheochromocytoma was defined as a paroxysmal rise in blood pressure accompanying pheochromocytoma-like symptoms and normal catecholamine values. The difference in systolic blood pressure between phase IV of the Valsalva maneuver and baseline (ΔSBP) was markedly smaller in the pheochromocytoma patients (8.4±18.4 mm Hg) than in the essential hypertension patients (n=30, 30.9±19.4 mm Hg) and normotensive control subjects (n=10, 31.3±11.4 mm Hg), whereas ΔSBP in the pseudopheochromocytoma patients (77.8±11.2 mm Hg) was markedly greater than in the other three groups. ΔSBP was markedly suppressed by the administration of both propranolol and prazosin. Baroreceptor reflex sensitivity index was lower in the pheochromocytoma group than in the other three groups. In conclusion, blood pressure reactivity responses to a Valsalva maneuver are disparate between pheochromocytoma and pseudopheochromocytoma. The high blood pressure reactivity to a Valsalva maneuver in pseudopheochromocytoma is due to hyperactivity in both β- and α1-adrenergic receptor functions, and the low blood pressure reactivity to a Valsalva maneuver in pheochromocytoma seems to be mainly due to the desensitization of both adrenergic systems associated with chronic catecholamine excess. In addition, the impaired baroreceptor function in pheochromocytoma is partially responsible for it.
Pheochromocytoma is a rare but important cause of clinical hypertension because when unrecognized it is potentially lethal.1 In addition, pheochromocytoma is one of the most often suspected but least frequently confirmed causes of secondary hypertension. On the other hand, many patients have symptoms and signs suggestive of pheochromocytoma but have a different condition called pseudopheochromocytoma.2 Awareness of the existence of pseudopheochromocytoma may help physicians in choosing effective medication and preventing unnecessary surgical exploration in patients strongly suspected of harboring a pheochromocytoma.3 The clinical similarity of the sudden rise of blood pressure in pheochromocytoma and pseudopheochromocytoma creates a diagnostic dilemma. The diagnosis of pheochromocytoma is based on biochemical evidence of excessive release of catecholamines, but a minority of patients with pheochromocytoma have normal plasma catecholamine levels under resting conditions,4 and high plasma levels of catecholamines can be observed in many clinical conditions.5 6
Many patients with pseudopheochromocytoma are responsive to treatment with β-adrenergic blocking drugs,3 but usually these patients are not responsive to them. This finding suggests that the procedures that stimulate the β-adrenergic receptor can differentiate pseudopheochromocytoma from pheochromocytoma. During a Valsalva maneuver, a rapid and marked change of blood pressure occurs, and this change is markedly modified by the use of β-adrenergic blocking drugs.7
In this study, we compared blood pressure reactivity during a Valsalva maneuver between patients with pseudopheochromocytoma and pheochromocytoma. The effects of β- and α1-adrenergic blocking drugs on the blood pressure response to a Valsalva maneuver were also studied.
Thirty patients were referred to our hospital because of symptoms and signs suggesting pheochromocytoma. Of the 30 patients, 22 did not have pheochromocytoma, based on diagnostic testing, including assays of catecholamines in plasma and urine and computed tomographic scans. Other secondary forms of hypertension were also eliminated. The remaining 8 patients (6 men and 2 women) had histologically proved pheochromocytoma. Clinical findings in 22 patients who had symptoms and signs suggesting pheochromocytoma but were determined to have pseudopheochromocytoma2 are shown in Table 1⇓. Common findings in this group were a repetition of paroxysmal rise in blood pressure accompanying palpitation, chest pain, headache, faintness, sweating, nausea, or vomiting, and a normal range of plasma catecholamine values. Hypertension, defined as systolic blood pressure (SBP) greater than 160 mm Hg and/or diastolic blood pressure (DBP) greater than 95 mm Hg in the outpatient clinic,8 was observed in 8 patients (36%). A family history of hypertension was observed in 7 patients (32%).
Table 2⇓ profiles 8 patients with pheochromocytoma. One patient (patient 7) had almost normal baseline catecholamine levels but showed a positive glucagon test. Another patient (patient 5) had a family history of pheochromocytoma.
Thirty patients (21 men and 9 women) with essential hypertension who had no such symptoms and signs as observed in patients with pseudopheochromocytoma served as controls. The mean age of this group was 47±10 years. Mean SBP and DBP values in this group were 174±20 and 103±16 mm Hg, respectively. Ten normotensive volunteers (8 men and 2 women) who had no history of hypertension and no abnormalities on physical examinations, electrocardiogram, chest x-ray film, or echocardiogram also served as controls. The mean age of this group was 48±6 years.
Of 8 patients with pheochromocytoma, 1 patient had received 20 mg/d nifedipine; 1 had received a combination of 25 mg/d captopril, 1.5 mg/d prazosin, and 20 mg/d nifedipine; 1 had received 10 mg/d carteolol; and 1 had received 25 mg/d captopril. The other 4 patients had received no medical treatment. The hemodynamic testing for the former 4 patients was carried out when patients were asymptomatic after medication had been discontinued for at least 1 week. Hemodynamic testing in patients with pseudopheochromocytoma and essential hypertension who had received medical therapy was carried out after medication had been discontinued for at least 1 week.
All subjects participated in this study after giving informed consent.
Blood Pressure Measurement and Valsalva Maneuver
Blood pressure during a Valsalva maneuver was measured directly with a catheter introduced percutaneously into the left brachial artery. The Valsalva maneuver was begun after subjects had rested 15 minutes after insertion of the catheter. Blood pressure was not significantly different before and after catheter insertion. The subject was told how to perform the Valsalva maneuver and then asked to perform the maneuver at the end of an inspiratory effort. The effectiveness of the procedure was assessed by noting whether the subject developed a florid face, distended neck veins, and increased abdominal muscle wall tone. After 10 seconds, the subject was instructed to relax the abdomen and resume normal quiet breathing. After the first study, 20 patients with pseudopheochromocytoma, 26 patients with essential hypertension, and 10 normotensive control subjects rested for at least 15 minutes or until heart rate and blood pressure had returned to control levels. Thereafter, propranolol (0.1 mg/kg body wt IV) was administered over 5 minutes, and the subject was allowed to rest for 10 minutes. Then, an identical Valsalva maneuver was performed. After the first study, 1 mg prazosin was administered orally to 2 patients with pseudopheochromocytoma and 4 patients with essential hypertension. The patients were allowed to rest for 60 minutes, after which an identical study was performed.
From the blood pressure response to a Valsalva maneuver, two indexes were measured as shown in Fig 1⇓. One was change in SBP (ΔSBP), which was calculated as the difference between peak SBP at phase IV and SBP at control level. The other was “recovery time,” defined as the interval from the point of peak SBP to the point at which SBP returned to control levels.
Measurement of Baroreceptor Reflex Sensitivity Index
Baroreceptor reflex sensitivity index was calculated from phase IV of the Valsalva maneuver as reported by Palmero et al.9 A first Valsalva maneuver was recorded at a lower paper speed to evaluate the hemodynamic response, and a second one was recorded at 50 mm/s to determine the change of the RR interval of the electrocardiogram and SBP. Each SBP measurement was plotted against the RR interval following it. The linear relation between SBP and RR interval was calculated where the regression coefficient corresponded to the index of baroreceptor sensitivity.
Measurement of Plasma Norepinephrine and Epinephrine
Blood samples for measurement of plasma norepinephrine and epinephrine levels were drawn through an indwelling plastic catheter inserted into the left brachial artery. Plasma norepinephrine and epinephrine were measured using high-speed ion-exchange column chromatography.10
Measurement of Hemodynamic Parameters
Echocardiographic studies were carried out using an SSD-870 echocardiograph with a 3.5-MHz transducer (ALOKA, Tokyo, Japan). M-mode echocardiographic recordings were made while the cardiac anatomy was visualized by two-dimensional echocardiography. Electrocardiogram, phonocardiogram, carotid pulse tracing, and M-mode echocardiogram were simultaneously recorded at a paper speed of 100 mm/s. Mean velocity of circumferential shortening (mVCF), ejection fraction (EF), stroke volume (SV), cardiac output (CO), and preejection period (PEP) were calculated from the following formulas: mVCF=Dd-Ds/Dd×LVET, where Dd, Ds, and LVET are left ventricular end-diastolic and end-systolic dimensions and left ventricular ejection time, respectively; EF=EDV−ESV/EDV, where EDV and ESV are end-diastolic and end-systolic volumes measured by Teichholz’s method; SV=EDV−ESV; CO=SV×HR, where HR is heart rate; and PEP=Q-II−LVET, where Q-II is electromechanical systole. SV and CO were corrected by body surface area (stroke index and cardiac index, respectively).
Values in the text and tables are mean±SD. Statistical evaluation was performed by ANOVA, and subsequent comparisons between group mean values were performed using Duncan’s multiple range test. A value of P<.05 was considered significant.
Fig 2⇓ shows the representative patterns of Valsalva reactions in a normotensive control subject, an essential hypertension patient, a pseudopheochromocytoma patient, and a pheochromocytoma patient. A marked elevation of blood pressure in overshoot phase was observed in the pseudopheochromocytoma patient, and no significant overshoot was observed in the pheochromocytoma patient. Fig 3⇓ shows ΔSBP in normotensive control subjects and essential hypertension, pseudopheochromocytoma, and pheochromocytoma patients. ΔSBP in pseudopheochromocytoma patients was significantly greater than in normotensive control subjects and essential hypertension patients, but ΔSBP in pheochromocytoma patients was significantly smaller than in normotensive control subjects and essential hypertension patients. There was no overlap in ΔSBP between patients with pheochromocytoma and pseudopheochromocytoma. Of the pheochromocytoma patients, only one patient, whose norepinephrine level was normal and epinephrine level was slightly high at baseline, showed a normal blood pressure response to the Valsalva maneuver. A marked reduction in overshoot in pheochromocytoma patients returned to normal in approximately 1 month after the operation. ΔSBP in all pseudopheochromocytoma patients was greater than 50 mm Hg. On the other hand, ΔSBP of greater than 50 mm Hg was observed in only 5 of 30 (17%) essential hypertension patients.
Recovery time was significantly longer in pseudopheochromocytoma patients (85±38 milliseconds) than in normotensive control subjects (20±12 milliseconds) and essential hypertension patients (22±23 milliseconds) but was markedly shorter in pheochromocytoma patients (8±15 milliseconds) than in the other three groups.
Plasma norepinephrine and epinephrine levels under basal conditions were 156±65 and 61±43 pg/mL, respectively, in pseudopheochromocytoma patients, 155±58 and 64±40 pg/mL in essential hypertension patients, and 165±46 and 59±27 pg/mL in normotensive control subjects. There were no significant differences in plasma norepinephrine and epinephrine levels among pseudopheochromocytoma and essential hypertension patients and normotensive control subjects. Both catecholamine levels during the attack episode in pseudopheochromocytoma patients were higher than at rest, but both remained within normal limits as shown in Table 1⇑.
Baroreceptor reflex sensitivity index showed no significant differences among pseudopheochromocytoma and essential hypertension patients and normotensive control subjects, as shown in Fig 4⇓. However, baroreceptor reflex sensitivity index was significantly lower in pheochromocytoma patients than in the other three groups.
Data of hemodynamic parameters in normotensive control subjects and essential hypertension and pseudopheochromocytoma patients are shown in Table 3⇓. Preejection period in essential hypertension patients was longer than in normotensive control subjects and pseudopheochromocytoma patients, but other hemodynamic parameters showed no significant differences among the three groups. Pseudopheochromocytoma patients did not show the hyperdynamic contraction.
Effects of propranolol on ΔSBP and baroreceptor reflex sensitivity index were examined. Both SBP and DBP were unchanged after the administration of propranolol. As shown in Fig 5⇓, ΔSBP decreased in all subjects. Baroreceptor reflex sensitivity index showed no significant change before and after the administration of propranolol in pseudopheochromocytoma and essential hypertension patients and normotensive control subjects (Fig 4⇑). After the administration of prazosin, SBP decreased from 153.0±11.0 to 135.5±8.5 mm Hg, and DBP decreased from 91.3±6.3 to 82.7±7.1 mm Hg. As shown in Fig 6⇓, ΔSBP was markedly suppressed by the oral administration of prazosin. ΔSBP in patients 21 and 22 with pseudopheochromocytoma was changed from 96 to 26 mm Hg and from 90 to 18 mm Hg, respectively. Mean ΔSBP in four essential hypertension patients was also decreased from 32.2±5.4 to 14.4±2.6 mm Hg by the oral administration of prazosin.
Our results indicate that blood pressure reactivity responses to a Valsalva maneuver are disparate between patients with pheochromocytoma and pseudopheochromocytoma. Blood pressure response in phase IV to the Valsalva maneuver in pseudopheochromocytoma patients was greater, and inversely that in pheochromocytoma patients was smaller than that in normotensive control subjects and essential hypertension patients. The exaggerated blood pressure response in pseudopheochromocytoma patients was attenuated by the administration of both propranolol and prazosin. This increased blood pressure response in pseudopheochromocytoma patients is not related to basal plasma catecholamine levels, cardiac function and performance, or baroreceptor reflex sensitivity. On the other hand, the decreased blood pressure response in pheochromocytoma patients may be partially related to impaired baroreceptor function.
Clinical profiles of the pseudopheochromocytoma patients in this study are similar to those in patients reported by Kuchel et al2 3 and Takabatake et al11 and are different from those in patients with a hyperdynamic β-adrenergic circulating state12 13 or hyperkinetic type of borderline hypertension14 15 in several ways. First, a characteristic in our patients is the paroxysmal elevation of blood pressure accompanied by various symptoms imitating pheochromocytoma. This paroxysmal hypertension is not observed in patients with a hyperdynamic β-adrenergic circulating state or hyperkinetic type of borderline hypertension. Second, the age of pseudopheochromocytoma patients is widely distributed, as shown in the present study, but patients who are in a hyperdynamic β-adrenergic state are usually young. Third, cardiac function and performance in our pseudopheochromocytoma patients and patients reported by Takabatake et al11 were normal, but in patients showing a hyperdynamic β-adrenergic state or hyperkinesis of the left ventricle, cardiac function and performance are in a high-output state. Incidentally, hemodynamic characteristics in pheochromocytoma patients include a marked shortening of electromechanical systole and left ventricular ejection time and normal preejection period. Low cardiac index, low stroke index, and high total peripheral resistance index are also characteristics in pheochromocytoma.16 Fourth, the blood pressure response to a Valsalva maneuver in our patients was markedly exaggerated but was within normal limits in patients reported by Frohlich et al.13 Thus, there is a marked difference in pathophysiological condition between patients with pseudopheochromocytoma and patients with a hyperdynamic state, although β-adrenergic blocking drugs are effective in both types of patients.
It is known that β-adrenergic blocking drugs influence hemodynamic responses to a Valsalva maneuver such as the attenuation of the increase in blood pressure during the overshoot7 and the prevention of Valsalva-induced ventricular arrhythmia in patients with long QT syndrome.17 The decrease in myocardial contractility and heart rate caused by the administration of β-adrenergic blocking drugs seems to be closely related to the decrease in stroke volume and cardiac output, resulting in a decrease in blood pressure overshoot. It is also known that ΔSBP during a Valsalva maneuver is markedly influenced by the condition of the heart. The height of SBP overshoot is also related to the left ventricular ejection fraction, and the overshoot is not observed in patients with heart failure.18 As shown in Table 3⇑, however, there were no differences in left ventricular ejection fraction, stroke index, cardiac index, and basal catecholamine levels among pseudopheochromocytoma and essential hypertension patients and normotensive control subjects. The difference in overshoot among the three groups seems to be mainly caused by the difference in β-adrenergic receptor function in each group. Thus, the exaggerated blood pressure response to a Valsalva maneuver in pseudopheochromocytoma patients seems to be mainly caused by the hyperactivity of the β-adrenergic receptor–mediated system. Furthermore, this is the reason why β-adrenergic blocking drugs are effective in the treatment of pseudopheochromocytoma patients.
Previously, we reported that α1-adrenergic receptor function was closely related to the blood pressure response to isometric handgrip exercise and that the increased α1-adrenergic receptor function was mainly responsible for the exaggerated blood pressure response to handgrip exercise in essential hypertension patients.19 In the present study, we showed that blood pressure change during phase IV of a Valsalva maneuver was also related to α1-adrenergic receptor function. Blood pressure overshoot in phase IV was markedly suppressed in both pseudopheochromocytoma and essential hypertension patients. This finding indicates that sufficient vascular tone mediated by α1-adrenergic receptors was necessary to maintain blood pressure during phase IV of the Valsalva maneuver. However, further examination must be done to determine whether the augmented α1-adrenergic receptor function itself is one of the responsible factors for the exaggerated blood pressure response during phase IV in pseudopheochromocytoma patients.
On the other hand, blood pressure response during phase IV of the Valsalva maneuver is markedly suppressed in pheochromocytoma patients. Decreased baroreceptor reflex sensitivity index in pheochromocytoma patients seems to be one of the reasons for the suppression of blood pressure elevation in response to a Valsalva maneuver. In addition, it is acknowledged that desensitization of adrenergic functions is observed in pheochromocytoma patients.20 This is another reason why the lack of overshoot in blood pressure during a Valsalva maneuver is observed in pheochromocytoma patients. Only one of the pheochromocytoma patients whose norepinephrine level was normal showed a normal blood pressure response. In addition, an abnormal blood pressure response during the Valsalva maneuver returned to normal in more than 1 month after the resection of the pheochromocytoma. These findings support the fact that the abnormal blood pressure response to a Valsalva maneuver is closely related to malfunctions of adrenergic receptor–mediated systems associated with chronic catecholamine excess from pheochromocytoma, such as the homogeneous and heterogeneous desensitizations of the adrenergic receptor system.
In the present study, we showed that there was a marked difference in the mechanism for the appearance of symptoms or signs of pseudopheochromocytoma and pheochromocytoma. Symptoms or signs in the former are due to the hyperactivity in both β- and α1-adrenergic receptor functions, and those in the latter may be due to the desensitization of the β- and α1-adrenergic systems associated with chronic catecholamine excess. Thus, β- or α1-adrenergic blocking drugs are helpful in relieving symptoms in pseudopheochromocytoma patients. On the other hand, the use of β-adrenergic blocking drugs alone in pheochromocytoma patients is dangerous because of the stimulation of the α-adrenergic receptor–mediated system. The Valsalva maneuver is easy to perform; therefore, it may be useful in assessing the effect of treatment with β-blocking drugs of pseudopheochromocytoma patients.
- Received November 8, 1993.
- Revision received December 14, 1993.
- Accepted October 17, 1994.
Kaplan NM. Pheochromocytoma (with a preface about incidental adrenal masses). In: Clinical Hypertension. Baltimore, Md: Williams & Wilkins; 1990:350-367.
Kuchel O. Pseudopheochromocytoma. Hypertension. 1985;7:151-158.
Kuchel O, Buu NT, Hamet P, Larochelle P, Bourque M, Genet J. Essential hypertension with low conjugated catecholamines imitates pheochromocytoma. Hypertension. 1981;3:347-355.
Kopin IJ, Lake RC, Ziegler M. Plasma levels of norepinephrine. Ann Intern Med. 1978;88:671-680.
Plouin PF, Duclos JM, Menard J, Comoy E, Bohuon C, Alexandre JM. Biochemical tests for diagnosis of pheochromocytoma: urinary versus plasma determinations. Br Med J. 1981;282:853-854.
Frohlich ED, Dunn FG, Messerli FH. Pharmacologic and physiologic considerations of adrenoceptor blockade. Am J Med. 1983:75:9-14.
Report of a WHO Expert Committee. Arterial hypertension. WHO Tech Rep Ser. 1978;628:9.
Palmero HA, Caeiro TF, Iosa DJ, Bas J. Baroreceptor reflex sensitivity index derived from phase 4 of the Valsalva maneuver. Hypertension. 1981;3(suppl II):II-134-II-137.
Julius S, Pascual AV, London R. Role of parasympathetic inhibition in the hyperkinetic type of borderline hypertension. Circulation. 1971;44:413-418.
Mitsutake A, Takeshita A, Kuroiwa A, Nakamura M. Usefulness of the Valsalva maneuver in management of the long QT syndrome. Circulation. 1981;63:1029-1035.
Zema MJ, Restivo B, Sos T, Sniderman KW, Kline S. Left ventricular dysfunction-bedside Valsalva manoeuvre. Br Heart J. 1980;44:560-569.