Clonidine Suppression Test Research Articles

Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma

Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma

Pheochromocytoma.

Pheochromocytoma, a relatively rare (<0.05% of hypertensives), catecholamine-secreting tumor, is almost always lethal unless recognized and appropriately treated. Clinical and biochemical manifestations are mainly caused by excess circulating catecholamines and hypertension. Manifestations mimic many conditions, which may result in erroneous diagnoses and improper treatment. Sustained or paroxysmal hypertension associated with headaches, sweating, or palpitations, occurs in 95% of patients, but at least 5% are normotensive. All patients with manifestations of hypercatecholaminemia or coexisting neoplasms should be investigated for pheochromocytoma. Plasma free metanephrines and fractionated urinary metanephrines are the most sensitive (about 100%) chemical tests for diagnosing sporadic and familial pheochromocytomas; plasma and urinary catecholamines and total metanephrines are fairly sensitive for identifying sporadic cases but are less sensitive for familial tumors. The clonidine suppression test helps exclude other conditions that may elevate plasma and urinary catecholamines and their metabolites. Magnetic resonance imaging is more sensitive than computed tomography for localizing pheochromocytomas; iodine-131-metaiodobenzylguanidine (131I-MIBG) tumor uptake confers specificity. Surgical resection is successful in 90% of cases, but 10% of tumors are malignant. Pheochromocytomas <5 cm in diameter can be removed laparoscopically; larger tumors should be removed by open surgery. Drug treatment prior to and during surgery is mandatory; drug treatment, chemotherapy, and radiation therapy are used to treat malignant lesions.

Catecholamine-induced hypertension in lumbosacral paraplegia: Five case reports

Hypertension in the patient with SCI is relatively rare and generally restricted to patients with high-level injuries where autonomic dysreflexia can occur. Resting blood pressure in individuals with SCI has been described as lower than that in the normal population. This report describes five previously normotensive teenagers with subsequent paraplegia as a result of gunshot wounds who presented with hypertension secondary to idiopathic elevation of plasma or urinary catecholamine levels. A clonidine suppression test was used as a neuroprobe to inhibit centrally mediated sympathetic outflow, excluding the probability of an extra-axial autonomous catecholamine-secreting tumor as the possible source of hypertension. Positive suppression was achieved in four patients (41%, 37.2%, 4.8%, and 37.2% decreases). One patient had values corresponding to orthostatic changes (an increase of 63%) because of poor compliance with the test. This patient was lost to follow-up; in the remaining four, hypertension resolved at 12, 8, 9, and 6 weeks postinjury. The increased circulating catecholamine level appears to be promoted by a centrally mediated response to the SCI. Elevated blood pressure probably results from an upgraded receptor regulation or an increased receptor sensitivity on the affected cells in the absence of restraining spinal reflexes. The pathophysiology of such hypertension seems to be secondary to autonomic dysfunction and, although it may be transient, it should be treated promptly and reevaluated periodically until stabilization is achieved.

Pheochromocytoma in Italy: a multicentric retrospective study.

To conduct an epidemiological study on pheochromocytoma in Italy. Data on 284 patients with pheochromocytoma observed between 1978 and 1997 were collected from 18 Italian centers through a questionnaire reporting epidemiological, clinical, laboratory, radiological and surgical data. 53.6% of the patients were females and 46.4% were males. Thirty-two tumors were discovered as incidental adrenal masses. The most frequent referred symptoms were palpitations (58.1%), headache (51.9%), sweating (48. 8%) and anxiety (35.3%). Their association was present only in 15.5% of patients. Paroxysmal symptoms were reported in 67.1% and hypertensive crises in 59.7% of patients. Normal blood pressure (systolic and diastolic) was present both in the supine and upright positions in 21.1% of patients. Among laboratory assays, urinary vanylmandelic acid (VMA) was the most widely used (58.1%) and was the least sensitive (25% of false negative results). Basal plasma catecholamines were found to be normal in 11.3% of patients but were always elevated when sampled during a hypertensive paroxysm. A clonidine suppression test was performed in 38 patients with no adverse side effects. It gave a false negative response in 2 patients. A glucagon test was performed in 21 patients. It was interrupted for acute hypertension in 52.4% of patients. Only 5/21 patients were normotensive and had normal basal plasma catecholamines. In these patients the test gave a positive response in four (80%). CT (79.6%) and I-MIBG scintigraphy (68.5%) were the most widely used methods for tumor localization. CT sensitivity was 98.9% for intra-adrenal and 90.9% for extra-adrenal tumors. MIBG sensitivity was 88.5%. In the 263 patients who underwent surgery, the tumor was intra-adrenal in 89.4%, extra-adrenal in 8.5%, intra- and extra-adrenal in 2.1%, and bilateral in 11.0% of patients. Malignancy was reported in 9.9% of cases. Surgery caused remission of hypertension in 59.3%, improvement in 26.8%, and no changes in 13. 9% of patients. In the last group the interval between initial symptoms and diagnosis was significantly longer. The present study confirms that the clinical presentation of pheochromocytoma is variable and aspecific. Normotension is often present and often the tumor is discovered incidentally. An indication for the routine use of screening methods more sensitive than urinary VMA is strongly suggested. The clonidine test was found to be safe and should be preferred to the glucagon test which has to be restricted to very selected patients. CT and MIBG scintigraphy are almost always successful in localizing the tumor. Reversal of hypertension by surgery seems to depend on an early diagnosis.

Autonomic function in hypertensive patients with neurovascular compression of the ventrolateral medulla oblongata.

To study whether abnormalities of autonomic function exist in patients with essential hypertension and neurovascular compression (NVC) of the medulla oblongata. We studied 25 untreated patients with essential hypertension (13 men and 12 women, 27-74 years old). High-resolution magnetic resonance imaging and magnetic resonance angiography were used to detect NVC. Twenty-four-hour ambulatory monitoring of blood pressure and electrocardiogram were performed, and the power spectrum of heart rate variability was analyzed. On a separate day, various autonomic activity tests, including mental stress, hand grip, cold pressor, and Valsalva maneuver were performed. Baroreflex sensitivity was calculated from changes of blood pressure and R-R interval during phenylephrine infusion. A clonidine suppression test was also performed, with measurement of plasma catecholamine levels. Fourteen of 25 patients (56%) had NVC (C group), and 11 patients did not have NVC (NC group). There were no significant differences in age, sex, family history, or duration of hypertension between the C and NC groups. Average 24-h systolic blood pressure was similar between the two groups, although 24-h diastolic blood pressure was higher in the C group than the NC group. Daytime, night-time, and 24-h heart rate was significantly higher in the C group than in the NC group. Night-time low frequency/high frequency ratio was slightly higher in the C group. Plasma norepinephrine levels were significantly higher (467 +/- 217 versus 299 +/- 122 pg/ml), and baroflex sensitivity was slightly lower in the C group than in the NC group. Responses of blood pressure and heart rate to mental stress, cold pressor, hand grip, Valsalva maneuver, phenylephrine infusion, and clonidine tests were not significantly different between the two groups. NVC of the medulla oblongata was frequently found in patients with essential hypertension. Patients with NVC appeared to have enhanced sympathetic nervous activity compared with those without the compression.

Clonidine Suppression Test Revisited

Background: The diagnosis of pheochromocytoma may be difficult because the clinical picture is variable. Objective: The purpose of this paper is to report our experience and to review the published data on the diagnostic significance and risks of the clonidine suppression test in the diagnosis of pheochromocytoma. Patients and Methods: 114 patients were evaluated for pheochromocytoma using the clonidine suppression test. Results: The diagnosis was established in four patients. Overall accuracy of the test in our own series was 98% when the normal response to clonidine was defined as total plasma catecholamines of less than 500 ng/L, or less than 70% of the baseline value. No serious complication was noted. Conclusion: Our data and the published series demonstrate that the clonidine suppression test is accurate and safe in patients with suspected pheochromocytoma.

Coexistence of MEN 2A and Papillary Thyroid Carcinoma and a Recurrent Pheochromocytoma 23 Years after Surgery: Report of a Case and a Review of the Japanese Literature

A 59-year-old woman who had undergone bilateral partial adrenalectomy 23 years previously was referred to our hospital because of neck masses and a left adrenal tumor. Fine needle aspiration biopsy of the neck tumor and elevated levels of calcitonin and CEA revealed medullary thyroid carcinoma. Slightly elevated levels of urinary normetanephrine and metanephrine, and results of a clonidine suppression test, CT, magnetic resonance imaging, and 131I-metaiodobenzylguanidine scintigraphy of the abdomen indicated that the left adrenal tumor was a recurrent pheochromocytoma in the residual adrenal gland. After total thyroidectomy, bilateral medullary thyroid carcinomas and papillary thyroid carcinoma were recognized pathologically. Although the coexistence of bilateral pheochromocytoma and medullary thyroid carcinoma is suggestive of multiple endocrine neoplasia (MEN), association of MEN type 2A (MEN 2A) with papillary thyroid carcinoma may have occurred incidentally. A retrospective analysis of 9 cases of pheochromocytoma associated with papillary thyroid carcinoma reported in the Japanese literature demonstrated a male-to-female ratio of 1:8, and an average patient age of 56.2 years. The present case indicates that association between pheochromocytoma and thyroid carcinoma may not always involve medullary thyroid carcinoma.

Pheochromocytoma: current diagnosis and management.

Pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells that causes hypertension. To review the clinical presentation, diagnosis, and treatment of this disease. Pheochromocytoma can mimic a number of other diseases, making recognition difficult. Hypertension may be paroxysmal or sustained. The signs and symptoms of pheochromocytoma are mostly due to hypercatecholaminemia, hypertension, complications, or coexisting diseases; however, measurements of catecholamines and their metabolites in the plasma and urine may be normal between "attacks", and other conditions can elevate these values. The clonidine suppression test confers specificity to the clinical and laboratory findings, and magnetic resonance imaging is the most reliable method of locating a tumor. Surgical resection is successful in 90% of patients; however, the disease is fatal if it is not detected and treated. Pheochromocytoma should be suspected in patients with paroxysmal or sustained hypertension, particularly if symptoms are present.

Clinical presentation, biochemical parameters and localization of catecholamine-secreting tumors

Background The diagnosis of these catecholamine-secreting tumors requires clinical awareness of the various presentations and syndromes in which these tumors are found. Any suspicion of a pheochromocytoma warrants aggressive diagnostic intervention. The aim of the present paper is to describe clinical manifestations, biochemical work-up and localization of pheochromocytoma. Methods Basic diagnostic method is urinary catecholamines and/or their metabolites. For confirmation, plasma catecholamines, other neuropeptides, and clonidine suppression test can be helpful in confirming the diagnosis. Results Once the diagnosis of pheochromocytomas has been established, alpha receptor blockade should be instituted prior to further investigations. Localization of the tumor is essential prior to surgical intervention. CT or MRI scanning are the first line modalities for localization of these tumors. If CT or MRI scan fails to localize the tumor, the patient has recurrent/malignant disease, or bilateral disease is suspected, then I-131 or I-123 MIBG scanning should be performed. Conclusions Pheochromocytoma are potentially lethal but usually benign tumors. High degree of clinical suspicion and accurate work-up is essential for successful outcome.

The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls

The intent of this study is to retrospectively evaluate our experience, as well as all published information, regarding the clonidine suppression test to determine its utility, accuracy, and safety in the diagnosis of pheochromocytoma. All 22 patients (including four with pheochromocytoma) evaluated at a major military referral hospital with the clonidine suppression test for suspected pheochromocytoma for more than 6 years were retrospectively reviewed. All published series of patients similarly evaluated were also critically reviewed. All studies confirm that a nonstressed plasma norepinephrine of more than 2000 pg/mL is diagnostic of pheochromocytoma. In those patients with a plasma norepinephrine of less than 2000 pg/mL, the clonidine suppression test is 92% accurate in diagnosing pheochromocytoma when the normal response to clonidine is defined as total plasma catecholamines of less than 500 pg/mL. Its accuracy diminishes in patients with low baseline plasma catecholamine levels, who may better be tested with a stimulatory test (ie, glucagon). The use of diuretics, beta-blockers, and antidepressants may cause false-positive results or severe hypotension during the clonidine suppression test. Those previously treated with clonidine or with baroreceptor dysfunction may also be prone to severe hypotension, but this complication is otherwise uncommon after acute clonidine ingestion. Although it is rarely necessary for the diagnosis of pheochromocytoma, the clonidine suppression test is an accurate and safe test in a select group of patients.

The Clonidine Suppression Test for Pheochromocytoma

The intent of this study is to retrospectively evaluate our experience, as well as all published information, regarding the clonidine suppression test to determine its utility, accuracy, and safety in the diagnosis of pheochromocytoma.All 22 patients (including four with pheochromocytoma) evaluated at a major military referral hospital with the clonidine suppression test for suspected pheochromocytoma for more than 6 years were retrospectively reviewed. All published series of patients similarly evaluated were also critically reviewed.All studies confirm that a nonstressed plasma norepinephrine of more than 2000 pg/mL is diagnostic of pheochromocytoma. In those patients with a plasma norepinephrine of less than 2000 pg/mL, the clonidine suppression test is 92% accurate in diagnosing pheochromocytoma when the normal response to clonidine is defined as total plasma catecholamines of less than 500 pg/mL. Its accuracy diminishes in patients with low baseline plasma catecholamine levels, who may better be tested with a stimulatory test (ie, glucagon). The use of diuretics, beta-blockers, and antidepressants may cause false-positive results or severe hypotension during the clonidine suppression test. Those previously treated with clonidine or with baroreceptor dysfunction may also be prone to severe hypotension, but this complication is otherwise uncommon after acute clonidine ingestion.Although it is rarely necessary for the diagnosis of pheochromocytoma, the clonidine suppression test is an accurate and safe test in a select group of patients.

Glucagon and clonidine testing in the diagnosis of pheochromocytoma.

We assessed the sensitivity and specificity of glucagon stimulation and clonidine suppression tests in the diagnosis of pheochromocytoma in 113 hypertensive patients, 39 with and 74 without the tumor. In the glucagon stimulation test, blood was sampled 2 minutes after intravenous injection of 0.28 mumol (1 mg) glucagon, and in the clonidine suppression test, blood was sampled 3 hours after administration of oral clonidine, 1.30 mumol (0.3 mg)/70 kg body wt. Baseline levels of catechols in antecubital venous blood were abnormal, with norepinephrine greater than 7.10 nmol/l (1,200 pg/m), epinephrine greater than 1.51 nmol/l (276 pg/ml), norepinephrine/dihydroxyphenylglycol (DHPG) ratio greater than 1.09, or dopa greater than 35.53 nmol/l (7,000 pg/ml), in 30 of 39 patients with pheochromocytoma (sensitivity 77%) and 1 of 74 patients without pheochromocytoma (specificity 99%). Results of the glucagon test were abnormal (norepinephrine greater than 11.83 nmol/l [2,000 pg/ml] or more than threefold increase from baseline) in 25 of 31 patients with pheochromocytoma (sensitivity 81%) and 0 of 72 patients without pheochromocytoma (specificity 100%). Results of the clonidine test were abnormal (after clonidine norepinephrine greater than 2.96 nmol/l [500 pg/ml] or less than 50% decrease from baseline) in 29 of 30 patients with pheochromocytoma (sensitivity 97%) and in 7 of 30 patients without pheochromocytoma (specificity 67%). Very high baseline levels of catechols therefore indicated the presence of pheochromocytoma, but there were several false-negative results when normal levels were obtained. The glucagon test alone was highly specific but not sensitive, and the clonidine test was highly sensitive but less specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Diuretic Therapy on the Clonidine Suppression Test

Moduretic has been reported to inhibit the suppression of plasma norepinephrine (NE) levels by the alpha 2 adrenoceptor agonist, clonidine. To determine whether plasma volume reduction by hydrochlorothiazide (HCTZ) or antagonism of Na+/H+ exchange by amiloride (the constituents of Moduretic) is responsible, the authors performed a modified clonidine suppression test (CST) in nine normal volunteers (aged 25 +/- 2 years), pretreated for 1 week with HCTZ 50 mg daily, amiloride 10 mg daily, or placebo, in a randomized, double-blind, crossover study. Baseline characteristics were identical on all study days, except serum [K+] and weight, which were lowest on HCTZ (3.6 +/- 0.2 mEq/L and 78.7 +/- 2.5 kg), compared with amiloride (4.2 +/- 0.1 mEq/L and 79.9 +/- 2.4 kg) and placebo (4.0 +/- 0.1 mEq/L and 80.2 +/- 2.7 kg, P less than .05). Oral clonidine (0.3 mg) produced a reduction in mean blood pressure by about 20%. Plasma norepinephrine levels were similar in patients receiving placebo, HCTZ, and amiloride (205 +/- 18, 272 +/- 40 and 277 +/- 44 pg/mL, P greater than .20), and decreased significantly during CST. The maximal reduction for each subject averaged 72.7 +/- 12.4%, 87.9 +/- 3.8%, and 82.9 +/- 5.7% for placebo, HCTZ, and amiloride. Clonidine also produced a four to seven-fold increase in plasma growth hormone levels, reduced salivary flow by about 75%, and increased the level of sedation. There were no differences among the three pretreatment regimens in the effects of clonidine, indicating that diuretic therapy does not need to be systematically discontinued in patients undergoing CST.

CLONIDINE SUPPRESSION TEST RELIABLY DIFFERENTIATES PHAEOCHROMOCYTOMA FROM ESSENTIAL HYPERTENSION

1. Clonidine resulted in significant suppression of both noradrenaline (NA) and adrenaline (ADR) in essential hypertensives (EHT) without any false positive findings. That is, every patient who failed to suppress had phaeochromocytoma (PH). 2. The clonidine suppression test (CST) produced minimal suppression of NA in NA-secreting PH (NA-PH) and correctly identified two NA-PH with normal basal plasma NA. 3. In ADR-secreting PH (ADR-PH) the CST did not result in significant suppression of ADR levels, whether elevated or normal basally. 4. The CST proved to be an accurate discriminator of PH from other forms of hypertension.

Neurilemoma of the retroperitoneum

A case is presented in which suprarenal neurilemoma was associated with paroxysmal attacks of hypertension, headache and sweating with elevated plasma and urinary catecholamines. Pheochromocytoma was excluded using an overnight clonidine suppression test. Ultrasonography, computed tomography and magnetic resonance imaging, which showed cystic mass with a pedicle continuing to the widened intervertebral foramen, were helpful for the preoperative diagnosis of retroperitoneal neurilemoma. The excised tumor was revealed to be benign neurilemoma and contain detectable levels of adrenaline, noradrenaline and dopamine. The relationships between tumor catecholamines and clinical manifestations will be discussed.

High permanent plasma adrenaline levels: a marker of adrenal medullary disease in medullary thyroid carcinoma

Increases in urinary, plasma and tumour adrenaline have been previously observed in MEN II patients with phaeochromocytoma. However, the sensitivity of adrenaline for early detection of adrenal medullary disease has not been accurately evaluated. Twenty-five patients with medullary thyroid carcinoma (MTC) histologically confirmed but without clinical or biological evidence of phaeochromocytoma have been studied. Medullary adrenal status was evaluated by adrenal CT-scan. MIBG scintigraphy, determination of urinary VMA, metanephrines and total catecholamine levels, measurement of nyctohemeral plasma adrenaline or noradrenaline concentrations (every 2 h during 24 h) and clonidine suppression test. Four of the 25 patients had evidence of adrenal medullary disease in view of the coexistence of CT-scan, MIBG scintigraphy and plasma adrenaline abnormalities. Moderate adrenal enlargement (unilateral, n = 3; bilateral, n = 1) was observed on scans together with a high adrenal MIBG uptake (bilateral, n = 4). Among the urinary parameters studied, a minor MN increase was observed in only one of the four patients. Plasma adrenaline levels were significantly (P less than 0.01) different from those of the other 21 patients (mean + SD 115 + 110 pmol/l). This plasma adrenaline increase is reproducible and not suppressed by clonidine. Unilateral adrenalectomy performed in one patient confirmed a phaeochromocytoma and induced normalization of plasma adrenaline levels. In contrast, the plasma noradrenaline levels of the four patients were not statistically different from those of the other 21 patients. These data suggest that persistent high plasma adrenaline levels may be selectively increased in MTC patients together with a moderate adrenal CT-scan enlargement and a high adrenal MIBG uptake, despite a normal urinary excretion of total catecholamines and catecholamines metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of Clonidine suppression and various provocation tests in the diagnosis of pheochromocytoma

Recent investigations have shown that the widely used clonidine suppression test is sometimes fallible for the diagnosis of pheochromocytoma. A comparative assessment was made of the following suppression and provocation tests, the clonidine suppression test, and the glucagon, metoclopramide, and naloxone provocation tests. The assessment was performed in 6 patients with pheochromocytoma and in 19 patients without pheochromocytoma who were initially suspected of harboring a tumor. BP response did not predict the presence of pheochromocytoma in any test. Plasma norepinephrine (NE) concentrations determined at 120 and 180 min after oral 150 micrograms of clonidine gave false negative results in 2 of the 5 patients with pheochromocytoma tested. Both plasma NE and epinephrine (E) concentrations were measured before and sequentially after each provocative agent. Neither NE nor E responded to 1 mg of glucagon iv in 2 of the 4 patients with pheochromocytoma tested. Determination of the peak level, peak increment, and % peak increment of NE and E following 10 mg of naloxone iv did not distinguish the two groups. The % peak increments of both NE and E in all 4 patients with pheochromocytoma given 5 mg of metoclopramide iv exceeded the mean + 3 SD values of the patients without pheochromocytoma (25 + 28% for NE, and 25 + 42% for E). These results suggested that, when performed with judicious patient selection (ambiguous plasma or urinary catecholamine levels), the measurement of plasma catecholamines in response to metoclopramide can be a useful adjunctive tool in the diagnosis of pheochromocytoma.

Phaeochromocytomas secreting adrenaline but not noradrenaline do not cause hypertension and require precise adrenaline measurement for diagnosis.

1. Urinary noradrenaline (NA) and adrenaline (ADR) determinations are a more sensitive index than plasma measurements for the diagnosis of phaeochromocytoma (phaeo). 2. Even though urinary NA excretion serve as a sufficient single diagnostic test for the majority of phaeos, it is necessary to measure urinary ADR excretion if ADR-only secreting phaeos are not to be missed, particularly in patients with multiple endocrine neoplasia (MEN) syndrome. 3. The clonidine suppression test confirmed all tumour diagnoses, and in this series was not responsible for any false negative or false positive results.

Improved Safety of Glucagon Testing for Pheochromocytoma by Prior a-Receptor Blockade

The glucagon stimulation test has been superseded in recent years by the clonidine suppression test because it can provoke dangerous increases in blood pressure in patients with pheochromocytomas. We describe the first patient in whom a pheochromocytoma was diagnosed by a glucagon test, after which the blood pressure (but not the plasma catecholamine) response to a second injection of glucagon was blocked by pretreatment with phenoxybenzamine. After the tumor (which contained both pheochromocytoma and ganglioneuroma tissue) was removed, a third glucagon test result was negative. This experience suggests that patients with normal plasma catecholamine levels who are suspected of harboring a pheochromocytoma may be accurately diagnosed, but potentially dangerous increases in blood pressure may be minimized, by performing the glucagon test after alpha-adrenergic blockade.

Evaluation of the clonidine-suppression test in the diagnosis of pheochromocytoma.

In this study we examined the preoperative value of the clonidine-suppression test in 15 patients with surgically proved pheochromocytomas. The result of the clonidine-suppression test was pathological (epinephrine plus norepinephrine above 500 ng/l 3 h after clonidine) in 10 of 15 patients (66%). These patients had relatively large tumors and higher basal norepinephrine plasma levels. Out of the 5 cases without a pathological clonidine test 4 had normal basal plasma catecholamine levels with the result that the clonidine test could not be properly applied and 1 case produced a false negative result. These 5 cases generally had smaller tumors and lower plasma catecholamine levels. Two of these cases had basally raised epinephrine values. The other three cases had either a paradoxical increase or a suspiciously low fall (less than 25%) in norepinephrine within the normal range. We conclude that the clonidine-suppression test is only reliable for the diagnosis of relatively large pheochromocytomas.