Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management.

The dangers of phaeochromocytomas are mainly due to the capability of these neuroendocrine tumours to secrete large quantities of vasoactive catecholamines, thereby increasing blood pressure and causing other related adverse events or complications. Phaeochromocytomas are often missed, sometimes only becoming apparent during therapeutic interventions that provoke release or interfere with the disposition of catecholamines produced by the tumours. Because phaeochromocytomas are rare, evidence contraindicating use of specific drugs is largely anecdotal or based on case reports. The heterogeneous nature of the tumours also makes adverse reactions highly variable among patients. Some drugs, such as dopamine D(2) receptor antagonists (e.g. metoclopramide, veralipride) and beta-adrenergic receptor antagonists (beta-blockers) clearly carry high potential for adverse reactions, while others such as tricyclic antidepressants seem more inconsistent in producing complications. Other drugs capable of causing adverse reactions include monoamine oxidase inhibitors, sympathomimetics (e.g. ephedrine) and certain peptide and corticosteroid hormones (e.g. corticotropin, glucagon and glucocorticoids). Risks associated with contraindicated medications are easily minimised by adoption of appropriate safeguards (e.g. adrenoceptor blockade). Without such precautions, the state of cardiovascular vulnerability makes some drugs and manipulations employed during surgical anaesthesia particularly dangerous. Problems arise most often when drugs or therapeutic procedures are employed in patients in whom the tumour is not suspected. In such cases, it is extremely important for the clinician to recognise the possibility of an underlying catecholamine-producing tumour and to take the most appropriate steps to manage and treat adverse events and clinical complications.

An overview of pheochromocytoma: history, current concepts, vagaries, and diagnostic challenges.

Tragically as many as 50% of pheochromocytomas are discovered at autopsy, mainly because the diagnosis of this neuroendocrine tumor was not considered. Missing the diagnosis almost invariably results in devastating cardiovascular complications or death. Clinicians must always think of pheochromocytoma whenever evaluating a patient with sustained or paroxysmal hypertension or any manifestations suggesting hypercatecholaminemia. Very rarely, familial pheochromocytomas may cause no hypertension, symptoms, or signs. But biochemical testing can always establish the presence or absence of a pheochromocytoma, and localization with magnetic resonance imaging, computed tomography, or 131I or 123I-MIBG is almost always possible.

Malignant pheochromocytoma: current status and initiatives for future progress.

Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th-18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multi-center studies.

Protective effects of dietary potassium chloride on hemodynamics of Dahl salt-sensitive rats in response to chronic administration of sodium chloride.

BACKGROUND: Dietary potassium supplementation decreases blood pressure and prevents strokes in humans, and prevents strokes and renal damage in Dahl salt-sensitive (DSS) rats. OBJECTIVE: To study the effects of various concentrations of dietary potassium chloride (KCl) on the hemodynamics of Dahl salt-resistant (DSR) and DSS rats receiving a 1% sodium chloride (NaCl) diet for 8 months, to determine whether there is an optimal dietary concentration of KCl that minimizes increases in blood pressure and causes least impairment of blood flow in the brain and kidneys. METHODS AND RESULTS: We found a biphasic effect on hemodynamic parameters as a function of dietary KCl in DSS rats of the Rapp strain fed 1% NaCl with increasing dietary KCl (0.7, 2.6, 4 and 8%). After 8 months receiving a diet containing 1% NaCl and 0.7% KCl, DSS rats had mean arterial pressures (MAP), plasma volumes, cardiac outputs and renal and cerebral vascular resistances that were significantly increased compared with those of DSR rats receiving the same diet. With a 2.6% KCl diet, all these parameters were significantly reduced compared with those in DSS rats fed the 0.7% KCl diet and were similar to those in DSR rats fed 2.6% KCl. Total peripheral resistance in DSR and DSS rats was similar on all diets. When KCl was increased to 4 and 8%, MAP, plasma volume, cardiac output and renal vascular resistance progressively increased in DSR and DSS rats, without changing total peripheral resistance. These changes paralleled increases in plasma aldosterone, which resulted from adrenocortical stimulation by the increasing dietary KCl; however, cerebral vascular resistance of DSR and DSS rats decreased significantly with a 4% KCl diet, despite increased aldosterone and sodium retention. Only DSS rats fed a 2.6% KCl diet had hemodynamics similar to those of DSR control rats fed the same diet, and hyperaldosteronism, sodium retention and increased plasma volume did not occur. CONCLUSION: 'Optimal' dietary KCl (2.6%) prevents hypertension and preserves cerebral and renal hemodynamics in DSS rats fed a diet containing 1% NaCl for 8 months, which causes hypertension when dietary KCl is limited or excessive.

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.

Obesity prevention in young schoolchildren: results of a pilot study.

BACKGROUND: Overweight and obesity occur in 17% of children in the United States. Complications of excess weight in Americans cause 216,000 to 300,000 deaths yearly and cost $147 billion. METHODS: A convenience sample of 14 intervention and 15 control schools in the Catholic Diocese of Pittsburgh was used. A program to improve lifestyle (Values Initiative Teaching About Lifestyle [VITAL®]), was implemented in young children to encourage healthy eating and appropriate physical activity. Students had annual evaluations of height and weight over a 2-year period, and teachers participating in VITAL completed questionnaires regarding the program. Changes in age- and sex-adjusted body mass index (BMI) percentiles in control and intervention groups were compared using linear mixed models regression. RESULTS: VITAL was highly rated by teachers and was popular with children. Over the 2-year period, adjusted mean BMI percentiles declined from 66.1 to 65.0 in control children and from 62.8 to 58.9 in intervention children. The rates of change in the 2 groups were significantly different (p = .015). CONCLUSION: VITAL improves lifestyle of young schoolchildren, is inexpensive, easy to implement, and should be expanded to improve health and reduce healthcare's financial burden.

Renal functional, not morphological, abnormalities account for salt sensitivity in Dahl rats.

BACKGROUND: The kidney's role in the pathogenesis of salt-induced hypertension remains unclear. However, it has been suggested that inherited morphological renal abnormalities may cause hypertension. We hypothesized that functional, not morphological, derangements in Dahl salt-sensitive rats' kidneys cause NaCl retention that leads to hypertension accompanied by renal pathologic changes and proteinuria. METHOD: We studied hemodynamic, renal morphologic, and biochemical differences in Dahl salt-resistant and Dahl salt-sensitive rats fed low (0.05-0.23% NaCl) or elevated (1% NaCl) salt diets. RESULTS: We found similar hemodynamics, equal numbers of glomeruli, normal renal medullary interstitial cells and their osmiophilic granules, and cortical morphology in normotensive Dahl salt-resistant and Dahl salt-sensitive rats fed low dietary salt. Furthermore, aldosterone secretion, caused by angiotensin II infusion in normotensive rats fed 0.23% NaCl, was significantly less in Dahl salt-sensitive than Dahl salt-resistant rats. Increasing NaCl to 1% caused renal vasoconstriction without changing cyclic GMP excretion in Dahl salt-sensitive rats; in Dahl salt-resistant rats, cyclic GMP increased markedly and renal vascular resistance remained unchanged. On 1% NaCl for 9 months, Dahl salt-sensitive rats developed marked hypertension, severe renal vasoconstriction, glomerulosclerosis, tubulointerstitial abnormalities, and marked proteinuria; hypertension resulted from increased total peripheral resistance, as occurs in essential hypertensive humans. No hemodynamic or renal pathologic changes occurred in Dahl salt-resistant rats, and proteinuria was minimal. CONCLUSION: We conclude that renal functional, not morphological, abnormalities cause salt sensitivity in Dahl rats.

Pheochromocytoma: diagnosis and management update.

Pheochromocytoma is a rare but extremely treacherous neuroendocrine tumor causing manifestations by secreting catecholamines into the circulation. It is usually fatal if unrecognized. Manifestations can mimic many diseases and cause erroneous diagnoses. Approximately 15% are malignant, 18% extra-adrenal, and 20% familial. Plasma or urinary metanephrines are approximately 98% sensitive for detecting pheochromocytomas. They can be localized by MRI and CT; (131)I- and (123)I-metaiodobenzylguanidine (MIBG) are highly specific and 81% to 90% sensitive, respectively. Suspect pheochromocytoma in patients with sustained or paroxysmal hypertension or in normotensives having manifestations of hypercatecholaminemia. Surgical removal is usually curative; chemotherapy and radiotherapy are palliative for malignant pheochromocytomas.