The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma

Study Overview
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Brief Summary
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Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors originating from catecholamine producing chromaffin cells in the adrenal medulla and extra-adrenal paraganglia. The overall age-standardized incidence rate is 0.18 per 100,000 person-years in Korea. The definitive treatment of PPGL is surgical excision of tumor. However, surgery is associated with a high risk of perioperative hemodynamic instability (HI). To avoid perioperative HI in patients diagnosed with PPGL, preoperative management including routine use of alpha blockade and volume expansion has been advocated by several guidelines. While unstable hypertension and tachycardia should be controlled in patients with PPGL, there is controversial that all patients diagnosed with PPGL should undergo preoperative pharmacological treatment, especially alpha blockade. The most important risk of preoperative alpha blockade use is perioperative hypotension. A recent study reported that patients diagnosed with PPGL postoperatively may have no further higher risk of intraoperative hypertension than those diagnosed preoperatively despite insufficient preoperatively management of PPGL. Therefore, it is a very important to study the relationship between HI and preoperative alpha blockade in normotensive patients diagnosed with PPGL. The aim this study is to analyze the effect and safety of omitting preoperative alpha-adrenergic blockade for normotensive pheochromocytoma through a prospective randomized controlled trial. The patients is divided into two groups. The patients in control group take a phenoxybenzamine at least 2 to 5 weeks before surgery. The patients in case group do not take a phenoxybenzamine. Primary outcome is to evaluate the percentage of time during surgery with systolic blood pressure more than 160mmHg or average blood pressure less than 60mmHg. And secondary outcomes are to evaluate hemodynamic instability in preoperative ward and postoperative ward.

Detailed Description
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Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors originating from catecholamine producing chromaffin cells in the adrenal medulla and extra-adrenal paraganglia. The overall age-standardized incidence rate is 0.18 per 100,000 person-years in Korea. The classical clinical presentations that occur due to the release of catecholamine include headache, palpitation, sweating and hypertension. Excessive catecholamine release from PPGLs can induce life-threatening complication such as myocardial infarction, heart failure, cardiomyopathy, shock, arrhythmias, and stroke. The definitive treatment of PPGL is surgical excision of tumor. However, surgery is associated with a high risk of perioperative hemodynamic instability (HI). To avoid perioperative HI in patients diagnosed with PPGL, preoperative management including routine use of alpha blockade and volume expansion has been advocated by several guidelines. While unstable hypertension and tachycardia should be controlled in patients with PPGL, there is controversial that all patients diagnosed with PPGL should undergo preoperative pharmacological treatment, especially alpha blockade. The most important risk of preoperative alpha blockade use is perioperative hypotension. The patients with prolonged preoperative alpha blockade may require intravenous fluid and vasopressors. In the recent randomized controlled trial comparing the efficacy of two different alpha blockade, 80-92% of patients reported mild to moderate side effect on alpha blockade. The proportion of patients who are incidentally diagnosed with PPGLs are increasing. According to the recent study, the European registry for endocrine tumors revealed that incidentaloma were present in 43.4% (239/551 patients) of pheochromocytoma patients, 11.8% (65/551 patients) of patients were diagnosed as pheochromocytoma after adrenalectomy. Patients who were diagnosed with PPGL postoperatively did not undergo proper preoperative management to prevent perioperative HI. Most of them were normotensive patients and there were no specific findings on laboratory or radiologic examination suggesting PPGLs. In addition, a recent study reported that patients diagnosed with PPGL postoperatively may have no further higher risk of intraoperative hypertension than those diagnosed preoperatively despite insufficient preoperatively management of PPGL. Therefore, it is a very important to study the relationship between HI and preoperative alpha blockade in normotensive patients diagnosed with PPGL. The department of endocrine surgery in Seoul National University Hospital intends to analyze the effect and safety of omitting preoperative alpha-adrenergic blockade for normotensive pheochromocytoma through a prospective randomized controlled trial. The patients is divided into two groups. The patients in control group take a phenoxybenzamine at least 2 to 5 weeks before surgery. If blood pressure is more than 130/80mmHg in the sitting position, the patient will take a more amount of phenoxybenzamine. If blood pressure is less than 90mmHg in the standing position, the patients will take a less amount of phenoxybenzamine. In the case group, there is no drug to be taken. Primary outcome is to evaluate the percentage of time during surgery with systolic blood pressure more than 160mmHg or average blood pressure less than 60mmHg. And secondary outcomes are to evaluate hemodynamic instability in preoperative ward and postoperative ward.

Official Title
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A Pilot Study for Randomized Controlled Trial on the Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma

Conditions
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Pheochromocytoma, Paraganglioma, Adrenalectomy; Status, Adrenergics Causing Adverse Effects in Therapeutic Use

Intervention / Treatment
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* Drug: Phenoxybenzamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 19 to 70 years old Patients who consented to the study and obtained consent for the study Patients undergoing unilateral total adrenalectomy due to normotensive pheochromocytoma/paraganglioma with less than five times of upper limits of serum metanephrine Exclusion Criteria: Patients under 18 or over 70 years old Pregnant women Patients with bilateral pheochromocytoma Patients suspected of malignant pheochromocytoma/paraganglioma or distant metastasis Patients requiring preoperative intensive care unit due to severe hemodynamic instability Patients with hypertension (the blood pressure measured more than two times is constantly greater than 140/90 mmHg) or already taking a antihypertensive medication Patients with a history of coronary artery disease Patients with a history of arrhythmia (atrial fibrillation, Paroxysmal supraventricular tachycardia) Patients with a history of cerebrovascular disease (cerebral aneurysm, cerebral infarction, cerebral hemorrhage) Patients judged unsuitable by the person in charge of the clinical trial

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients in control group take a phenoxybenzamine at least 2 to 5 weeks before surgery. If blood pressure is more than 130/80 mmHg in the sitting position, the patient will take a more amount of phenoxybenzamine. If blood pressure is less than 90 mmHg in the standing position, the patient will take a less amount of phenoxybenzamine. In the case group, there is no drug to be taken.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Phenoxybenzamine before surgery<br>Phenoxybenzamine, an alpha receptor blocker, is taken at least 2 to 5 weeks before surgery | Drug: Phenoxybenzamine<br>* Patients in sham comparator group take a phenoxybenzamine at least 2 to 5 weeks before surgery. If blood pressure is more than 130/80 mmHg in the sitting position, the patient will take a more amount of phenoxybenzamine. If blood pressure is less than 90 mmHg in the standing position, the patient will take a less amount of phenoxybenzamine. In active comparator group, there is no drug to be taken.<br>|
| Active Comparator: No phenoxybenzamine before surgery<br>Phenoxybenzamine, an alpha receptor blocker, is not taken before surgery | Drug: Phenoxybenzamine<br>* Patients in sham comparator group take a phenoxybenzamine at least 2 to 5 weeks before surgery. If blood pressure is more than 130/80 mmHg in the sitting position, the patient will take a more amount of phenoxybenzamine. If blood pressure is less than 90 mmHg in the standing position, the patient will take a less amount of phenoxybenzamine. In active comparator group, there is no drug to be taken.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect and safety of omitting preoperative alpha blockade during surgery | Percentage of time during the surgery with systolic blood pressure > 160mmHg or average blood pressure < 60mmHg | during surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect and safety of omitting preoperative alpha blockade during surgery | Percentage of the surgery time greater than 100 times per pulse minute Average systolic/diastolic blood pressure in millimeters of mercury and pulse in beats each minutes during surgery Types and amount of antihypertensive drugs in mg per day during surgery Types and amount of vasopressor drugs in mg per day during surgery | during surgery | 
| The effect and safety of omitting preoperative alpha blockade before surgery | The number of times systolic blood pressure more than 130 mmHg and diastolic blood pressure more than 80mmHg in the preoperative ward The number of times of pulse rate per minute more than 80 times in the preoperative ward | 3 days, 2 days, 1 day before surgery | 
| The effect and safety of omitting preoperative alpha blockade after surgery | The number of times of average blood pressure less than 60mmHg in postoperative ward Average blood pressure in postoperative ward Types and amount of antihypertensive drugs in mg per day after surgery Types and amount of vasopressor drugs in mg per day after surgery | 1 day, 2 day, 2 weeks, 3 months after surgery |