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You have free access to this content What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism?

F. Young1,

W. Stanson2

Article first published online: 20 OCT 2008

DOI: 10.1111/j.1365-2265.2008.03450.x

© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd

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Clinical Endocrinology

Volume 70, Issue 1, pages 14–17, January 2009

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Young, W. F. and Stanson, A. W. (2009), What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism?. Clinical Endocrinology, 70: 14–17. doi: 10.1111/j.1365-2265.2008.03450.x

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1 Divisions of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine,

2 the Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA

*Correspondence: F. Young Jr, Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 ; Fax: +1 ; E-mail: young.william@...

Publication History

Issue published online: 30 DEC 2008 Article first published online: 20 OCT 2008 (Received 4 September 2008; returned for revision 27 September 2008; finally revised 11 October 2008; accepted 13 October 2008)

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Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Summary

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

Adrenal venous sampling (AVS) is the criterion standard to distinguish between unilateral and bilateral adrenal disease in patients with primary aldosteronism. The keys to successful AVS include appropriate patient selection, careful patient preparation, focused technical expertise, defined protocol, and accurate data interpretation. The use of AVS should be based on patient preferences, patient age, clinical comorbidities, and the clinical probability of finding an aldosterone-producing adenoma. AVS is optimally performed in the fasting state in the morning. AVS is an intricate procedure because the right adrenal vein is small and may be difficult to locate – the success rate depends on the proficiency of the angiographer. The key factors that determine the successful catheterization of both adrenal veins are experience, dedication and repetition. With experience, and focusing the expertise to 1 or 2 radiologists at a referral centre, the AVS success rate can be as high as 96%. A centre-specific, written protocol is mandatory. The protocol should be developed by an interested group of endocrinologists, radiologists and laboratory personnel. Safeguards should be in place to prevent mislabelling of the blood tubes in the radiology suite and to prevent sample mix-up in the laboratory.

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Introduction

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

Adrenal venous sampling (AVS) is the criterion standard to distinguish between unilateral and bilateral adrenal disease in patients with primary aldosteronism.1–3 Although AVS has been in clinical use for more than 45 years,3,4 the indications for and successful use of AVS continue to be challenging clinical issues. Our objective herein is to answer the question `What are the keys to successful AVS in patients with primary aldosteronism?' The answer to this question is based on our clinical experience and the performance of AVS in more than 400 patients over 18 years at Mayo Clinic. The keys to successful AVS include appropriate patient selection, careful patient preparation, focused technical expertise, defined protocol and accurate data interpretation.

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Appropriate patient selection

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

Although matching patients to specific tests is important across medicine, it is especially critical in the setting of AVS. For example, although AVS was initially proposed to assist in the localization of catecholamine-secreting neoplasms,4 with the development of computer-assisted imaging (e.g. computed tomography [CT], magnetic resonance imaging, 123I-m-iodobenzylguanidine scintigraphy), AVS is now contraindicated in patients with these tumours.2

Most patients with primary aldosteronism have either bilateral idiopathic hyperplasia (IHA) – optimally treated with mineralocorticoid receptor blockade – or a unilateral aldosterone-producing adenoma (APA) that may be treated with unilateral laparoscopic adrenalectomy.1,5 The use of AVS to distinguish between IHA and APA was first proposed by Melby et al. 1967.2 However, with the catheter and angiographic technology available at that time, most centres relied on less direct methods to lateralize aldosterone excess as they become available (e.g. [6â-131I]iodomethyl-19-norcholesterol [NP-59] scintigraphy, posture stimulation test, serum 18-hydroxycorticosterone concentration, and adrenal CT scan).5 By the early 1980s, adrenal CT became the localizing procedure of choice.5

However, multiple studies have shown that the accuracy of adrenal CT in localizing the source of aldosterone excess is poor (approximately 50%) and that in patients with primary aldosteronism who wish to pursue the surgical option for hypertension management, AVS is a key step in distinguishing between unilateral and bilateral adrenal disease.1,5–13 Some centres and a recent clinical practice guideline recommend that AVS be performed in all patients who have the diagnosis of primary aldosteronism and who want to pursue surgical management.1,13 A more practical approach is the selective use of AVS on the basis of patient preferences, patient age, clinical comorbidities, and the clinical probability of finding an APA.5,6,14 AVS should be performed only in patients with confirmed primary aldosteronism who want to pursue the surgical option in the management of their hypertension.1

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Careful patient preparation

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

AVS is optimally performed in the fasting state, in the morning, and in a patient in the supine position for at least 1 h before sampling. Experts agree that it would be optimal to evaluate all patients with primary aldosteronism in the absence of antihypertensive medications. However, because of the risk of severe untreated hypertension, most patients must be tested while treated with antihypertensive medications.1,5 Medications that may increase renin secretion (e.g. mineralocorticoid receptor antagonists [spironolactone and eplerenone], high-dose amiloride [i.e. > 5 mg/day], and renin inhibitors [e.g. aliskiren]) should be discontinued 6 weeks before AVS. When mineralocorticoid receptor antagonist therapy results in a nonsuppressed renin level in a patient with an APA, there is the risk that the contralateral normal adrenal may produce enough aldosterone that lateralization on AVS is lost and the patient is inaccurately diagnosed with IHA. Alternate antihypertensive medications that may be used in this setting include extended release verapamil and peripheral á1-adrenergic receptor antagonists (e.g. doxazosin, terazosin and prazosin). In addition, hypokalaemia reduces the secretion of aldosterone, and it is optimal to restore the serum level of potassium to normal before performing AVS.

At Mayo Clinic, we use continuous cosyntropin infusion during AVS (50 µg/h started 30 min before sampling and continued throughout the procedure) for the following reasons: (i) to minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS; (ii) to maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal veins; and (iii) to maximize the secretion of aldosterone from an APA.6,12,15,16 Some investigators have suggested that when given as a bolus injection and when the adrenal veins are sampled simultaneously, cosyntropin administration does not improve the diagnostic accuracy of AVS.17,18 However, confidence in successful cannulation of both adrenal veins is critical to patient care. When cosyntropin infusion is not used, some centres require only a 10% cortisol gradient between an adrenal vein and the IVC17,18– a change that can be seen in minute-to-minute adrenal cortisol secretion and a change that is within the coefficient of variation of some cortisol assays. Thus, we favour the use of cosyntropin infusion during AVS.6

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Focused technical expertise

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

AVS is a difficult procedure because the right adrenal vein is small and may be difficult to identify, cannulate, and withdraw a blood sample from; the success rate depends on the proficiency of the angiographer. According to a review of 47 reports, the success rate for cannulating both adrenal veins in 384 patients was 74%.19 The key factors are experience, dedication, and repetition. In one report, where four radiologists performed AVS in 60 patients, the success rate of bilateral adrenal vein cannulation was only 42%, leading the authors to conclude that they should limit AVS to a single radiologist to maximize expertise.20 With experience, and focusing the expertise to one or two radiologists at a referral centre, the AVS success rate can increase to 96%.6,11,12

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Defined protocol

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

A centre-specific, written protocol is mandatory. The protocol should be developed by an interested group of endocrinologists, radiologists, and laboratory personnel. Safeguards should be in place to prevent mislabelling of the blood tubes in the radiology suite and to prevent sample mix-up in the laboratory. The adrenal veins are sequentially catheterized through the percutaneous femoral vein approach under fluoroscopic guidance – correct catheter tip location is confirmed with injection of a small amount of contrast medium (Fig. 1a). Blood is obtained by gentle aspiration from both adrenal veins. Successful catheterization may require an array of catheter configurations; intra-procedure steam-shaping of the catheter tip may be helpful to facilitate access to the adrenal veins. In addition, the placement of side holes, very close to the catheter tip, may facilitate the blood draw.

Figure 1. A 56-year-old-man had a 20-year history of hypertension and a 1-year history of hypokalaemia. The case-detection test results for primary aldosteronism were positive, with a plasma aldosterone concentration (PAC) of 666 pmol/l and low plasma renin activity (PRA) of less than 0·6 ng/ml per hour (PAC to PRA ratio > 1000; normal < 555). The confirmatory test results for primary aldosteronism were also positive, with 24-h urinary excretion of aldosterone of 111 nmol/day (normal < 33·3 nmol/day) on a high sodium diet (urinary sodium, 261 mmol/day). The adrenal-directed computed tomography scan showed normal adrenal glands. (a) Adrenal venous sampling images showing the catheter in the right and left adrenal veins. ( Adrenal venous sampling lateralized aldosterone secretion to the left adrenal and three cortical adenomas (measuring 7, 3 and 4·5 mm) were found at laparoscopic left adrenalectomy. The postoperative PAC concentration was < 28 pmol/l. Hypokalemia was cured and blood pressure control improved on 50% less antihypertensive medications.

The right adrenal vein enters the IVC posteriorly several centimeters above the right renal vein. It is more difficult to catheterize than the left one for a variety of reasons – it is short, small in calibre, and often has an angulated path causing the catheter tip to impact the intima making blood aspiration problematic. Because of its short length, sometimes it does not support a stable catheter position during respiratory motion. Rarely, it arises in conjunction with a hepatic vein branch and needs to be separately engaged using a specific catheter shape to match the anatomy. Additionally, some physicians confuse the right adrenal vein with adjacent small hepatic vein branches, which are frequently encountered entering the IVC near the adrenal vein region. However, contrast injections will clearly distinguish hepatic vein anatomy from that of the adrenal gland.

The left adrenal vein is a tributary of the inferior phrenic vein, which enters the roof of the left renal vein near the lateral margin of the vertebral column in almost all patients. The venous sample from the left side is typically obtained from the common inferior phrenic vein close to the junction of the adrenal vein. Usually, it is rapidly catheterized and the blood aspiration is easy to achieve. Rarely, anomalous venous anatomy is encountered, which challenges angiographers to recall their knowledge of venous embryology to find the left adrenal drainage.

The final sample needs to be from a pure background source isolated from any possible contamination from the adrenal venous drainage, including that from frequently identified collateral venous drainage. Traditionally it is stated to be the `IVC' sample. However, we draw the sample from the external iliac vein – it is free of contamination from collateral left adrenal venous effluent, which on rare occasions drains through a large left gonadal vein caudally into the internal iliac veins.

To minimize the time lag between the sampling of the adrenal veins, we sample the right adrenal vein first because it is usually more time-consuming and will be quickly followed by the left sample in almost all cases. The final sample is from the external iliac vein. This approach allows all three samples to be close in physiologic time frame.

Some centres have used additional measures to enhance the success rate of sampling both adrenal veins. For example, pre-AVS CT imaging can offer value in identifying anatomy and relationships of the adrenal vein on the left side and, on the right side, the adrenal gland with respect to the liver and IVC.21 Another method that may assist the radiologist to ensure accurate catheter placement is a rapid automated cortisol assay used to measure intraprocedure adrenal vein cortisol concentrations.22

Aldosterone and cortisol concentrations are measured in the blood from all three sites (right adrenal vein, left adrenal vein, and `IVC'). All of the blood samples should be assayed at 1 : 1, 1 : 10, and 1 : 50 dilutions – absolute values are mandatory. Accurate laboratory assays for cortisol and aldosterone are keys to successful interpretation of the AVS data. An AVS-specific report should be developed by the laboratory to prevent any confusion on data interpretation.

At centres with experience with AVS, the complication rate is 2·5% or less.6,18,21 Complications can include symptomatic groin haematoma, adrenal haemorrhage, and dissection of an adrenal vein.

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences Accurate data interpretation

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

The cortisol concentrations from the adrenal veins and IVC are used to confirm successful catheterization; the adrenal vein to IVC cortisol ratio is typically more than 10 : 1 with the continuous cosyntropin infusion protocol (Fig. 1b).6 When cosyntropin infusion is used, an adrenal vein to IVC cortisol gradient of at least 5 : 1 is required to be confident that the adrenal veins were successfully catherterized. This gradient is achieved in 96% of our patients.6 However, when cosyntropin infusion is not used, an adrenal vein to IVC cortisol gradient of more than 3 : 1 is recommended;21 although, as mentioned, others have suggested even lower cut-offs.17,18

Dividing the right and left adrenal vein plasma aldosterone concentrations (PAC) by their respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein; these are termed cortisol–corrected ratios. At our centre, in patients with APA, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol to normal adrenal PAC/cortisol) is 18 : 16 We use a cut-off for the cortisol–corrected aldosterone ratio from high-side to low-side of more than 4 : 1 to indicate unilateral aldosterone excess.6 In patients with presumed IHA, the mean cortisol-corrected aldosterone ratio is 1·8 : 1 (high-side to low-side); a ratio less than 3 : 1 is suggestive of bilateral aldosterone hypersecretion.6 Therefore, most patients with an unilateral source of aldosterone will have cortisol–corrected aldosterone lateralization ratios > 4·0; ratios > 3·0 but < 4·0 represent a zone of overlap. A ratio < 3·0 is consistent with bilateral aldosterone hypersecretion.6 In addition, the contralateral aldosterone : cortisol ratio is less than the IVC aldosterone : cortisol ratio in 93% of patients with surgically confirmed APA.6 Centres that perform AVS without the benefit of cosyntropin infusion use lower lateralization cut-off values.17,18 Using the preceding diagnostic cut-offs, the test characteristics of AVS for detecting unilateral aldosterone hypersecretion include a specificity of 100% and an apparent sensitivity of 95%. However, it should be noted that to determine a true sensitivity for AVS, all patients undergoing AVS would need to undergo surgery – a treatment step that, for ethical reasons, is not and should not be done.

Jump to…Top of pageAbstractIntroductionAppropriate patient selectionCareful patient preparationFocused technical expertiseDefined protocolAccurate data interpretationReferences References

Top of page Abstract Introduction Appropriate patient selection Careful patient preparation Focused technical expertise Defined protocol Accurate data interpretation References

1 Funder, J.W., Carey, R.M., Fardella, C., Gomez-, C.E., Mantero, F., Stowasser, M., Young, W.F. Jr & Montori, V.M. (2008) Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 93, 3266–3281.

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3 Melby, J.C., Spark, R.F., Dale, S.L., Egdahl, R.H. & Kahn, P.C. (1967) Diagnosis and localization of aldosterone-producing adenomas by adrenal vein catheterization. New England Journal of Medicine, 277, 1050–1056.

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4 Mahoney, E.M., Friend, D.G., Dexter, L. & on, J.H. (1963) Localization of (adrenal and extra-adrenal) pheochromocytomas by vena caval blood sampling. Surgery Forum, 14, 495–496.

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22 Mengozzi, G., Rossato, D., Bertello, C., Garrone, C., Milan, A., Pagni, R., Veglio, F. & Mulatero, P. (2007) Rapid cortisol assay during adrenal vein sampling in patients with primary aldosteronism. Clinical Chemistry, 53, 1968–1971.

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