CT of Pheochromocytoma and Paraganglioma: Risk of Adverse Events with IV

Administration of Nonionic Contrast Material

Richard Bessell-Browne; Martin E. O'Malley
Authors and Disclosures
Posted: 06/27/2007; Am J Roentgenol. 2007;188(4):970-974. © 2007 American
Roentgen Ray Society
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Abstract and Introduction

Abstract

Objective: When pheochromocytoma or paraganglioma is suspected, many institutions

perform only unenhanced CT because of a perceived risk of inducing a hypertensive
crisis with IV administration of contrast material. The purpose of this study was to
review our experience with the use of nonionic IV contrast material for CT of patients
with pheochromocytoma or paraganglioma. The specific goal was to determine whether
adverse events occurred.
Materials and Methods: A retrospective review of radiology records identified 25
patients (17 women, eight men; mean age, 43 years; age range, 27-70 years) with 40
pathologically proven pheochromocytomas or paragangliomas who received nonionic IV
contrast material for CT. There were 16 adrenal pheochromocytomas, 12 abdominal
paragangliomas, five neck paragangliomas, and seven metastatic lesions. Medical
records were reviewed to determine whether the tumors were sporadic or associated
with a syndrome, incidentally detected, or biochemically active; and whether patients
were taking α-blocking medication at the time of CT. Adverse events were documented.
Results: Nineteen patients had 23 sporadic tumors, and six patients had 17 tumors
associated with a syndrome. In 12 (48%) of the 25 patients the diagnosis was clinically
unsuspected at the time of CT. Elevated levels of urinary catecholamines or their
metabolites were found in 19 (90%) of the 21 patients for whom this test was
performed. No patients were taking α-blocking medication at the time of CT. No adverse
events occurred in association with IV administration of nonionic contrast material.
Conclusion: IV administration of nonionic contrast material for CT is a safe practice for
patients with pheochromocytoma and related tumors even without α-blocking
medication.

Introduction

Pheochromocytoma is a neoplasm of the adrenal chromaffin cells, and paraganglioma is

a neoplasm of the extraadrenal paraganglia. These tumors secrete catecholamines that
can induce life-threatening hypertensive crises. Although there are reports that IV or
intraarterial administration of ionic contrast material can induce hypertensive crisis in
patients with pheochromocytoma or paraganglioma, [1-3] in only one study[4] to our
knowledge has the issue of IV administration of nonionic contrast material to patients
with pheochromocytoma and related tumors been systematically addressed. In that
study, there was no statistically significant increase in catecholamine levels after
peripheral IV administration of nonionic contrast material versus injection of normal
saline solution. Despite the findings of that study, there remains, both anecdotally and
in the literature, a perceived risk of inducing hypertensive crisis with IV administration
of nonionic contrast material to patients with pheochromocytoma or paraganglioma. [5-
8]
 The purpose of our study was to review our experience with the administration of
nonionic IV contrast material for CT of patients with pheochromocytoma or
paraganglioma.

Materials and Methods

This retrospective study was approved by our research ethics boards. Informed consent
was not required. A computerized search of radiologic records at our institution from
January 1999 to September 2005 was performed to identify patients with known or
suspected pheochromocytoma or paraganglioma. In addition, our cancer registry
records, which were available from January 1999 to December 2003, were searched
electronically to identify additional patients with a diagnosis of pheochromocytoma or
paraganglioma.

To be included in the study, each patient was required to have pathologically proven
pheochromocytoma or paraganglioma and to have undergone CT with nonionic contrast
material at our institution between January 1999 and September 2005. We identified 28
CT studies performed with nonionic IV contrast medium on 25 patients with one or
more pathologically proven pheochromocytomas or paragangliomas, and these patients
formed the study group. The patients were 17 women and eight men with a mean age
of 43 years (range, 27-70 years).

The lesions were 16 adrenal pheochromocytomas, 12 abdominal paragangliomas

(including one primary liver paraganglioma), five neck paragangliomas, and seven
metastatic lesions. The medical records were reviewed to determine whether the
tumors were sporadic or associated with a syndrome, clinically unsuspected or
incidental as opposed to clinically suspected or known, and biochemically active and
whether the patients were taking α-blocking medication at the time of CT.

Patients were classified as having symptomatic tumors if there was a history of

hyperadrenergic symptoms such as paroxysmal flushing, sweating, palpitations, and
headaches. The presence of hypertension also was recorded. Patients with hypertension
alone were considered to have asymptomatic lesions. [9] The type, volume, and rate of IV
administration of contrast material were recorded.
At our institution, all CT scans are obtained and monitored by a CT technologist. Any
adverse event is reported to the supervising radiologist at the time of scanning, and
these patients are clinically examined by a radiologist. For each adverse event, an
incident report is completed by the technologist and radiologist and recorded
electronically. An electronic search was performed to match our study group with the
incident reports at our institution during the study period to determine whether any of
these patients experienced adverse events related to IV administration of nonionic
contrast material.

The anatomic location, number, and type of tumor in each patient were recorded. One
reviewer retrospectively recorded the maximal axial size and appearance of each tumor,
including the presence of necrosis, cystic components, and calcification. The attenuation
of each tumor was measured with the largest region of interest possible, excluding any
necrotic, cystic, or calcified component. If a patient had multiple pheochromocytomas
or paragangliomas, the attenuation value of the largest lesion of each type was recorded
for each phase available to avoid the issue of correlated data. If the patient underwent
CT more than once, only the attenuation values on the initial study were recorded.

Results

Twenty-five patients with 40 tumors underwent 28 CT examinations with IV

administration of nonionic contrast material. Twenty-two patients underwent one CT
examination, and three patients underwent two examinations. The patient- and tumor-
related data are summarized in Table 1 . Nineteen patients had 23 sporadic lesions, that
is, the lesions were not associated with a known syndrome. The other six patients had
17 lesions associated with a documented or suspected syndrome.

In 12 (48%) of the 25 patients, the diagnosis of pheochromocytoma or paraganglioma

was clinically unsuspected at the time of CT. Five of these patients, however, had at
least one paroxysmal hyperadrenergic symptom of palpitation, diaphoresis, or headache
before CT that was revealed only at subsequent clinical assessment. Ten of these 12
patients had hypertension. Blood pressure measurements were available for only five
patients, and they ranged from 150/80 to 170/105 mm Hg. For the other five patients,
there was only a reference in the notes to the presence of hypertension.

Thirteen (52%) of the 25 patients had clinically suspected or known pheochromocytoma

or paraganglioma. Four of these patients had at least one paroxysmal hyperadrenergic
symptom, and one patient had stress cardiomyopathy from catecholamine excess. Four
of these 13 patients had hypertension, with blood pressure levels ranging from 130/90
to 200/100 mm Hg.
Twenty-one of the 25 patients underwent biochemical testing. Levels of urine
catecholamines or their metabolites were elevated in 19 (90%) of the 21 patients. One
of the two patients with negative biochemical results had a small (20 mm) pelvic lymph
node metastatic lesion from a previously resected functional paraganglioma of the
bladder. The other patient had three small (20 mm, 7 mm, 7 mm) hepatic metastatic
lesions from a previously resected functional pheochromocytoma.

Biochemical results were not available for four patients. Two of these patients were
presumed to have functionally active tumors. One of these two patients had
documented labile blood pressure at the time of unrelated surgery, and the other who
had primary liver paraganglioma had severe hypertension that resolved after resection
of the lesion. One of the other two patients had labile blood pressure when the
paraganglioma was handled at surgery. The other patient, who had multiple endocrine
neoplasia type 2a, had a 13-mm pheochromocytoma without symptoms of hypertension
that was probably too small to be functionally significant.

In summary, in the entire study population 10 (40%) of the 25 patients had symptoms
related to catecholamine excess. Hypertension was documented in 14 (56%) of the
patients. Twenty-one (84%) of the patients were considered to have functionally active
tumors, 19 having positive catecholamine results and two having hypertension likely the
direct result of the tumors.

All CT scans were obtained with nonionic contrast material: iohexol 300 mg I/mL
(Omnipaque 300, GE Healthcare) in 15 CT studies and iodixanol 270 mg I/mL (Visipaque
270, GE Healthcare) in 13 CT studies. In three patients, the volume of contrast material
was not recorded. According to the CT protocol used for these patients, however, each
would have received 100 mL. The mean volume of contrast material administered was
105 mL (range, 60-192 mL). Most CT scans (19/28) were obtained with 100 mL of
contrast material. The mean rate of IV infusion was 3 mL/s (range, 2-5 mL/s).

None of the patients were taking α-blocking medications at the time of CT. No adverse
events related to IV administration of nonionic contrast material were recorded;
specifically, no patient had hyperadrenergic symptoms. Blood pressure measurements
were obtained immediately after completion of CT scanning for only two patients. For
both patients, the CT report indicated that neither patient had hypertension; the blood
pressure measurements were not recorded.

The mean diameter of the largest tumor in each patient was 54 mm (range, 13-135
mm). Including all 40 tumors, the mean diameter was 40.5 mm (range, 7-135 mm). The
tumors were roughly grouped into three main morphologic types: 15 solid or
predominantly solid tumors (Figure 1), seven tumors with mixed solid and necrotic
components (Figure 2), and three predominantly cystic lesions (Figure 3). Calcification
was present in three tumors.

Figure 1.

38-year-old woman with left paraaortic paraganglioma. IV contrast-

enhanced CT scan shows homogeneous enhancement of solid mass.

(Enlarge
Image)

Figure 2.

29-year-old man with large primary hepatic paraganglioma. IV contrast-

enhanced CT scan shows evidence of central necrosis.

(Enlarge
Image)

Figure 3.

45-year-old woman with right adrenal pheochromocytoma. IV contrast-

enhanced CT scan shows predominantly cystic lesion.

(Enlarge
Image)

Unenhanced images from 16 CT examinations of 16 patients were available for review.

No solid component of a tumor had an attenuation value less than 23 H, the mean
attenuation of the solid components measured 41 H (range, 23-53 H). Arterial phase
images obtained in 11 CT examinations of 11 patients showed a mean tumor
attenuation of 172 H (range, 71-263 H). Portal venous phase images in 22 CT
examinations of 22 patients showed a mean tumor attenuation of 114 H (range, 55-176
H).

Discussion

None of the 25 patients with pheochromocytoma or paraganglioma in this study had

adverse events related to IV administration of nonionic contrast material for CT. Most of
the patients (21/25, 84%) were considered to have functionally active tumors, and no
patients were taking α-blocking medication at the time of IV administration of nonionic
contrast material. Our results support the hypothesis that IV administration of nonionic
contrast material for CT of patients with pheochromocytoma or paraganglioma is a safe
practice.

In patients with pheochromocytoma, precipitation of hyperadrenergic symptoms and

hypertensive crises have been known to occur with anesthesia, adrenal venography and
arteriography with ionic contrast material, manipulation of the tumor during surgery,
and biopsy of the tumor.[1-3,10-12] Few studies have addressed the risk that IV
administration of nonionic contrast material can induce a hypertensive crisis in
association with pheochromocytoma. We found only one report [13] in the literature of
induction of hypertensive crisis by IV administration of contrast material for CT. In that
report, CT was performed with ionic contrast material, and the patient was given
glucagon, which is a known potent inducer of catecholamine release. Using MEDLINE
and EMBASE databases, we found no reports in the English-language literature of
induction of hypertensive crisis by peripheral IV administration of nonionic contrast
material.

The main systematic study of the possibility of induction of catecholamine release from
these tumors with the use of IV administration of ionic, as opposed to nonionic, contrast
material was conducted by Raisanen et al. [14]Those investigators studied the effects of
the ionic contrast agent iothalamate meglumine 60% (Conray 60, Mallinckrodt) on eight
patients with pheochromocytoma and related tumors and on 12 control patients. In that
study, there was an unpredictable rise in norepinephrine and epinephrine levels among
the patients with pheochromocytoma and related tumors, but the increase was not
statistically significant. The patients were taking α-blockers, and no hypertension was
induced. However, five patients had an increase in catecholamine level that the authors
stated would have been high enough to have led to a pressor effect in a patient not
taking an α-blocker. The authors recommended that such patients be given an α-blocker
before IV administration of IV contrast medium. These investigators, however, took only
one measurement of catecholamine release 10 minutes after infusion of contrast
material. This factor makes it unclear whether a direct effect of the contrast material
can be inferred, particularly because release of catecholamines by these tumors during
direct venography and arteriography is known to occur almost immediately after
injection.[2,3]

A study by Mukherjee et al. [4] is the only study of which we are aware that was a
systematic examination of the catecholamine release induced by IV administration of
nonionic contrast material in patients with pheochromocytoma and paraganglioma.
That study included 10 patients with pheochromocytoma and related tumors who were
taking α-blocking medication and six healthy volunteers who were given the nonionic
contrast agent iohexol (Omnipaque, Nycomed, now GE Healthcare). In the study, there
was no statistically significant increase in epinephrine or norepinephrine levels in the 10
patients or six control subjects given injections of iohexol in comparison with 0.9% saline
solution. The authors measured plasma catecholamine levels up to 60 minutes after
injection in nine of the 10 patients. Catecholamine levels also were found to be highly
fluctuant among these patients. In two patients, peak catecholamine changes occurred
25 and 60 minutes after injection. This finding led the authors to suggest that any
apparent increase in catecholamine level after the injection of contrast material was
probably spontaneous and unrelated to the injection of contrast material. The authors
concluded that "pressor crises are unlikely to be evoked by the peripheral IV use of the
nonionic contrast medium iohexol" and that "specific blockade may not be required
before contrast medium-enhanced scanning with iohexol."

We reviewed five published articles [5-7,9,15] that included a total of 58 patients with

pheochromocytoma who underwent CT studies with IV administration of nonionic
contrast material in which the presence or absence of adverse effects was recorded.
Although the focus of those studies was not the effect of nonionic IV contrast material
on catecholamine release, no adverse events were reported. It was not stated in the
articles whether the patients were taking an α-blocker. It is likely, however, that most of
the patients were not taking the medication because many of the tumors either were
incidentally detected or were part of screening CT studies of patients with von Hippel-
Lindau disease.[5-7,9,15] In another study,[16] investigators directly compared the washout
characteristics of 17 pheochromocytomas against adrenal adenomas. Adverse events
were not mentioned in that article, and it was not stated whether the patients were
taking α-blocking medication.

In our study, 12 (48%) of the patients had incidental tumors. The high percentage of
incidental tumors in our patient population is in accordance with the findings of four
studies[9,16-18] involving a total of 137 patients in whom 41-58% of pheochromocytomas
were discovered incidentally on radiologic imaging. Adrenal incidentaloma is common,
and washout CT is being used increasingly to characterize lipid-poor adrenal lesions, a
small percentage of which are unsuspected pheochromocytoma. As a result, many
pheochromocytomas are likely to be imaged with nonionic IV contrast-enhanced CT, so
it is important that IV administration of nonionic contrast material is safe in this setting.

Our study had limitations. It was a retrospective review of a relatively small number of
cases and relied on accurate record keeping. However, all CT scans are closely
monitored at our institution, and all adverse events are reported to the supervising
radiologist, who is responsible for documentation. A hypertensive crisis is a dramatic
symptomatic event and is extremely unlikely to have occurred and gone unrecorded.
Likewise, it is highly unlikely that any hyperadrenergic symptoms would not have been
recorded.

In the past, because of the theoretic risk of induction of hyperadrenergic symptoms, it

has been the general practice at our institution to avoid IV contrast material in patients
with suspected or known pheochromocytoma. However, 13 patients underwent
contrast-enhanced CT for which the indication on the requisition form was suspicion of
pheochromocytoma or pheochromocytoma based on the patient's syndrome. The use
of IV contrast material in imaging of these patients likely reflects a relative lack of clearly
defined guidelines in the literature regarding this issue, and the situation is likely to be
similar in other large medical imaging departments in which many staff radiologists and
trainees are involved in protocols of CT studies.

Although approximately 90% of pheochromocytomas and paragangliomas are detected

on unenhanced CT, the use of IV contrast medium can improve this sensitivity,
particularly for extraabdominal lesions and for small retroperitoneal tumors and distant
metastasis.[19-21] Routine use of IV contrast material also allows accurate assessment of
blood vessels, and this capability may aid in surgical planning. This issue has become
more relevant with the increasing use of laparoscopic surgery for adrenal lesions.
[22]
 Some institutions may require α-blocking medication for patients with
pheochromocytoma before performing contrast-enhanced CT. However, these
medications may have side effects such as orthostatic hypotension. In addition, IV
administration of some α-blockers may interfere with 123I metaiodobenzylguanidine
(MIBG) uptake.[23] At some institutions, MIBG is used to localize and identify
pheochromocytoma and paraganglioma, especially when the presence of more than
one tumor is suspected. Therefore, administration of α-blockers for the specific purpose
of performing IV contrast-enhanced CT may delay the evaluation and treatment of some
patients.

In conclusion, none of the patients with pheochromocytoma or paraganglioma in this

study experienced adverse events related to the peripheral IV administration of
nonionic contrast material. Our results and the clinical practice described in the recent
literature suggest that α-blockade is not specifically required before IV administration of
nonionic contrast material to patients with suspected or known pheochromocytoma or
related tumors.
Reaction:

As I read the article, this states that when pheochromocytoma or paraganglioma

is suspected, many institutions perform only unenhanced CT because of a perceived risk
of inducing a hypertensive crisis with IV administration of contrast material. So thay
made this study to review our experience with the use of nonionic IV contrast material
for CT of patients with pheochromocytoma or paraganglioma. The specific goal was to
determine whether adverse events occurred. Here they studied 25 patients with
different tumors associated with a syndrome. After the test it concludes that No
patients were taking a-blocking mediaction at the time of CT. and no adverse events
occurs in association with IV administration of non-ionic contrast material. With these
study, institutions can now freely administer non-ionic contrast material for CT, for it is a
safe practice for patience with pheocrhomocytoma and related tumors even without a-
blocking medication.