CHEST
Small Cell Lung Cancer
Presenting as a Paraneoplastic
Syndrome Characterized by
Recurrent Episodic
Hypotension and Bradycardia*
Case Report
Mike G. Martin, MD; Amer K. Ardati, MD;
Shannon M. Dunlay, MD; Amy P. Abernethy, MD; and
Michael A. Blazing, MD
A 56-year-old man presenting with a 6-month history
of recurrent episodic hypotension and bradycardia
was found to have limited-stage small cell lung can-
cer. During both quiescence and episodes of hemo-
dynamic embarrassment, extensive evaluations were
conducted. Possible explanations included the fol-
lowing: intermittent great vessel obstruction;
baroreceptor failure/hypersensitivity; and auto-
nomic dysfunction. His clinical course favored an
antibody-negative dysautonomic paraneoplastic
syndrome. (CHEST 2007; 131:290 –293)
Key words: critical care; hypotension; lung cancer
Abbreviation: CCU ⫽ cardiac care unit
A icant
56-year-old white man with a medical history signif-
for hypertension, coronary artery disease status
post-single-vessel coronary angioplasty ⬎ 10 years ago,
COPD (smoking history, 100⫹ pack-years; FEV1, 3.24 L
or 98% predicted), and mild anxiety was evaluated in our
cardiac care unit (CCU) for episodic hypotension and
bradycardia.
Six months prior to hospital admission, the patient
began experiencing episodes of “falling out.” The episodes
were characterized by flushing, followed by agitation,
*From the Departments of Internal Medicine (Drs. Martin,
Ardati, and Dunlay), Hematology and Oncology (Dr. Abernethy),
and Cardiology (Dr. Blazing), Duke University Medical Center,
Durham, NC.
The authors have reported to the ACCP that no significant
conflicts of interest exist with any companies/organizations whose
products or services may be discussed in this article.
Manuscript received May 18, 2006; revision accepted June 22,
2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Mike G. Martin, MD, Duke University, 1322
Arnette Ave, Durham, NC 27707; e-mail: marti157@mc.duke.edu
DOI: 10.1378/chest.06-1281
290
Selected Report
diaphoresis, nausea, and feeling “faint.” At the climax of
his episodes, the patient developed left-sided crushing
chest pain and confusion. The patient would respond by
becoming recumbent. The episodes lasted between 5 and
30 min and concluded without any intervention. The
attacks initially occurred every 4 to 6 weeks, but were
following a crescendo pattern and becoming increasingly
frequent. He identified no triggers or alleviating factors.
The attacks started both when he was standing and lying,
and had no relationship to food or the position of his head.
The patient’s antihypertensive regimen consisted of ther-
apy with atenolol, lisinopril, and felodipine. The patient
also used paroxetine, lorazepam, simvastatin, clopidogrel,
naproxen, aspirin, and hydrocodone.
After experiencing several of these attacks at home, he
presented to the emergency department of another insti-
tution for evaluation. By the time of his arrival at the other
facility, his attack had terminated. There, he had a normal
ECG and negative findings for cardiac enzymes. He was
referred back to his primary care physician, who obtained
a persantine exercise stress test and a chest radiogram.
The stress test had negative adequate findings. The chest
radiogram showed a left lung field opacity that was further
defined by chest CT scan to be a well-demarcated
2.4 ⫻ 2.5 cm mass in left mid-lung field. He was referred
2 months later to the thoracic surgery department at our
institution for video-assisted thorascopic surgery. A wedge
biopsy sample of the mass revealed small cell lung cancer.
On postoperative day 7, the patient reported that he was
having a typical episode. He was found to be hypotensive
(60/30 mm Hg) and bradycardic (pulse, 50 beats/min). A
250-mL bolus of normal saline solution was administered,
and his vital signs normalized after 10 min. The findings of
the physical examination were normal including clear lung
fields and no peripheral edema. The results of his chem-
istry panel, liver function test, thyroid stimulation hor-
mone, free T 4 measurement, and coagulation profile were
all normal. His CBC count was remarkable only for a
stable normocytic anemia with a hemoglobin level of 10.6
g/dL. His treatment with antihypertensive medications
was stopped, and he was transferred to the CCU for
further monitoring.
After spending 24 h in the CCU without showing
telemetry abnormalities or changes in his ECG and with
negative serial cardiac markers, he experienced another
episode. Again, his pulse dropped to the 50 beats/min, and
BP to 60/30 mm Hg. The patient received 1 L of normal
saline solution without a response. An ECG demonstrated
only sinus bradycardia, and the finding of a portable chest
radiograph was without acute change. Emergent echocar-
diography showed a left ventricular ejection fraction of
⬎ 55% without any wall motion abnormalities. Treatment
Selected Report
with dopamine was started without a response in either BP
or pulse. The episode spontaneously terminated after
approximately 30 min.
Further evaluation included serial cardiac enzyme tests,
the results of which remained negative, and a CT scan of
the chest, abdomen, and pelvis. The latter showed no
pericardial effusion, a prevascular mediastinal soft-tissue
mass measuring 7.2 ⫻ 2.4 cm abutting the transverse aorta
and main pulmonary artery as well as partially encasing the
left main pulmonary artery, and a left suprahilar mass
measuring 4.8 ⫻ 3.2 cm that was associated with postob-
structive atelectasis. These additional masses were new
when compared with the CT scan that had been per-
formed 2 months previously at the outside institution. The
remainder of the CT scan was notable only for diverticu-
losis without diverticulitis. The findings of an MRI study of
the brain were normal.
Autonomic reflexes (ie, with orthostatic vital sign test,
Valsalva test, and ice-water immersion test) were intact at
rest, and the former two were absent during the episodes.
He had normal heart rate variability between episodes.
Due to his extremis with the episodes, we were unable to
test his orthostatic response during one. He had an
appropriate response to an adrenocorticotropic hormone
stimulation test. His serum histamine, serotonin, VDRL,
and 24-h urine 5-HIAA levels were normal. An arterial
line was placed, and serum norepinephrine, epinephrine,
dopamine, and total catecholamine levels were measured
both during an episode and during quiescence (Table 1).
The results of a paraneoplastic antibody panel (ie, Ach
receptor [muscle] binding antibody, striational antibody,
Ca channel binding antibody N-type, Ca channel binding
antibody P/Q-type, parietal cell antibody Tr, CRMP-5-IgG
antibody, anti-neutrophil nuclear antibodies 1, 2, and 3,
parietal cell antibodies 1 and 2, amphiphysin antibody, and
Achr ganglionic neuronal antibody) were negative.
Further episodes were easily managed initially with IV
phenylephrine, which the patient immediately responded
to, and then subcutaneous ephedrine, again with excellent
results. His small cell lung cancer was then treated with
carboplatin and etoposide followed by radiation therapy.
His last episode occurred during his first carboplatin
infusion. Six months after the initiation of chemotherapy,
he continues to do well, having had no further episodes
and only 10% of his original tumor burden.
Table 1—Catecholamine Levels at Baseline and During an Episode*
Catecholamines Normal Baseline
Norepinephrine, nmol/d 0–399 310
Epinephrine, nmol/d 0–99 ⬍ 10
Dopamine, nmol/d 0–142 21
Total catecholamines, nmol/d 0–642 ⬍ 341
*NA ⫽ not available.
†Values are given as the mean ⫾ SD.
‡Patients with Bradbury-Eggleston syndrome.
www.chestjournal.org
Discussion
There is a broad differential diagnosis for episodic
hypotension (Table 2). Three of these possible explana-
tions fit this patient’s clinical context, as follows: intermit-
tent great-vessel obstruction; baroreceptor failure; and
autonomic dysfunction instigated by a paraneoplastic syn-
drome.
A large residual mass abutting the transverse aorta and
main pulmonary artery, and partially encasing the left
pulmonary artery (Fig 1) remained after the surgery. It is
possible that there was intermittent compression of these
vascular structures leading to hypotension through sudden
drops in cardiac output. Occlusion of the outflow tracts
should result in a reflexive tachycardia in order to maintain
cardiac output. Moreover, one would also expect to find
other signs of outlet obstruction such as pulmonary
edema, hypoxia, or jugular venous distension. The absence
of a positional character to the patient’s symptoms also
suggests that there is no intermittent obstruction.
Baroreceptor failure/hypersensitivity was also consid-
ered. Baroreceptors and associated reflexes respond to
changes in arterial pressure in order to buffer against
excessive fluctuations in BP. In the thorax, baroreceptors
that lie in the aortic arch and great vessels communicate
with the brainstem via the vagus nerve. Outside of the
thorax, the carotid sinuses have receptors that respond to
distention of the vessel wall and, through the glossopha-
ryngeal nerves, communicate to the brainstem. Further-
more, the blood volume in the thorax is monitored by
low-pressure receptors that also communicate to the CNS
by way of the vagus. Both the vagal and glossopharyngeal
afferents feed into the nucleus tractus solitarii.1–3 Lesions
anywhere along these pathways may lead to baroreceptor
failure. Given the intimate relationship between the tumor
and great vessels, it was postulated that the tumor could
either be invading or mechanically compressing barore-
ceptors.
This raises a point of common clinical confusion.4 The
terms baroreflex failure and autonomic failure are often
used interchangeably, which is inappropriate. Baroreflex
failure usually presents clinically volatile hypertension, not
hypotension. This is particularly true for patients with
anatomic lesions, such as tumors, involving the barorecep-
tors or removal of the baroreceptors during neck dissec-
tion.5–7
The patient’s catecholamine profile was normal at base-
During Baroreceptor Autonomic
Episode Failure† Failure†‡
290 1,840 ⫾ 320 28 ⫾ 3
104 110 ⫾ 21 10 ⫾ 3
87 64 ⫾ 12 11 ⫾ 4
481 NA NA
CHEST / 131 / 1 / JANUARY, 2007 291
 Table 2—Disorders of Episodic Hypotension*
Cardiac Dysrhythmias
(Both Tachycardic and Bradycardic)
Intermittent vascular obstruction
Abnormal activation of autonomic reflexes
Abnormal release of vasoactive substances
*IVC ⫽ interior vena cava; SVC ⫽ superior vena cava. From the article by Williams and Bashore.8
line in contrast to persons with primary autonomic failure
or baroreceptor failure (Table 1).4 Also, during his acute
decompensations he was able to mount an endogenous
catecholamine surge. A patient with a similar clinical
presentation has been described.8 This patient, though,
experienced a dramatic fall in his endogenous catechol-
amine levels during acute episodes, therefore arguing that
the lesion is centrally mediating the inhibition of sympa-
thetic discharge or the episodic release of an unknown
endogenous compound with inhibitory effects on the
central or preganglionic sympathetic neurons or postgan-
glionic sympathetic neurons by a presynaptic inhibition of
norepinephrine release. That patient did not have a known
tumor.
In contrast to that patient, our patient was able to
mount a primary biochemical response to stress, implying
Figure 1. CT scan of the thorax showing a mass abutting the
aorta and in intimate association with the pulmonary arteries.
292
Description
Atrial myxoma
Defective cardiac valve prosthesis
Pregnancy or large intraabdominal tumor compressing the IVC
Thoracic tumor compressing the SVC or great vessels
Aortic stenosis
Idiopathic hypertrophic subaortic stenosis
Vasovagal syncope
Autonomic failure (orthostatic hypotension)
Hypersensitive carotid sinus syndrome
Micturition syncope
Cough syncope
Paraneoplastic syndromes
Carcinoid syndrome (serotonin syndrome)
Systemic mastocytosis (histamine)
Anaphylactic shock
Hereditary angioedema
the intact fidelity of cholinergic transmission and the
postganglionic sympathetic and adrenal medulla path-
ways.9 He apparently experienced an intermittent failure
to respond to both endogenous and exogenous cat-
echolamines. It is plausible that, given the appropriate
temporal relationship with the onset of his small cell lung
cancer, that the tumor elaborated or provoked an inter-
mittent blockade of adrenergic signaling at the receptor
level.
The usual presentation of autonomic dysfunction is
orthostatic hypotension and other dysautonomias. Multi-
ple patients have been described with paraneoplastic
dysautonomia, which is often related to a positive anti-Hu
(ie, ANNA-1) antibody.10,11 These patients present with
constant, progressive dysfunction as opposed to the inter-
mittent episodes seen in our patient.
Per the diagnostic criteria proposed for neurologic
paraneoplastic syndromes, our patient who had a known
malignancy, a nonclassic neurologic syndrome, and reso-
lution of the syndrome with chemotherapy would be
classified as having a “definite” paraneoplastic syndrome.12
Antibody negativity does not exclude this diagnosis as
antibodies are frequently absent in dysautonomia.
The pathogenesis of paraneoplastic syndromes remains
clouded. The current opinion is that they most likely
originate with T-cell or antibody recognition of neural
epitopes, possibly through the expression of previously
sequestered epitopes from the testes and CNS by the
neoplasm (onconeural antigens).12
Finally, why is this condition not just vasovagal syncope?
Several lines of argument go against this possibility. First,
the duration of the episodes and the degree of prostration
the patient experienced would be markedly atypical for
vasovagal syncope. Second, one would expect that the
levels of endogenous catecholamines would decrease
rather than increase during the episodes if they were
Selected Report
vasovagal. Third, the patient should respond to a surge of
exogenous catecholamines during an episode if this con-
dition were simple syncope. Finally, the episodes abated
with the appropriate treatment of his tumor.
Given the lack of an alternative explanation for our
patient’s clinical syndrome, its synchronous evolution with
his cancer, and his response to generalized antitumor
therapy, we feel that the patient had a small cell lung
cancer related paraneoplastic syndrome, which intermit-
tently impaired the ability of his body to respond to
adrenergic stimulation.
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