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clinical problem-solving

A Crisis in Late Pregnancy

Akshay S. Desai, M.D., M.P.H., William A. Chutkow, M.D., Ph.D.,
Elazer Edelman, M.D., Ph.D., Katherine E. Economy, M.D.,
and G. William Dec, Jr., M.D.
In this Journal feature, information about a real patient is presented in stages (boldface type)
to an expert clinician, who responds to the information, sharing his or her reasoning with
the reader (regular type). The authors’ commentary follows.

A 31-year-old woman in the 37th week of an uncomplicated pregnancy presented to From the Division of Cardiovascular Medi-
cine (A.S.D., W.A.C., E.E.) and the Center
the emergency department with sudden onset of severe bitemporal headache and for Maternal–Fetal Medicine, Department
shortness of breath. Her medical history was notable for hypothyroidism and perni- of Obstetrics and Gynecology (K.E.E.),
cious anemia (both treated). She had had four previous pregnancies: the first was Brigham and Women’s Hospital: and the
Division of Cardiology, Massachusetts
terminated therapeutically for elective reasons, the next two resulted in spontaneous General Hospital (G.W.D.) — both in
abortions, and the fourth resulted in the birth of a healthy girl, delivered vaginally, Boston. Address reprint requests to Dr.
3 years earlier. The patient had never smoked and did not drink alcohol or use illicit Desai at the Division of Cardiovascular
Medicine, PBB-A3, AB370, Brigham and
drugs. Her family history was unremarkable. Women’s Hospital, 75 Francis St., Boston,
MA 02115, or at adesai@partners.org.
Shortness of breath in the third trimester of pregnancy has a broad differential
N Engl J Med 2009;361:2271-7.
diagnosis. This symptom may simply reflect increased minute ventilation due to Copyright © 2009 Massachusetts Medical Society.
central chemoreceptor alterations or mechanical interference with diaphragmatic
expansion by the gravid uterus. However, pathologic causes must also be considered,
such as volume overload, anemia, and infection. Pulmonary embolism, supraventricu-
lar or ventricular arrhythmias, heart failure, coronary-artery dissection, and aortic
dissection, as well as complications associated with pregnancy such as preeclamp-
sia and peripartum cardiomyopathy, are among the “must not miss” diagnoses and
should be ruled out. An Interactive Medical
Case related to this
Clinical Problem-Solving
The patient was in apparent respiratory distress and reported that she felt like she was article is available at
“drowning.” She reported no fever, cough, chest pain, nausea, vomiting, visual NEJM.org
changes, abdominal pain, contractions, or vaginal bleeding. On examination, she was
afebrile. Her pulse was 120 beats per minute, blood pressure was 180/110 mm Hg,
respiratory rate was 32 breaths per minute, and oxygen saturation was 70% while
she was breathing ambient air. She was unable to lie flat without having more diffi-
culty breathing. Funduscopic examination was normal. Jugular venous pressure was
estimated at 15 cm of water. Auscultation of the lungs was notable for bibasilar rales.
Cardiovascular examination revealed tachycardia, a summation gallop, and a grade
2/6 apical holosystolic murmur. The apical cardiac impulse was diffuse but not dis-
placed. Her abdomen was gravid and not tender to palpation. The extremities were
warm, with no petechiae or edema. Mild uterine contractions were noted every 5 min-
utes. On pelvic examination, her cervix was 1 cm dilated and 80% effaced, with the
head at –2 cm. Doppler examination revealed normal fetal heart tones at a rate of
about 130 beats per minute, with moderate variability.

Her physical examination suggests biventricular heart failure. Although malignant

hypertension could account for the headache and heart failure, her funduscopic
examination does not reveal papilledema or hemorrhages. It would be helpful to

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 The n e w e ng l a n d j o u r na l
review any blood-pressure measurements obtained
before pregnancy and to know whether her previ-
ous pregnancies were complicated by similar blood-
pressure lability. Preeclampsia would explain the
headache and hypertension and remains the most
likely diagnosis, although severe pulmonary ede-
ma is not typical of this condition. In the absence
of a preexisting cardiomyopathy, the severe hyper-
tension alone would not be expected to precipitate
acute heart failure in a young person. If there is
an underlying cardiomyopathy, it has to be rela-
tively recent in onset, since the heart does not
appear to be enlarged on physical examination.
Her blood pressure needs to be controlled, and
she requires supplemental oxygen and intrave-
nous loop diuretics. Despite the tachycardia,
I would avoid giving her a beta-blocker because
of its negative inotropic effects. Since vasodila-
tion is often helpful in patients with acute heart
failure (particularly when there is severe hyper-
tension), treatment with hydralazine, nifedipine,
or nitroglycerin may be useful and would not
be contraindicated in pregnancy; hemodynamic
monitoring is also warranted. I would order an
electrocardiogram and an urgent echocardiogram,
as well as measurements of arterial blood gases
and cardiac biomarkers. Urinalysis should be car-
ried out to see whether the patient has proteinu-
ria; the combination of hypertension of recent
onset and proteinuria would be diagnostic of pre­
eclampsia, in the absence of another cause of
the hypertension. Unusual disorders that should
be considered in a younger woman include hu-
man immunodeficiency virus infection with as-
sociated cardiomyopathy or an underlying col-
lagen vascular disease such as systemic lupus
erythematosus, which might explain her previous
spontaneous abortions and might cause a cardio-
myopathy due to myopericarditis.
An electrocardiogram showed sinus tachycardia
with ST-segment elevations in leads I and aVL and
inferolateral ST-segment depressions suggestive of
myocardial ischemia (Fig. 1). A chest radiograph
obtained with abdominal shielding revealed bilat-
eral alveolar infiltrates, which were consistent
with pulmonary edema. Computed tomography
of the head performed without the administration
of contrast material revealed no intracranial hem-
orrhage or cerebral edema.
The results of initial laboratory tests were as
follows: sodium level, 134 mmol per liter; potas-
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of m e dic i n e
sium level, 5.4 mmol per liter; chloride level, 109
mmol per liter; bicarbonate level, 15 mmol per
liter; blood urea nitrogen level, 11 mg per decili-
ter (3.9 mmol per liter of urea); creatinine level,
0.9 mg per deciliter (80 μmol per liter); white-cell
count, 21,800 per cubic millimeter; hemoglobin
level, 14 g per deciliter; platelet count, 356,000 per
cubic millimeter; albumin level, 4.0 g per deciliter;
total bilirubin level, 0.5 mg per deciliter (8.6 μmol
per liter); alkaline phosphatase level, 127 U per li-
ter; alanine aminotransferase level, 74 U per liter;
uric acid level, 4.0 mg per deciliter (238 μmol per
liter); prothrombin time, 12.3 seconds (interna-
tional normalized ratio, 0.9); creatine kinase level,
1353 U per liter, with an MB fraction of 2.3%; and
troponin I level, 23.2 U per liter (normal value, <0.1).
Urinalysis was notable for 3+ protein by dipstick.
Arterial blood gas measurements with the patient
breathing 100% oxygen revealed a pH of 7.42, a
partial pressure of carbon dioxide of 27 mm Hg,
and a partial pressure of oxygen of 48 mm Hg.
The impressive regional ST-segment changes are
not characteristic of acute myocarditis and thus
raise concern about ischemia. Coronary-artery dis-
section may occur late in pregnancy and can cause
acute heart failure. An echocardiogram is warrant-
ed urgently, since the finding of a circumscribed
lateral wall-motion abnormality would increase
concern about an acute coronary syndrome and
prompt urgent referral for diagnostic coronary an-
giography (with appropriate shielding to protect
the fetus). Should this patient be found to have
global left ventricular dysfunction, a coronary-
artery problem would be much less likely, and
angiography could be deferred in favor of medi-
cal stabilization.
The high hemoglobin level is consistent with
hemoconcentration, which is typical of preeclamp-
sia. The elevated white-cell count may reflect an
acute stress reaction or an underlying infection.
The pattern of biomarker findings — that is,
a normal creatine kinase MB fraction and a high
troponin I level — suggests either a late presen-
tation of myocardial infarction (since troponin
stays elevated longer than creatine kinase MB does
after an acute ischemic event) or myocarditis (since
troponins are more sensitive than is creatine ki-
nase MB for picking up low-grade inflammation
within the heart). Still, given this patient’s severe
hypertension and significant proteinuria, my pri-
mary concern is preeclampsia. Immediate admin-
 clinical problem-solving

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

Figure 1. Electrocardiogram Obtained on Presentation.

The electrocardiogram reveals sinus AUTHOR: Desai RETAKE 1st
ICMtachycardia with ST-segment elevations in leads I and aVL and inferolateral
FIGURE: 1ischemia.
of 4 2nd
ST-segment depressions suggestiveREGofFmyocardial 3rd
CASE Revised
EMail Line 4-C SIZE
istration of magnesium sulfate
Enon
forARTIST:
prophylaxis
ts prolonged
H/T H/T maternal
33p9 hypoxemia may all have con-
Combo
against seizures is warranted, and the fetus should tributed to this tragic complication. Given her se-
AUTHOR, PLEASE NOTE:
be delivered as soon as possible. Figure has been redrawn vere hypertension,
and type has been reset. placental abruption should also
becarefully.
Please check considered as a possible contributor, although
The working diagnosis was pulmonary edema the absence of vaginal bleeding makes this less
JOB: 360xx ISSUE: xx-xx-09
due to severe preeclampsia. The patient was treat- likely.
ed with intravenous labetalol, magnesium sulfate,
and furosemide, as well as bilevel positive airway The patient’s respiratory status gradually improved
pressure. In consultation with the high-risk ob- with medical therapy. A transthoracic echocardio-
stetrical service, plans were made for delivery. In gram revealed global left ventricular dysfunction
this multiparous woman who was already in early without cavity dilatation, an ejection fraction of
labor, it was thought that vaginal delivery would 20%, and moderate mitral regurgitation.
probably be expeditious and associated with sig-
nificantly fewer maternal risks than would deliv- A nondilated left ventricle with markedly depressed
ery by cesarean section. Labor was augmented systolic function is most compatible with acute-
with the use of a combination of gradual mechan- onset cardiomyopathy. Such severe ventricular dys-
ical dilation of the cervix with a Foley bulb and in- function may complicate preeclampsia in rare
travenous administration of oxytocin. The patient’s cases. It is possible that the patient had acute
status remained tenuous from a hemodynamic myocarditis or peripartum cardiomyopathy, but I
and respiratory standpoint. She needed to sit bolt would have difficulty explaining her hypertension
upright and was agitated, permitting only inter- if ventricular dysfunction were a primary process.
mittent monitoring of fetal heart tones. Approxi­ Given her positive troponin test, poor ventricular
mately 2 hours after presentation, the heart rate of function, and unexplained ischemic changes on
the fetus was noted to be identical to that of the the electrocardiogram, cardiac catheterization is
mother, at 120 beats per minute. Emergency ultra- warranted.
sonographic imaging revealed intrauterine fetal
death. No vaginal bleeding was noted. Induction Cardiac catheterization was performed, and an-
progressed rapidly, and vacuum-assisted vaginal giographic studies showed elevated biventricular
delivery was performed to minimize any Valsalva filling pressures with normal coronary arteries.
response. Endomyocardial biopsy was not performed. The
patient was given a diagnosis of peripartum car-
In this case, difficulty in monitoring the fetus, the diomyopathy, which was managed with digoxin,
wide variations in the mother’s blood pressure, and captopril, and furosemide. Her clinical condition

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 The n e w e ng l a n d j o u r na l
and blood pressure continued to improve with
medical therapy, with the exception of mild symp-
toms of orthostatic hypotension exacerbated by a
trial of low-dose carvedilol. A repeat echocardio-
gram before discharge revealed mild improvement
in left ventricular function, with an estimated
ejection fraction of 30 to 35%.
Although peripartum cardiomyopathy could ex-
plain this patient’s acute presentation in the third
trimester of pregnancy, atypical findings include
the very low ejection fraction without ventricular
dilatation, the rapid improvement in the first week
with treatment, and the severe hypertension and
orthostatic hypotension. I am increasingly con-
cerned about the possibility of a pheochromo­
cytoma, which might account for the various
presenting features, including the severe hyper-
tension, orthostatic hypotension, cardiomyopathy,
and hemoconcentration. I agree with the decision
not to obtain a biopsy specimen, since the diag-
nostic yield is low and histologic findings rarely
help direct treatment. I would plan on repeating
echocardiography in a few weeks to reassess her
ventricular function.
The patient was discharged home on digoxin,
lisinopril, and metoprolol succinate. One week af-
ter discharge, the patient returned with severe
headache of sudden onset that was associated with
nausea, vomiting, and diaphoresis. Serial blood-
pressure measurements obtained at home by her
husband documented a progressive rise in systolic
pressure from 140 to 200 mm Hg over the few
hours before admission. Her initial vital signs in-
cluded a heart rate of 110 beats per minute, a respi-
ratory rate of 15 breaths per minute, and a blood
pressure of 145/95 mm Hg. Her examination was
notable for profuse diaphoresis and tachycardia.
The initial electrocardiogram revealed sinus
tachycardia with trifascicular block. While in the
emergency department, she had frequent parox-
ysms of narrow-and wide-complex tachycardia as
well as episodic hypertension, with blood-pressure
increases exceeding 180/100 mm Hg. Intravenous
nitroprusside and labetalol were administered,
with improvement in her headache and blood
pressure, and she was admitted to the coronary
care unit for observation.
Hypertension associated with preeclampsia com-
monly improves after delivery, though blood pres-
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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
sure occasionally remains elevated. However, the
combination of paroxysmal hypertension, ortho-
static hypotension, and tachyarrhythmias strong-
ly suggests an adrenergically mediated process
such as pheochromocytoma. At this point, I would
order measurements of urine catecholamine and
plasma metanephrine levels to investigate this pos-
sibility. Alpha-adrenergic–receptor blockers and
direct arterial vasodilators are the preferred anti-
hypertensive agents in this setting to avoid precipi-
tating intense vasoconstriction with unopposed
beta-adrenergic–receptor blockade. Labetalol, which
has mixed alpha- and beta-blocking properties, has
been used effectively for many years in the man-
agement of pheochromocytoma-associated hyper-
tension and would be a reasonable alternative.
The plasma metanephrine level was 35.3 nmol per
liter (normal value, <0.5), and the normetaneph-
rine level was 35.2 nmol per liter (normal value,
<0.9). The plasma epinephrine level was 3038 pg
per milliliter (normal range, 10 to 200), and the
norepinephrine level was 9322 pg per milliliter
(normal range, 80 to 520). The results of analysis
of a 24-hour urine specimen were as follows: total
volume, 5800 ml; creatinine level, 1647 mg (nor-
mal range, 800 to 1800); epinephrine level, 4779 μg
(normal range, 0 to 25); norepinephrine level,
7308 μg (normal range, 0 to 100); vanillylman-
delic acid level, 111.4 mg (normal range, 0.0 to 7.0);
normetanephrine level, 11,745 μg (normal range,
60 to 650); and metanephrine level, 26,245 μg
(normal range, 30 to 350).
Even in the context of the stress of pregnancy
and acute illness, the rise in urine and plasma cat-
echolamine and metanephrine levels by a factor
of more than 10 was thought to be diagnostic of a
pheochromocytoma. The patient underwent gad-
olinium-enhanced magnetic resonance imaging
of the abdomen, which identified a mass, 5.0 by
4.5 cm, in the right adrenal gland that was hyper-
intense on T2-weighted sequences (Fig. 2). No
other lesions were noted.
The endocrine and surgical teams were con-
sulted, and a plan was made to administer the
­alpha-blocker phenoxybenzamine and gradually
increase the dose in preparation for resection of
the adrenal mass. In view of the patient’s de-
pressed left ventricular function, cautious attempts
were made to expand plasma volume during
treatment by liberalizing the patient’s dietary-­
sodium intake and administering normal saline
 clinical problem-solving

C om men ta r y
Pheochromocytomas are rare but potentially le-
thal neuroendocrine tumors that arise from the
chromaffin cells of the adrenal medulla or extra-
adrenal paraganglia. Reports from outpatient hy-
pertension clinics indicate a community prevalence
between 0.1 and 0.6%,1,2 but autopsy studies sug-
gest that many cases go undiagnosed.3,4 Although
the clinical presentation is highly variable, symp-
toms are typically those of catecholamine excess,
such as hypertension, tachycardia, headache, and
Figure 2. Magnetic Resonance Imaging of the Abdomen. feelings of panic or anxiety. Unexplained ortho­
This T2 -weighted image, obtained after gadolinium in- static hypotension on a background of paroxysmal
fusion, shows a bright adrenal mass on the right side or refractory hypertension, as seen in this patient,
(arrow).
ICM AUTHOR Desai RETAKE 1st is an important diagnostic clue. Myocyte necro-
REG F FIGURE 2 2nd sis and inflammatory infiltration and hemor-
3rd
CASE TITLE Revised rhage are well-recognized pathological hallmarks
EMail
intravenously,
Enon
graduallyLine increasing4-C theSIZE
dose of of catecholamine excess, and repetitive ventric-
ARTIST: mst H/T H/T
phenoxybenzamine.
FILL The dose
Combo of phenoxyben-
16p6 ular stunning in some patients with pheochro-
zamine was successfully increased
AUTHOR, PLEASE NOTE: over a 2-week mocytoma may lead to severe (but reversible)
period Figure
to 80hasmg
beenper day,andattype
redrawn which point
has been reset. symp- ventricular dysfunction (“catecholaminergic car­
Please check carefully.
tomatic orthostatic hypotension precluded fur- diomyopathy”).5-10 Sudden massive surges in cir-
ther increases,
JOB: 00000 and the patient underwent
ISSUE: open
Unscheduled culating catecholamines (“pheochromocytoma
right adrenalectomy without complications. Path- crisis”) may occur spontaneously or may be pre-
ological examination of the surgical specimen cipitated by induction of anesthesia, administra-
confirmed a 4.5-cm pheochromocytoma (Fig. 3 tion of sympathomimetic medications, or tumor
and 4). manipulation during surgery. Hypertensive emer-
gency, acute pulmonary edema, malignant ar-
Pheochromocytoma is a rare cause of cardiomyo- rhythmias, myocardial ischemia or infarction, aor-
pathy in pregnancy, but in retrospect, this patient’s tic dissection, cardiac failure, and hemodynamic
headache, labile blood pressure, orthostatic hy- collapse are well-recognized complications of
potension, arrhythmias, and heart failure were all pheochromocytoma, and the risk of death is high
clues. Had a myocardial biopsy been performed, after such acute presentations unless appropriate
one would have seen contraction-band necrosis, therapy is instituted quickly.
the pathological hallmark and cause of the car- Pheochromocytoma in pregnancy demands
diac failure in pheochromocytoma. With resec- special attention, since both maternal and fetal
tion of the tumor, I am hopeful that her ventricu- outcomes are historically poor; maternal mortal-
lar function will recover completely. ity in excess of 40% and fetal mortality exceed-
ing 50% have been reported in the absence of
After resection of the tumor, the patient’s blood appropriate treatment.11 Hypertensive crises dur-
pressure, left ventricular function, and functional ing pregnancy in a patient with pheochromocy-
capacity returned to normal. Serial postoperative toma may be provoked by tumor stimulation as
measurements showed that the urine and plasma a consequence of postural changes, pressure from
catecholamine levels were in the normal range. the gravid uterus, uterine contractions, or tumor
No evidence of a familial multiple endocrine neo- hemorrhage. The peripartum period is especially
plasia syndrome was identified. One year later, dangerous, since anesthesia, labor, and normal
she again became pregnant and carried the preg- vaginal delivery may precipitate abrupt hemody-
nancy to term without complication, giving birth namic deterioration. The risk of death for both
to a healthy baby girl. the mother and the fetus can be reduced sub-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 3. Adrenal Mass as Seen during Surgery. Figure 4. Histopathological Specimen of the
Adrenal Mass.
stantially by antepartum diagnosis and Nests of tumor cells with abundant granules are evi-
ICM AUTHOR Desai RETAKEearly 1stin- ICM AUTHOR Desai RETAKE 1st
dent, a finding that is characteristic of pheochromocy-
stitution
REG F of appropriate
FIGURE 3 therapy.12,13 However, 2nd as REG F FIGURE 4 2nd
3rd toma (hematoxylin and eosin). 3rd
in the caseTITLE
CASE presented here, distinguishing Revised pheo- CASE TITLE Revised
EMail EMail
chromocytoma
Enon
from preeclampsia
Line 4-C may SIZE
be ex- Enon
Line 4-C
SIZE
ARTIST: mst H/T H/T ARTIST: mst H/T H/T
tremely
FILL challenging, particularly
Combo when 16p6protein­ several
FILLdays of alpha-adrenergic
Combo blockade, but
16p6 they
uria is present.AUTHOR,
A highPLEASEindex of suspicion and
NOTE: are not suitableAUTHOR,
for initial therapy
PLEASE NOTE: owing to the
careful Figure
history taking
has been mayandhelp
redrawn highlight
type has been reset.charac- risk of unopposed
Figure has beenalpha-adrenergic–receptor
redrawn and type has been reset. stim-
Please check carefully. Please check carefully.
teristic signs and symptoms of pheochromocy- ulation, vasoconstriction, and hypertensive crisis.
tomaJOB:
(e.g.,00000
paroxysmal sweats,ISSUE: headaches, or pal-
Unscheduled In this
JOB:case,
00000the clinical deterioration that oc-
ISSUE: Unscheduled
pitations) that should prompt further evaluation. curred shortly after the patient’s initial hospital
Unfortunately, typical historical features were ab- discharge may have been unintentionally acceler-
sent in this case, and only the cardiomyopathy (an ated by the initiation of treatment with the beta-
extremely unusual complication of preeclampsia) blocker metoprolol succinate to manage her heart
and orthostatic hypotension provided early hints failure without concomitant alpha-blockade.
of an alternative diagnosis. Our case highlights the critical importance of
Once a pheochromocytoma has been identified a broad differential diagnosis and careful atten-
definitively, the patient requires surgical excision tion to all the diagnostic clues in a complex clini-
after appropriate preparation. With adequate pre- cal presentation. In addition, this case highlights
treatment and an experienced anesthesiologist the perils of “premature closure” in medical di-
and surgeon, perioperative mortality is less than agnosis; here, although preeclampsia and peripar-
1 to 3%, whereas surgery performed on an emer- tum cardiomyopathy were important consider-
gency basis may be associated with poor out­ ations, neither was sufficient to explain all the
comes.14,15 As in this case, typical preoperative patient’s symptoms and signs. Both diagnoses
management includes aggressive alpha-adrener- were promptly revisited when she presented with
gic–receptor blockade with phenoxybenzamine, recurrent symptoms, and after treatment associ-
which is started at a low dose and gradually in- ated with the correct diagnosis — pheochromocy-
creased over a period of 10 to 14 days, in combi- toma — a subsequent pregnancy had a success-
nation with a high-salt diet, until blood pressure is ful outcome.
controlled and symptoms are suppressed or side No potential conflict of interest relevant to this article was
reported.
effects prevent further dose increases. Beta-adren- We thank Polly MacIsaac for her assistance with the prepara-
ergic–receptor blockers can be introduced after tion of the manuscript.

References
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Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 clinical problem-solving

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S, Sharma BK. Pheochromocytoma asso-
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