a crisis in late pregnancy

8/8/2019 A Crisis in Late Pregnancy

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clinical problem-solving

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 361;23 nejm.org december 3, 2009 2271

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.

From the Division of Cardiovascular Medi-cine (A.S.D., W.A.C., E.E.) and the Centerfor MaternalFetal Medicine, Departmentof Obstetrics and Gynecology (K.E.E.),Brigham and Womens Hospital: and theDivision of Cardiology, Massachusetts

General Hospital (G.W.D.) both inBoston. Address reprint requests to Dr.Desai at the Division of CardiovascularMedicine, PBB-A3, AB370, Brigham andWomens Hospital, 75 Francis St., Boston,MA 02115, or at [email protected].

N Engl J Med 2009;361:2271-7.Copyright 2009 Massachusetts Medical Society.

A 31-year-old woman in the 37th week of an uncomplicated pregnancy presented tothe emergency department with sudden onset of severe bitemporal headache andshortness of breath. Her medical history was notable for hypothyroidism and perni-cious anemia (both treated). She had had four previous pregnancies: the first wasterminated therapeutically for elective reasons, the next two resulted in spontaneousabortions, and the fourth resulted in the birth of a healthy girl, delivered vaginally,3 years earlier. The patient had never smoked and did not drink alcohol or use illicit drugs. Her family history was unremarkable.

Shortness of breath in the third trimester of pregnancy has a broad differentialdiagnosis. This symptom may simply reflect increased minute ventilation due tocentral chemoreceptor alterations or mechanical interference with diaphragmaticexpansion 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 aorticdissection, as well as complications associated with pregnancy such as preeclamp-sia and peripartum cardiomyopathy, are among the must not miss diagnoses andshould be ruled out.

The patient was in apparent respiratory distress and reported that she felt like she wasdrowning. She reported no fever, cough, chest pain, nausea, vomiting, visualchanges, abdominal pain, contractions, or vaginal bleeding. On examination, she wasafebrile. 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% whileshe was breathing ambient air. She was unable to lie flat without having more diffi-culty breathing. Funduscopic examination was normal. Jugular venous pressure wasestimated 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 werewarm, 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 thehead 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 funduscopicexamination does not reveal papilledema or hemorrhages. It would be helpful to

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.

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n engl j med 361;23 nejm.org december 3, 20092272

review any blood-pressure measurements obtainedbefore pregnancy and to know whether her previ-ous pregnancies were complicated by similar blood-pressure lability. Preeclampsia would explain theheadache and hypertension and remains the most likely diagnosis, although severe pulmonary ede-ma is not typical of this condition. In the absenceof a preexisting cardiomyopathy, the severe hyper-tension alone would not be expected to precipitateacute heart failure in a young person. If there isan 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, andshe requires supplemental oxygen and intrave-nous loop diuretics. Despite the tachycardia,I would avoid giving her a beta-blocker becauseof 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; hemodynamicmonitoring is also warranted. I would order anelectrocardiogram and an urgent echocardiogram,as well as measurements of arterial blood gasesand 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 shouldbe 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 lupuserythematosus, which might explain her previousspontaneous abortions and might cause a cardio-myopathy due to myopericarditis.

An electrocardiogram showed sinus tachycardiawith ST-segment elevations in leads I and aVL and

inferolateral ST-segment depressions suggestive of myocardial ischemia ( Fig. 1). A chest radiographobtained with abdominal shielding revealed bilat-eral alveolar infiltrates, which were consistent with pulmonary edema. Computed tomographyof the head performed without the administrationof contrast material revealed no intracranial hem-orrhage or cerebral edema.

The results of initial laboratory tests were asfollows: sodium level, 134 mmol per liter; potas-

sium level, 5.4 mmol per liter; chloride level, 109mmol 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 mol per liter); white-cellcount, 21,800 per cubic millimeter; hemoglobinlevel, 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 molper 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 mol 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%; andtroponin I level, 23.2 U per liter (normal value,


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istration of magnesium sulfate for prophylaxisagainst seizures is warranted, and the fetus shouldbe delivered as soon as possible.

The working diagnosis was pulmonary edemadue to severe preeclampsia. The patient was treat-ed with intravenous labetalol, magnesium sulfate,and furosemide, as well as bilevel positive airwaypressure. In consultation with the high-risk ob-stetrical service, plans were made for delivery. Inthis multiparous woman who was already in earlylabor, it was thought that vaginal delivery wouldprobably be expeditious and associated with sig-nificantly fewer maternal risks than would deliv-ery by cesarean section. Labor was augmentedwith the use of a combination of gradual mechan-ical dilation of the cervix with a Foley bulb and in-travenous administration of oxytocin. The patientsstatus remained tenuous from a hemodynamicand respiratory standpoint. She needed to sit bolt upright and was agitated, permitting only inter-mittent monitoring of fetal heart tones. Approxi-mately 2 hours after presentation, the heart rate of

the fetus was noted to be identical to that of themother, at 120 beats per minute. Emergency ultra-sonographic imaging revealed intrauterine fetaldeath. No vaginal bleeding was noted. Inductionprogressed rapidly, and vacuum-assisted vaginaldelivery was performed to minimize any Valsalvaresponse.

In this case, diff iculty in monitoring the fetus, the wide variations in the mothers blood pressure, and

prolonged maternal hypoxemia may all have con-tributed to this tragic complication. Given her se-

vere hypertension, placental abruption should alsobe considered as a possible contributor, althoughthe absence of vaginal bleeding makes this lesslikely.

The patients respiratory status gradually improvedwith medical therapy. A transthoracic echocardio-gram revealed global left ventricular dysfunctionwithout cavity dilatation, an ejection fraction of 20%, and moderate mitral regurgitation.

A nondilated left ventricle with markedly depressedsystolic function is most compatible with acute-onset cardiomyopathy. Such severe ventricular dys-function may complicate preeclampsia in rarecases. It is possible that the patient had acutemyocarditis or peripartum cardiomyopathy, but I

would have difficulty explaining her hypertensionif ventricular dysfunction were a primary process.Given her positive troponin test, poor ventricularfunction, and unexplained ischemic changes on

the electrocardiogram, cardiac catheterization is warranted.

Cardiac catheterization was performed, and an-giographic studies showed elevated biventricular filling pressures with normal coronary arteries.Endomyocardial biopsy was not performed. Thepatient was given a diagnosis of peripartum car-diomyopathy, which was managed with digoxin,captopril, and furosemide. Her clinical condition

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

Figure 1. Electrocardiogram Obtained on Presentation.The electrocardiogram reveals sinus tachycardia with ST-segment elevations in leads I and aVL and inferolateralST-segment depressions suggestive of myocardial ischemia.




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and blood pressure continued to improve withmedical therapy, with the exception of mild symp-toms of orthostatic hypotension exacerbated by atrial of low-dose carvedilol. A repeat echocardio-gram before discharge revealed mild improvement in left ventricular function, with an estimatedejection fraction of 30 to 35%.

Although peripartum cardiomyopathy could ex-plain this patients acute presentation in the thirdtrimester of pregnancy, atypical f indings includethe very low ejection fraction without ventriculardilatation, the rapid improvement in the first week

with treatment, and the severe hypertension andorthostatic hypotension. I am increasingly con-cerned about the possibility of a pheochromo-cytoma, which might account for the variouspresenting features, including the severe hyper-tension, orthostatic hypotension, cardiomyopathy,and hemoconcentration. I agree with the decisionnot to obtain a biopsy specimen, since the diag-nostic yield is low and histologic findings rarely help direct treatment. I would plan on repeatingechocardiography 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 severeheadache of sudden onset that was associated withnausea, vomiting, and diaphoresis. Serial blood-pressure measurements obtained at home by her husband documented a progressive rise in systolicpressure from 140 to 200 mm Hg over the fewhours 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 bloodpressure of 145/95 mm Hg. Her examination wasnotable for profuse diaphoresis and tachycardia.

The initial electrocardiogram revealed sinustachycardia with trifascicular block. While in theemergency department, she had frequent parox-

ysms of narrow-and wide-complex tachycardia aswell as episodic hypertension, with blood-pressureincreases exceeding 180/100 mm Hg. Intravenousnitroprusside and labetalol were administered,with improvement in her headache and bloodpressure, and she was admitted to the coronarycare unit for observation.

Hypertension associated with preeclampsia com-monly improves after delivery, though blood pres-

sure occasionally remains elevated. However, thecombination of paroxysmal hypertension, ortho-static hypotension, and tachyarrhythmias strong-ly suggests an adrenergically mediated processsuch as pheochromocytoma. At this point, I wouldorder measurements of urine catecholamine andplasma metanephrine levels to investigate this pos-sibility. Alpha-adrenergicreceptor blockers anddirect arterial vasodilators are the preferred anti-hypertensive agents in this setting to avoid precipi-tating intense vasoconstriction with unopposedbeta-adrenergicreceptor blockade. Labetalol, whichhas mixed alpha- and beta-blocking properties, hasbeen 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,


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intravenously, gradually increasing the dose of phenoxybenzamine. The dose of phenoxyben-zamine was successfully increased over a 2-weekperiod to 80 mg per day, at which point symp-tomatic orthostatic hypotension precluded fur-ther increases, and the patient underwent openright adrenalectomy without complications. Path-ological examination of the surgical specimenconfirmed a 4.5-cm pheochromocytoma (Fig. 3and 4).

Pheochromocytoma is a rare cause of cardiomyo-pathy in pregnancy, but in retrospect, this patientsheadache, labile blood pressure, orthostatic hy-potension, arrhythmias, and heart failure were allclues. Had a myocardial biopsy been performed,one would have seen contraction-band necrosis,the pathological hallmark and cause of the car-diac failure in pheochromocytoma. With resec-tion of the tumor, I am hopeful that her ventricu-lar function will recover completely.

After resection of the tumor, the patients bloodpressure, left ventricular function, and functional

capacity returned to normal. Serial postoperativemeasurements showed that the urine and plasmacatecholamine levels were in the normal range.No evidence of a familial multiple endocrine neo-plasia syndrome was identified. One year later,she again became pregnant and carried the preg-nancy to term without complication, giving birthto a healthy baby girl.

Commenta ry

Pheochromocytomas are rare but potentially le-thal neuroendocrine tumors that arise from thechromaffin cells of the adrenal medulla or extra-adrenal paraganglia. Reports from outpatient hy-pertension clinics indicate a community prevalencebetween 0.1 and 0.6%, 1,2 but autopsy studies sug-gest that many cases go undiagnosed. 3,4 Althoughthe clinical presentation is highly variable, symp-toms are typically those of catecholamine excess,such as hypertension, tachycardia, headache, andfeelings of panic or anxiety. Unexplained ortho-static hypotension on a background of paroxysmalor refractory hypertension, as seen in this patient,is an important diagnostic clue. Myocyte necro-sis and inflammatory infiltration and hemor-rhage are well-recognized pathological hallmarksof catecholamine excess, and repetitive ventric-ular stunning in some patients with pheochro-mocytoma may lead to severe (but reversible)

ventricular dysfunction (catecholaminergic car-diomyopathy). 5-10 Sudden massive surges in cir-culating catecholamines (pheochromocytomacrisis) may occur spontaneously or may be pre-cipitated by induction of anesthesia, administra-tion of sympathomimetic medications, or tumormanipulation during surgery. Hypertensive emer-gency, acute pulmonary edema, malignant ar-rhythmias, myocardial ischemia or infarction, aor-tic dissection, cardiac failure, and hemodynamiccollapse are well-recognized complications of pheochromocytoma, and the risk of death is highafter such acute presentations unless appropriatetherapy is instituted quickly.

Pheochromocytoma in pregnancy demandsspecial attention, since both maternal and fetaloutcomes are historically poor; maternal mortal-ity in excess of 40% and fetal mortality exceed-ing 50% have been reported in the absence of appropriate treatment. 11 Hypertensive crises dur-ing pregnancy in a patient with pheochromocy-

toma may be provoked by tumor stimulation asa consequence of postural changes, pressure fromthe gravid uterus, uterine contractions, or tumorhemorrhage. The peripartum period is especially dangerous, since anesthesia, labor, and normal

vaginal delivery may precipitate abrupt hemody-namic deterioration. The risk of death for boththe mother and the fetus can be reduced sub-

Figure 2. Magnetic Resonance Imaging of the Abdomen.This T2 -weighted image, obtained after gadolinium in-fusion, shows a bright adrenal mass on the right side(arrow).




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stantially by antepartum diagnosis and early in-stitution of appropriate therapy. 12,13 However, asin the case presented here, distinguishing pheo-chromocytoma from preeclampsia may be ex-tremely challenging, particularly when protein-uria is present. A high index of suspicion andcareful history taking may help highlight charac-teristic signs and symptoms of pheochromocy-toma (e.g., paroxysmal sweats, headaches, or pal-pitations) that should prompt further evaluation.Unfortunately, typical historical features were ab-sent in this case, and only the cardiomyopathy (anextremely unusual complication of preeclampsia)and orthostatic hypotension provided early hintsof an alternative diagnosis.

Once a pheochromocytoma has been identifieddefinitively, the patient requires surgical excisionafter appropriate preparation. With adequate pre-treatment and an experienced anesthesiologist and surgeon, perioperative mortality is less than1 to 3%, whereas surgery performed on an emer-gency basis may be associated with poor out-comes. 14,15 As in this case, typical preoperativemanagement includes aggressive alpha-adrener-gicreceptor blockade with phenoxybenzamine,

which is started at a low dose and gradually in-creased over a period of 10 to 14 days, in combi-

nation with a high-salt diet, until blood pressure iscontrolled and symptoms are suppressed or sideeffects prevent further dose increases. Beta-adren-ergicreceptor blockers can be introduced after

several days of alpha-adrenergic blockade, but they are not suitable for initial therapy owing to therisk of unopposed alpha-adrenergicreceptor stim-ulation, vasoconstriction, and hypertensive crisis.In this case, the clinical deterioration that oc-curred shortly after the patients initial hospitaldischarge may have been unintentionally acceler-ated by the initiation of treatment with the beta-blocker metoprolol succinate to manage her heart failure without concomitant alpha-blockade.

Our case highlights the critical importance of a broad differential diagnosis and careful atten-tion to all the diagnostic clues in a complex clini-cal presentation. In addition, this case highlightsthe perils of premature closure in medical di-agnosis; here, although preeclampsia and peripar-tum cardiomyopathy were important consider-ations, neither was sufficient to explain all thepatients symptoms and signs. Both diagnoses

were promptly revisited when she presented withrecurrent symptoms, and after treatment associ-ated with the correct diagnosis pheochromocy-toma a subsequent pregnancy had a success-

ful outcome.No potential conflict of interest relevant to this article wasreported.

We thank Polly MacIsaac for her assistance with the prepara-tion of the manuscript.

Figure 3. Adrenal Mass as Seen during Surgery.

Figure 4. Histopathological Specimen of theAdrenal Mass.Nests of tumor cells with abundant granules are evi-dent, a finding that is characteristic of pheochromocy-toma (hematoxylin and eosin).

References

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collections of articles on the journal s web site

The Journals Web site ( NEJM.org ) sorts published articles intomore than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reversechronologic order, with the most recent first.

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Van Vliet PD, Burchell HB, Titus JL.5.Focal myocarditis associated with pheo-chromocytomas. N Engl J Med 1966;274:1102-8.

Szakacs JE, Cannon AL. L-norepi-6.nephrine myocarditis. Am J Clin Pathol

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Salathe M, Weiss P, Ritz R. Rapid re-8. versal of heart failure in a patient withphaeochromocytoma and catecholamine-

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mocytoma in pregnancy: five cases and areview of the literature. Br J Obstet Gy-naecol 1989;96:594-606.

Ahlawat SK, Jain S, Kumari S, Varma13.S, Sharma BK. Pheochromocytoma asso-ciated with pregnancy: case report andreview of the literature. Obstet GynecolSurv 1999;54:728-37.

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M, Pacak K. Pheochromocytoma. Lancet 2005;366:665-75.Kinney MA, Warner ME, vanHeerden15.

JA, et al. Perianesthetic risks and outcomesof pheochromocytoma and paraganglio-ma resection. Anesth Analg 2000;91:1118-23.Copyright 2009 Massachusetts Medical Society.


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a crisis in late pregnancy

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