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CLINICAL PROBLEM-SOLVING

Prashant D. Bhave, M.D., Elyse Foster, M.D., and Gurpreet Dhaliwal, M.D.

N Engl J Med 2012; 367:2241-2247 December 6, 2012 DOI: 10.1056/NEJMcps1115057

Commentsopen through December 12, 2012

In this Journalfeature, 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 63-year-old woman presented to the emergency department with edema and red discoloration of the skin of her legs.

The edema had first appeared almost 2 years earlier but had worsened markedly within the past week and now

extended to her midabdomen. She was able to walk about half a block before stopping to catch her breath. She also

reported orthopnea, paroxysmal nocturnal dyspnea, and occasional sharp chest pains while walking. She noted that

she had gained weight and had mild leg pain but did not have fevers, chills, or night sweats.

Isolated, bilateral lower-extremity swelling and erythema that have been stable over a long period suggest venous stasis, but the

abrupt worsening along with new symptoms warrants prompt evaluation for other possible causes of such swelling, including

cardiac, hepatic, and renal dysfunction. Lymphedema can cause profound lower-extremity edema but should not cause

orthopnea or exertional dyspnea. The acute illness is highly suggestive of biventricular failure. The association with chest pain

raises suspicion for coronary artery disease, though the stated character of the pain is somewhat atypical of coronary ischemia.

Constrictive pericarditis and chronic pulmonary thromboembolic disease are indolent processes that may cause dyspnea and

chronic, stable right-sided volume overload for months to years before worsening. Pulmonary arterial hypertension and

previously unrecognized congenital heart disease should also be considered.

The patient was born in El Salvador and immigrated to the United States when she was 45 years of age. She had a

remote history of tuberculosis but did not recall any details of the treatment for it; she also reported a history of back

pain and depression, as well as an episode of Streptococcus viridansbacteremia 2 years previously (with associated

psoas and epidural abscesses that required surgical drainage). Her medications included escitalopram, pantoprazole,

and oxycodone. She did not smoke and did not use alcohol or illicit substances.

A history of tuberculosis could put this patient at risk for constrictive pericarditis. In addition, histoplasmosis, which is also seen in

Central America, can cause constrictive pericarditis, as well as fibrosing mediastinitis; either condition could raise cardiac fillingpressures. Her history of complicated S. viridansbacteremia raises the possibility of a recurrence as a result of either incomplete

eradication or sustained risk factors (e.g., poor dentition). Valvular dysfunction after a previously unrecognized episode of

endocarditis could precipitate heart failure. Because the patient lived in Central America for most of her life, she is also at risk for

Chagas' disease.

The patient was alert and comfortable. The temperature was 37.6C, the blood pressure 104/44 mm Hg, the heart rate

100 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 97% while she was

breathing ambient air. She had normal dentition. Jugular venous distention above the angle of the jaw, with a prominent

V wave, was present with the patient seated upright. The cardiac examination revealed a prominent right ventricular

heave, tachycardia and regular heart sounds, a grade 3/6 systolic murmur best heard at the left lower sternal border,

and a right-sided S sound. Bibasilar rales were present. There was no abdominal tenderness or organomegaly. The

extremities were warm and well perfused; the skin over the legs was erythematous and mildly painful to the touch, and3+ pitting edema extended from the legs to the level of the midabdomen. A well-healed surgical scar was present over

the right lower back. The neurologic examination was normal, and there was no pain with percussion of the spine.

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FIGURE 1

Electrocardiogramon Admission.

FIGURE 2

Echocardiogram onAdmission.

The results of this examination suggest acute heart failure, with prominent right-sided findings, including signs suggestive of

severe tricuspid regurgitation. The patient does, however, have orthopnea and paroxysmal nocturnal dyspnea, which also

suggest left ventricular dysfunction. The wide pulse pressure and warm extremities imply that the tachycardia in this patient is

not a response to low cardiac output and associated baroreceptor-mediated vasoconstriction. She has no fever or back pain to

suggest a recurrence of S. viridansspinal infection. The leg pain, swelling, and erythema are most likely due to venous

congestion in association with right ventricular failure. Thiamine deficiency should be considered, since it is associated with

painful peripheral neuropathy, erythema of the extremities due to peripheral vasodilation, and heart failure due to high cardiac

output.

The white-cell count was 5700 per cubic millimeter, the hemoglobin level 10.3 g per deciliter (with a mean corpuscular

volume of 83 fl), and the platelet count 331,000 per cubic millimeter. The sodium level was 139 mmol per liter,

potassium 3.3 mmol per liter, creatinine 0.8 mg per deciliter (70.7 mol per liter), glucose 99 mg per deciliter (5.5 mmol

per liter), aspartate aminotransferase 29 U per liter (normal range, 16 to 41), alanine aminotransferase 8 U per liter

(normal range, 11 to 54), alkaline phosphatase 148 U per liter (normal range, 29 to 111), total bilirubin 1.0 mg per

deciliter (17.1 mol per liter) (normal range, 0.3 to 1.3 mg per deciliter [5.1 to 22.2 mol per liter]), serum albumin 2.5 g

per deciliter, B-type natriuretic peptide 735 pg per milliliter (normal value,

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FIGURE 3

PressureMeasurements andOxygen SaturationMeasured during

CardiacCatheterization.

FIGURE 4

deciliter (114.9 mol per liter), with a serum urea nitrogen level of 24 mg per deciliter (8.6 mmol per liter).

Results of the evaluation for pulmonary hypertension do not point to a secondary cause. The normal 24-hour urine protein level

rules out the nephrotic syndrome. Constrictive pericarditis can be resistant to diuretic therapy, but the echocardiogram shows

right ventricular dilatation and does not show features consistent with a constrictive process; in addition, CT of the chest does

not show pericardial thickening. The acute kidney injury may be due to a combination of renal hypoperfusion and renal venous

congestion that accompanies heart failure (the cardiorenal syndrome), depleted effective circulating volume from diuresis, or

contrast-induced nephropathy. Invasive hemodynamic assessment by means of cardiac catheterization is indicated.

The patient was referred for hemodynamic studies and coronary angiography (Figure 3).

Measured oxygen consumption was 274 ml per minute. Body-surface area was 1.56 m . There

were no clinically significant coronary arterial stenoses. Pressure measurements were as follows:

mean central aortic pressure 72 mm Hg; mean right atrial pressure 20 mm Hg, with V waves to 28

mm Hg and prominent y descents; right ventricular systolic pressure 57 mm Hg; pulmonary-

artery pressure 56/21 mm Hg (mean, 36); and mean pulmonary-capillary wedge pressure 21 mm

Hg, with V waves to 34 mm Hg (Fig. S3 in the Supplementary Appendix). Oxygen saturations were

71% in the superior vena cava, 77% in the pulmonary artery, and 98% in the femoral artery.

Cardiac output was 9.4 liters per minute as measured by the Fick method, with a cardiac index of

6.0 liters per minute per square meter of body-surface area. Pulmonary vascular resistance was

128 dynseccm and systemic vascular resistance was 440 dynseccm (both calculated with

the use of the cardiac output as measured by the Fick method).

Despite equalization of diastolic pressures, the high cardiac output (cardiac index >4.0 liters per minute per square meter), as

well as the echocardiographic findings and the elevated B-type natriuretic peptide level, make the diagnosis of constrictive

pericarditis unlikely. The fact that pulmonary vascular resistance was normal suggests that the patient does not have pulmonary

arterial hypertension. The differential diagnosis for high-output heart failure includes thiamine deficiency, hyperthyroidism, severe

anemia, Paget's disease, and arteriovenous fistula.

Hyperthyroidism is a reasonable consideration given the patient's tachycardia while at rest and wide pulse pressure, but the

thyrotropin level was normal. Although a modestly low thiamine level was detected, thiamine supplementation has not led to

clinical improvement. It is possible that the elevated alkaline phosphatase level and leg pain signal Paget's disease of bone,

which is associated with high-output heart failure due to intraosseous arteriovenous malformations. However, the elevation of the

alkaline phosphatase level is modest; measurement of -glutamyltransferase could help distinguish a bone-related disorder from

a disorder of hepatic origin. An arteriovenous fistula that was created during her back surgery or from tissue damage related to

the prior tuberculosis infection might go unrecognized and may only be detected by imaging.

A diagnosis of high-output heart failure was made. On review of the echocardiogram, the velocitytime integral at the

left ventricular outflow tract was found to be 0.30 m (indicating supranormal stroke volume).

There was no improvement with diuresis. The cause of the patient's high-output heart failure remained uncertain. Given

the finding of severe tricuspid regurgitation, which her clinicians believed could not be explained by the degree of

pulmonary hypertension, tricuspid-valve repair with annuloplasty was considered.

Primary tricuspid-valve dysfunction is not likely to cause high cardiac output. In this scenario, an exhaustive search for an

alternate cause of high-output heart failure should be undertaken before tricuspid-valve repair is planned, especially since the

valve appeared to be normal on the echocardiogram.

A focused physical examination was repeated to search for signs of an arteriovenous fistula. A loud, continuous bruit

was detected over the surgical scar in the right lumbar paraspinal region. Angiography showed a large fistula between

the right internal iliac artery and the right internal iliac vein (Figure 4and Video 2).

The fistula was closed surgically, without complications. At hospital discharge 5 days later, the

patient's functional status had improved markedly, the edema had almost resolved, the creatininelevel was 0.8 mg per deciliter, and the hemoglobin level was 13.5 g per deciliter.

Two months after surgical closure of the fistula, the edema had completely resolved.

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Contrast-EnhancedAortogram.

FIGURE 5

Echocardiogramafter SurgicalIntervention.

Transthoracic echocardiography showed normalization of the right ventricular dimensions and

pulmonary arterial pressures, as well as a marked decrease in the grade of tricuspid

regurgitation (Video 3, Figure 5, and Fig. S4 in the Supplementary Appendix). The

electrocardiogram showed normalization of the QRS axis and morphologic features (Fig. S5 in the

Supplementary Appendix). By the 6-month follow-up visit, the patient's exercise tolerance had

improved to within normal limits for her age.

The differential diagnosis of heart failure of new onset starts with a stepwise assessment of causes,

beginning with the most common, which include coronary ischemia, hypertension, and valvular disease;hypertrophic and restrictive cardiomyopathies also warrant consideration. The constellation of normal

left ventricular function, normal coronary arteries, and normal blood pressure combined with signs of right

heart failure suggested pulmonary hypertension and tricuspid-valve or pulmonic-valve disease as the

most likely causes of this patient's symptoms. The unexpected finding of high cardiac output during the hemodynamic study

shifted the diagnostic considerations and management approach.

High cardiac output is defined as a cardiac output at rest that is greater than 8.0 liters per minute (or a cardiac index >4.0 liters

per minute per square meter). The initial physiological derangement is usually low systemic vascular resistance, which incites a

neurohormonal response culminating in the retention of salt and water and in volume overload. Patients with high-output heart

failure often have signs similar to those seen in a low-output state (pulmonary congestion, peripheral edema, and hypotension),

but the presence of a wide pulse pressure (in the absence of clinically significant aortic regurgitation) and warm, well-perfused

extremities can help differentiate the two entities. Echocardiography is a sensitive tool for identifying the elevated cardiac filling

pressures, enlarged cardiac chambers, and supranormal stroke volume that accompany a high-output state. The high

velocitytime integral on echocardiography was an early but initially unappreciated clue to the presence of a high-output state.

Cardiac catheterization, with hemodynamic assessments and a shunt study, is usually required to make a definitive diagnosis. In

retrospect, additional venous sampling in the inferior vena cava, where a step-up in oxygen saturation would have been

observed, may have facilitated a diagnosis.

High cardiac output can be driven by elevated systemic metabolic demands (e.g., with hyperthyroidism), diminished oxygen

delivery per unit of cardiac output (e.g., with anemia), abnormal augmentation of venous return (e.g., when an arteriovenous

fistula is present), or nutritional deficiencies (e.g., with wet beriberi). Recognition of the high-output state is critical because a

large number of cases are reversible. The low thiamine level provided a plausible provisional diagnosis in this case, although the

severity of cardiomyopathy does not correlate reliably with laboratory thiamine assays. Measurement of erythrocyte thiamine

transketolase activity (with or without thiamine loading) is a more specific assessment for thiamine deficiency than is

measurement of the serum thiamine level and is the preferred confirmatory test, though the whole-blood assay used in thiscase is a validated alternative. Most cases of thiamine deficiency are attributable to malnutrition, but this deficiency can also

develop as a result of long-term administration of diuretics in patients who are being treated for heart failure. Ultimately the

absence of neurologic signs and symptoms of thiamine deficiency, the absence of alcoholism or a severely restricted diet, and

the lack of rapid improvement with thiamine supplementation made this diagnosis unlikely.

Arteriovenous fistula is a rare but treatable cause of high-output heart failure and can be classified as either congenital or

acquired. Acquired arteriovenous fistulae are typically traumatic or iatrogenic in origin; a majority of cases with associated

high-output heart failure occur after cardiac catheterization (at the femoral access site) or in patients with fistulas for dialysis

access. Cases of high-output heart failure due to arteriovenous fistulas after lumbar-disk surgery are rare but have been

reported. Therapeutic options include surgical closure of the fistula or endovascular embolization to close the fistulous tract.

This case documents echocardiographic and electrocardiographic resolution of right ventricular dilatation and strain after closure

of the arteriovenous fistula. The pivotal step in identifying this condition as the cause of high-output heart failure in this patient

was auscultation over a surgical scar. Although this is not a routine maneuver, it can provide crucial information in a patient with

undiagnosed volume overload. The turbulent flow through a fistulous arteriovenous connection often creates an audible bruit that

can pinpoint an otherwise elusive diagnosis. This case serves as a reminder that nonvascular operations can alter vascular

anatomy and lead to unanticipated consequences years later. In an era of increasingly sophisticated tests and treatments, this

case of a missed connection reminds us that seemingly minor details in the medical history can hold the key to diagnosis and

that the history and physical examination remain the foundation of safe, efficient, and effective care.

Dr. Foster reports receiving lecture fees from Pri-Med and MCE Conferences, consulting fees to her institution from Actelion and MAQUET, grant

support to her institution from Evalve/Abbott, and payment to her institution for expert testimony from various law firms regarding cardiac complications

of a psychoactive drug and missed endocarditis. No other potential conflict of interest relevant to this article was reported.

Disclosure formsprovided by the authors are available with the full text of this article at NEJM.org.

We thank Drs. Elizabeth Davis, James McCabe, Kurt Hoffmayer, and Sharon Shen for their guidance on an earlier draft of the manuscript.

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rehabilitation centre in Malaysia. Med J Malaysia 2006;61:519-525

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1 Bahaa M. Fadel, Abdelmohsen Alhashim, Mohamad Al-Admawi, Odd Bech-Hanssen,

Giovanni Di Salvo. (2013) Heart Failure Following Creation of an Arteriovenous Fistula for

Hemodialysis. Echocardiography, n/a-n/a

From the Division of Cardiology, Northwestern University, Chicago (P.D.B.); and the Division of Cardiology (E.F.) and Department of Medicine (G.D.),

University of California at San Francisco, and the San Francisco Veterans Medical Center (G.D.) both in San Francisco.

Address reprint requests to Dr. Bhave at Northwestern University, Division of Cardiology, 251 E. Huron St., Feinberg 8-503, Chicago, IL 60611, or at

[email protected].

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