Hypertension

2087CHAPTER 277

arterial blood pressure by no more than 25% within minutes to

2 h or to a blood pressure in the range of 160/100–110 mmHg. This

may be accomplished with IV nitroprusside, a short-acting vasodilator with a rapid onset of action that allows for minute-to-minute

control of blood pressure. Parenteral labetalol and nicardipine are

also effective agents for the treatment of hypertensive encephalopathy. In the absence of encephalopathy or another catastrophic

event, it is preferable to reduce blood pressure over hours or longer

rather than minutes. This goal may effectively be achieved initially

with frequent dosing of short-acting oral agents such as captopril,

clonidine, and labetalol.

Acute, transient blood pressure elevations that last days to

weeks frequently occur after thrombotic and hemorrhagic strokes.

Autoregulation of cerebral blood flow is impaired in ischemic cerebral tissue, and higher arterial pressures may be required to maintain cerebral blood flow. Aggressive reductions of blood pressure

should be avoided. With the increasing availability of improved CT

technology for the noninvasive measurement of cerebral blood flow,

studies are in progress to evaluate the effects of different classes of

antihypertensive agents on both blood pressure and cerebral blood

flow after an acute stroke. To prevent recurrence of cerebrovascular

events, reduction of blood pressure appears to be more important

TABLE 277-10 Preferred Parenteral Drugs for Selected Hypertensive

Emergencies

Hypertensive encephalopathy Nitroprusside, nicardipine, labetalol

Malignant hypertension (when IV

therapy is indicated)

Labetalol, nicardipine, nitroprusside,

enalaprilat

Stroke Nicardipine, labetalol, nitroprusside

Myocardial infarction/unstable angina Nitroglycerin, nicardipine, labetalol,

esmolol

Acute left ventricular failure Nitroglycerin, enalaprilat, loop

diuretics

Aortic dissection Nitroprusside, esmolol, labetalol

Adrenergic crisis Phentolamine, nitroprusside

Postoperative hypertension Nitroglycerin, nitroprusside, labetalol,

nicardipine

Preeclampsia/eclampsia of pregnancy Hydralazine, labetalol, nicardipine

Source: Reproduced with permission from DG Vidt, in S Oparil, MA Weber (eds):

Hypertension, 2nd ed. Philadelphia, Elsevier Saunders, 2005.

TABLE 277-11 Usual Intravenous Doses of Antihypertensive Agents

Used in Hypertensive Emergenciesa

ANTIHYPERTENSIVE

AGENT INTRAVENOUS DOSE

Nitroprusside Initial 0.3 (μg/kg)/min; usual 2–4 (μg/kg)/min; maximum

10 (μg/kg)/min for 10 min

Nicardipine Initial 5 mg/h; titrate by 2.5 mg/h at 5–15 min intervals;

max 15 mg/h

Labetalol 2 mg/min up to 300 mg or 20 mg over 2 min, then

40–80 mg at 10-min intervals up to 300 mg total

Enalaprilat Usual 0.625–1.25 mg over 5 min every 6–8 h; maximum

5 mg/dose

Esmolol Initial 80–500 μg/kg over 1 min, then 50–300 (μg/kg)/min

Phentolamine 5–15 mg bolus

Nitroglycerin Initial 5 μg/min, then titrate by 5 μg/min at 3–5-min

intervals; if no response is seen at 20 μg/min,

incremental increases of 10–20 μg/min may be used

Hydralazine 10–50 mg at 30-min intervals

a

Constant blood pressure monitoring is required. Start with the lowest dose.

Subsequent doses and intervals of administration should be adjusted according to

the blood pressure response and duration of action of the specific agent.

than the choice of specific agents. In the absence of comorbid conditions requiring acute therapy, for patients with a systolic blood

pressure ≥220 mmHg or a diastolic blood pressure ≥120 mmHg,

who are not candidates for thrombolytic therapy or endovascular

treatment, the benefit of instituting antihypertensive therapy within

the first 48–72 h is uncertain. One suggestion for these patients is

to lower blood pressure by 15% during the first 24 h after onset

of the stroke. For patients with less severe hypertension, acute

reduction of blood pressure is not effective in preventing death or

dependency. If thrombolytic therapy or endovascular treatment is

to be used, the recommended goal is to reduce blood pressure to

<185 mmHg systolic pressure and <110 mmHg diastolic pressure

before thrombolytic therapy is initiated. For neurologically stable

patients with blood pressure >140/90 mmHg, starting or restarting

antihypertensive therapy after the first 24 h to improve long-term

blood pressure control is reasonable. In patients with hemorrhagic

stroke, who have systolic blood pressure >220 mmHg, it is reasonable to use continuous intravenous drug infusion to lower blood

pressure. However, there is no consistent evidence that acute reductions of systolic blood pressure to a more aggressive target than

140–179 mmHg improve functional outcome. The management

of hypertension after subarachnoid hemorrhage is controversial.

Cautious reduction of blood pressure is indicated if mean arterial

pressure is >130 mmHg.

In addition to pheochromocytoma, an adrenergic crisis due to

catecholamine excess may be related to cocaine or amphetamine

overdose, clonidine withdrawal, acute spinal cord injuries, and an

interaction of tyramine-containing compounds with monoamine

oxidase inhibitors. These patients may be treated with phentolamine or nitroprusside.

Treatment of hypertension in patients with acute aortic dissection is discussed in Chap. 280, and treatment of hypertension

in pregnancy is discussed in Chap. 479.

■ FURTHER READING

Dzau VJ, Balatbat CA: Future of hypertension: The need for transformation. Hypertension 74:450, 2019.

Ettehad D et al: Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and meta-analysis.

Lancet 387:957, 2016.

Feinberg AP, Fallin MD: Epigenetics at the crossroads of genes and

the environment. JAMA 314:1129, 2015.

Iadecola C et al: Impact of hypertension on cognitive function: A

scientific statement from the American Heart Association. Hypertension 68:e67, 2016.

Mansukhani MP et al: Neurological sleep disorders and blood pressure: Current evidence. Hypertension 74:726, 2019.

Maric-Bilkan C et al: Research recommendations from the National

Institutes of Health Workshop on Predicting, Preventing, and Treating Preeclampsia. Hypertension 73:757, 2019.

Mattson DL: Immune mechanisms of salt-sensitive hypertension and

renal end-organ damage. Nat Rev Nephrol 15:290, 2019.

Norlander AE et al: The immunology of hypertension. J Exp Med

215:21, 2018.

Oh YS et al: National Heart, Lung, and Blood Institute Working Group

report on salt in human health and sickness: Building on the current

scientific evidence. Hypertension 68:281, 2016.

Safar ME et al: Interaction between hypertension and arterial stiffness: An expert reappraisal. Hypertension 72:796, 2018.

Whelton PK et al: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APHA/

ASH/ASPC/NMA/PCNA guidelines for the prevention, detection,

evaluation and management of high blood pressure in adults: A

report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension

71:e13, 2018.

2088 PART 6 Disorders of the Cardiovascular System

The renal vasculature is unusually complex with rich arteriolar flow

to the cortex in excess of metabolic requirements, consistent with its

primary function as a filtering organ. After delivering blood to cortical

glomeruli, the postglomerular circulation supplies deeper medullary

segments that support energy-dependent solute transport at multiple

levels of the renal tubule. These postglomerular vessels deliver less

blood and, with high oxygen consumption, leave the deeper medullary

regions at the margin of hypoxemia. Vascular disorders that commonly

threaten the blood supply of the kidney include large-vessel atherosclerosis, fibromuscular diseases, and embolic disorders. Microvascular

injury, including inflammatory and primary hematologic disorders,

is described in Chap. 317.

MECHANISMS OF VASCULAR INJURY AND

HYPERTENSION

The glomerular capillary endothelium shares susceptibility to oxidative

stress, pressure injury, and inflammation with other vascular territories. Endothelial injury can be manifest by urinary albumin excretion

(UAE), which is predictive of systemic atherosclerotic disease events.

Increased UAE may develop years before cardiovascular events. UAE

and the risk of cardiovascular events are both reduced with pharmacologic therapy such as antihypertensive drugs and statins. Experimental studies demonstrate functional changes and rarefaction of renal

microvessels under conditions of accelerated atherosclerosis and/or

compromise of proximal perfusion pressures with large-vessel disease

(Fig. 278-1).

Large-vessel renal artery occlusive disease can result from extrinsic

compression of the vessel, intimal dissection, aortic stent graft placement, fibromuscular dysplasia (FMD), or, most commonly, atherosclerotic disease. Any disorder that reduces perfusion pressure to the

kidney can activate mechanisms that tend to restore renal pressures at

the expense of developing systemic hypertension. Because restoration

of perfusion pressures can reverse these pathways, renal artery stenosis

is considered a specifically treatable “secondary” cause of hypertension.

278 Renovascular Disease

Stephen C. Textor

Renal artery stenosis is common and often has only minor hemodynamic effects. FMD is reported in 3–5% of normal subjects presenting

as potential kidney donors without hypertension. It may present clinically with hypertension in younger individuals (between age 15 and

50), most often women. FMD does not often threaten kidney function,

but sometimes produces total occlusion and can be associated with

renal artery aneurysms. Atherosclerotic renal artery stenosis (ARAS)

is common in the general population (6.8% of a community-based

sample above age 65). The prevalence increases with age and for

patients with other vascular conditions such as coronary artery disease

(18–23%) and/or peripheral aortic or lower extremity disease (>30%).

If untreated, ARAS progresses in nearly 50% of cases over a 5-year

period, sometimes to total occlusion. Intensive treatment of arterial

blood pressure and statin therapy can slow these rates and improve

clinical outcomes.

Critical levels of stenosis lead to a reduction in perfusion pressure

that activates the renin-angiotensin system, reduces sodium excretion,

and activates sympathetic adrenergic pathways. These events lead to

systemic hypertension characterized by angiotensin dependence in

the early stages, widely varying pressures, loss of circadian blood pressure (BP) rhythms, and accelerated target organ injury, including left

ventricular hypertrophy and renal fibrosis. Renovascular hypertension

can be treated with agents that block the renin-angiotensin system and

other drugs that modify these pressor pathways. It can also be treated

with restoration of renal blood flow by either endovascular or surgical

revascularization. Most patients require continued antihypertensive

drug therapy due to preexisting hypertension and because revascularization alone rarely lowers BP to normal.

ARAS and systemic hypertension tend to affect both the poststenotic

and contralateral kidneys, reducing overall glomerular filtration rate

(GFR) in ARAS. When kidney function is threatened by large-vessel

disease primarily, it has been labeled ischemic nephropathy. Moderately reduced blood flow that develops gradually is associated with

reduced GFR and limited oxygen consumption with preserved tissue

oxygenation. Hence, kidney function often remains stable during medical therapy, sometimes for years. With more advanced disease, reductions in cortical perfusion and overt tissue hypoxia develop. Unlike

FMD, ARAS develops in patients with other risk factors for atherosclerosis and is commonly superimposed upon preexisting small-vessel

disease in the kidney resulting from hypertension, aging, and diabetes.

Nearly 85% of patients considered for renal revascularization have

Normal MV proliferation

(early atherosclerosis)

MV rarefaction

(chronic renal ischemia)

Cortex Medulla

FIGURE 278-1 Examples of micro-CT images from vessels defined by radiopaque casts injected into the renal vasculature. These illustrate the complex, dense cortical

capillary network supplying the kidney cortex that can either proliferate or succumb to rarefaction under the influence of atherosclerosis and/or occlusive disease.

Changes in blood supply are followed by tubulointerstitial fibrosis and loss of kidney function. MV, microvascular. (Reproduced with permission from LO Lerman, AR Chade.

Angiogenesis in the kidney: A new therapeutic target?. Curr Opin Nephrol Hypertens 18:160, 2009.)

Renovascular Disease

2089CHAPTER 278

stage 3–5 chronic kidney disease (CKD) with GFR <60 mL/min per

1.73 m2

. The presence of ARAS is a strong predictor of morbidity- and

mortality-related cardiovascular events, independent of whether renal

revascularization is undertaken.

DIAGNOSIS OF RENOVASCULAR DISEASE

Diagnostic approaches to renal artery stenosis depend partly on the

specific clinical questions to be addressed. Noninvasive characterization of the renal vasculature may be achieved by several techniques,

summarized in Table 278-1. Although activation of the reninangiotensin system is a key step in developing renovascular hypertension, it is transient. Levels of renin activity are therefore subject to timing, the effects of drugs, and sodium intake, and do not reliably predict

the response to vascular therapy. Peak systolic renal artery velocities

by Doppler ultrasound >200 cm/s generally predict hemodynamically

important lesions (>60% vessel lumen occlusion), although some treatment trials have required velocity >300 cm/s to avoid false positives.

The renal resistive index has predictive value regarding the viability of

the kidney. It remains operator- and institution-dependent, however.

Contrast-enhanced computed tomography (CT) with vascular reconstruction provides excellent vascular images and functional assessment, but carries a small risk of contrast toxicity. It provides a more

reliable evaluation of accessory vessels and the distal vasculature than

duplex or magnetic resonance imaging (MRI). Magnetic resonance

angiography (MRA) is now less often used, as gadolinium contrast

has been associated with nephrogenic systemic fibrosis particularly

in patients with reduced GFR. Captopril-enhanced renography has a

strong negative predictive value when entirely normal.

TREATMENT

Renal Artery Stenosis

While restoring renal blood flow and perfusion seems intuitively

beneficial for high-grade occlusive lesions, revascularization procedures also pose hazards and expense. Patients with FMD are

commonly younger females with otherwise normal vessels and a

long life expectancy. These patients often respond well to percutaneous renal artery angioplasty. If BP can be controlled to goal

levels and kidney function remains stable in patients with ARAS,

it may be argued that medical therapy with follow-up for disease

progression is equally effective over periods of 3–5 years. Multiple

prospective randomized controlled trials have failed to identify

compelling benefits for interventional revascularization procedures

regarding short-term results of BP and renal function. Studies of

cardiovascular outcomes, including stroke, congestive heart failure,

myocardial infarction, and end-stage renal failure, suggest a small

mortality benefit for stented patients without proteinuria. Medical

therapy should include blockade of the renin-angiotensin system,

attainment of goal BPs, cessation of tobacco, statins, and aspirin.

Follow-up requires surveillance for progressive occlusion manifest by worsening renal function and/or loss of BP control. Renal

revascularization is now often reserved for patients failing medical

therapy or developing additional complications.

Techniques of renal revascularization are improving. With experienced operators, major complications occur in <5% of cases,

including renal artery dissection, capsular perforation, hemorrhage,

and occasional atheroembolic disease. Although not common,

atheroembolic disease can be catastrophic and accelerate both

hypertension and kidney failure, precisely the events that revascularization is intended to prevent. Although renal blood flow usually

can be restored by endovascular stenting, recovery of renal function is limited to ~25% of cases, with no change in 50% and some

deterioration evident in others. Patients with rapid loss of kidney

function, sometimes associated with antihypertensive drug therapy,

or with vascular disease affecting the entire functioning kidney

mass are more likely to recover function after restoring blood flow.

When hypertension is refractory to effective therapy, revascularization offers real benefits. Table 278-2 summarizes currently accepted

guidelines for considering renal revascularization in addition to

optimal medical therapy.

ATHEROEMBOLIC RENAL DISEASE

Emboli to the kidneys arise most frequently as a result of cholesterol

crystals breaking free of atherosclerotic vascular plaque and lodging

in downstream microvessels. Most clinical atheroembolic events

follow angiographic procedures, often of the coronary vessels. It has

been argued that nearly all vascular interventional procedures lead to

plaque fracture and release of microemboli, but clinical manifestations

develop only in a fraction of these. The incidence of clinical atheroemboli has been increasing with more vascular procedures and longer life

spans. Atheroembolic renal disease is suspected in >3% of elderly subjects with end-stage renal disease (ESRD) and is likely underdiagnosed.

It is more frequent in males with a history of diabetes, hypertension,

and ischemic cardiac disease. Atheroemboli in the kidney are strongly

associated with aortic aneurysmal disease and renal artery stenosis.

Most clinically evident cases can be linked to precipitating events, such

as angiography, vascular surgery, anticoagulation with heparin, thrombolytic therapy, or trauma. Clinical manifestations of this syndrome

TABLE 278-1 Summary of Imaging Modalities for Evaluating the Kidney Vasculature

Vascular Studies to Evaluate the Renal Arteries

Duplex ultrasonography Shows the renal arteries and measures

flow velocity as a means of assessing

the severity of stenosis

Inexpensive; widely available, suitable

for follow-up studies

Heavily dependent on operator’s

experience; less useful than invasive

angiography for the diagnosis

of fibromuscular dysplasia and

abnormalities in accessory renal

arteries

Computed tomographic angiography Shows the renal arteries and perirenal

aorta

Provides excellent images; stents do not

cause artifacts

Expensive, moderate volume of contrast

required

Magnetic resonance angiography Shows the renal arteries and perirenal

aorta

Not nephrotoxic, but concerns for

gadolinium toxicity exclude use in

GFR <30 mL/min per 1.73 m2

; provides

excellent images

Expensive; gadolinium excluded in

renal failure, unable to visualize stented

vessels

Intraarterial angiography Shows location and severity of vascular

lesion

Considered “gold standard” for

diagnosis of large-vessel disease,

usually performed simultaneous with

planned intervention

Expensive, associated hazard of

atheroemboli, contrast toxicity,

procedure-related complications, e.g.,

dissection

Perfusion Studies to Assess Differential Renal Blood Flow

Captopril renography with technetium

99mTc mertiatide (99mTc MAG3)

Captopril-mediated fall in filtration

pressure amplifies differences in renal

perfusion

Normal study excludes renovascular

hypertension

Multiple limitations in patients with

advanced atherosclerosis or creatinine

>2.0 mg/dL (177 μmol/L)

Abbreviation: GFR, glomerular filtration rate.

2090 PART 6 Disorders of the Cardiovascular System

commonly develop between 1 and 14 days after an inciting event and

may continue to develop for weeks thereafter. Systemic embolic disease

manifestations, such as fever, abdominal pain, and weight loss, are

present in less than half of patients, although cutaneous manifestations

including livedo reticularis and localized toe gangrene may be more

common. Worsening hypertension and deteriorating kidney function

are common, sometimes reaching a malignant phase. Progressive

renal failure can occur and require dialytic support. These cases often

develop after a stuttering onset over many weeks and have an ominous

prognosis. Mortality rate after 1 year exceeds 38%, and although some

may eventually recover sufficiently to no longer require dialysis, many

do not.

Beyond the clinical manifestations above, laboratory findings

include rising creatinine, transient eosinophilia (60–80%), elevated

sedimentation rate, and hypocomplementemia (15%). Establishing this

diagnosis can be difficult and is often by exclusion. Definitive diagnosis

depends on kidney biopsy demonstrating microvessel occlusion with

cholesterol crystals that leave a “cleft” in the vessel. Biopsies obtained

from patients undergoing surgical revascularization of the kidney

indicate that silent cholesterol emboli are frequently present before any

further manipulation is performed.

No effective therapy is available for atheroembolic disease once it

has developed. Withdrawal of anticoagulation is recommended. Late

recovery of kidney function after supportive measures sometimes

occurs, and statin therapy may improve outcome. The role of embolic

protection devices in the renal circulation during angiography is

unclear, but a few prospective trials have failed to demonstrate major

benefits. The effect of such devices is limited to distal protection during

the endovascular procedure, and they offer no protection from embolic

debris developing after removal.

THROMBOEMBOLIC RENAL DISEASE

Thrombotic occlusion of renal vessels or branch arteries can lead to

declining renal function and hypertension. It is difficult to diagnose

and is often overlooked, especially in elderly patients. Thrombosis

can develop as a result of local vessel abnormalities, such as local dissection, trauma, or inflammatory vasculitis. Local microdissections

sometimes lead to patchy, transient areas of infarctions labeled “segmental arteriolar mediolysis.” Although hypercoagulability conditions

sometimes present as renal artery thrombosis, this is rare. It can also

TABLE 278-2 Clinical Factors That Determine the Role of

Revascularization in Addition to Medical Therapy for Renal Artery

Stenosis

Factors Favoring Medical Therapy with Revascularization for Renal

Artery Stenosis

• Progressive decline in GFR during treatment of systemic hypertension

• Failure to achieve adequate blood pressure control with optimal medical

therapy (medical failure)

• Rapid or recurrent decline in the GFR in association with a reduction in

systemic pressure

• Decline in the GFR during therapy with ACE inhibitors or ARBs

• Recurrent congestive heart failure in a patient in whom left ventricular

dysfunction does not fully explain the cause

Factors Favoring Medical Therapy and Surveillance of Renal Artery

Disease

• Controlled blood pressure with stable renal function (e.g., stable renal

insufficiency)

• Stable renal artery stenosis without progression on surveillance studies (e.g.,

serial duplex ultrasound)

• Advanced age and/or limited life expectancy

• Extensive comorbidity that make revascularization too risky

• High risk for or previous experience with atheroembolic disease

• Other concomitant renal parenchymal diseases that cause progressive renal

dysfunction (e.g., interstitial nephritis, diabetic nephropathy), particularly with

proteinuria

Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor

blockers; GFR, glomerular filtration rate.

derive from distant embolic events, e.g., the left atrium in patients

with atrial fibrillation or from fat emboli originating from traumatized

tissue, most commonly large bone fractures. Cardiac sources include

vegetations from subacute bacterial endocarditis. Systemic emboli to

the kidneys may also arise from the venous circulation if right-to-left

shunting occurs, e.g., through a patent foramen ovale.

Clinical manifestations vary depending on the rapidity of onset and

extent of occlusion. Acute arterial thrombosis may produce flank pain,

fever, leukocytosis, nausea, and vomiting. If kidney infarction results,

enzymes such as lactate dehydrogenase (LDH) rise transiently to

extreme levels. If both kidneys are affected, renal function will decline

precipitously with a drop in urine output. If a single kidney is involved,

renal functional changes may be minor. Hypertension related to sudden release of renin from ischemic tissue can develop rapidly, as long

as some viable tissue in the “peri-infarct” border zone remains. If the

infarct zone demarcates precisely, the rise in BP and renin activity may

resolve. Diagnosis of renal infarction may be established by vascular

imaging with CT angiography, MRI, or arteriography (Fig. 278-2).

■ MANAGEMENT OF ARTERIAL THROMBOSIS OF

THE KIDNEY

Options for interventions of newly detected arterial occlusion include

surgical reconstruction, anticoagulation, thrombolytic therapy,

endovascular procedures, and supportive care, particularly antihypertensive drug therapy. Application of these methods depends on the

patient’s overall condition, the precipitating factors (e.g., local trauma

or systemic illness), the magnitude of renal tissue and function at risk,

and the likelihood of recurrent events in the future. For unilateral disease, for example, arterial dissection with thrombosis and supportive

care with anticoagulation may suffice. Acute, bilateral occlusion is

potentially catastrophic, producing anuric renal failure. Depending on

the precipitating event, surgical or thrombolytic therapies can sometimes restore kidney viability if undertaken early in the course of the

acute event.

MICROVASCULAR INJURY ASSOCIATED

WITH HYPERTENSION

■ ARTERIOLONEPHROSCLEROSIS

“Malignant” Hypertension Although BP rises with age, it has

long been recognized that some individuals develop rapidly progressive BP elevations with target organ injury including retinal

hemorrhages, encephalopathy, and declining kidney function. Placebo arms during the early controlled trials of hypertension therapy

identified progression to severe levels in 20% of subjects over 5 years.

If untreated, patients with target organ injury including papilledema

and declining kidney function suffered mortality rates in excess of

50% over 6–12 months, hence the designation “malignant.” Postmortem studies of such patients identified vascular lesions, designated

“fibrinoid necrosis,” with breakdown of the vessel wall, deposition

of eosinophilic material including fibrin, and a perivascular cellular

infiltrate. A separate lesion was identified in the larger interlobular

arteries in many patients with hyperplastic proliferation of the vascular

wall cellular elements, deposition of collagen, and separation of layers,

designated the “onionskin” lesion. For many of these patients, fibrinoid

necrosis led to obliteration of glomeruli and loss of tubular structures.

Progressive kidney failure ensued and, without dialysis support, led to

early mortality in untreated malignant-phase hypertension. These vascular changes could develop with pressure-related injury from a variety

of hypertensive pathways, including but not limited to activation of

the renin-angiotensin system and severe vasospasm associated with

catecholamine release. Occasionally, endothelial injury is sufficient to

induce microangiopathic hemolysis, as discussed below.

Antihypertensive therapy is the mainstay of therapy for malignant

hypertension. With effective BP reduction, manifestations of vascular

injury, including microangiopathic hemolysis and renal dysfunction,

can improve over time. Whereas prior reports before the era of drug

therapy suggested that 1-year mortality rates exceeded 90%, current

survival over 5 years exceeds 50%.

Deep-Venous Thrombosis and Pulmonary Thromboembolism

2091CHAPTER 279

A B

FIGURE 278-2 A. CT angiogram illustrating loss of circulation to the upper pole of the right kidney in a patient with fibromuscular disease and a renal artery aneurysm.

Activation of the renin-angiotensin system produced rapidly developing hypertension. B. Angiogram illustrating high-grade renal artery stenosis affecting the left kidney. This

lesion is often part of widespread atherosclerosis and sometimes is an extension of aortic plaque. This lesion develops in older individuals with preexisting atherosclerotic

risk factors.

Malignant hypertension is less common in Western countries,

although it persists in parts of the world where medical care and

antihypertensive drug therapy are less available. It most commonly

develops in patients with treated hypertension who neglect to take

medications or who may use vasospastic drugs, such as cocaine. Renal

abnormalities typically include rising serum creatinine and occasionally hematuria and proteinuria. Biochemical findings may include

evidence of hemolysis (anemia, schistocytes, and reticulocytosis) and

changes associated with kidney failure. African-American males are

more likely to develop rapidly progressive hypertension and kidney

failure than are whites in the United States. Genetic polymorphisms for

APOL1 that are common in the African-American population predispose to focal sclerosing glomerular disease, with severe hypertension

developing at younger ages secondary to renal disease in this instance.

“Hypertensive Nephrosclerosis” Based on experience with

malignant hypertension and epidemiologic evidence linking BP with

long-term risks of kidney failure, it has long been assumed that lesser

degrees of hypertension induce less severe, but prevalent, changes in

kidney vessels and loss of kidney function. As a result, a large portion

of patients reaching ESRD without a specific etiologic diagnosis are

assigned the designation “hypertensive nephrosclerosis.” Pathologic

examination commonly identifies afferent arteriolar thickening with

deposition of homogeneous eosinophilic material (hyaline arteriolosclerosis) associated with narrowing of vascular lumina. Clinical manifestations include retinal vessel changes associated with hypertension

(arteriolar narrowing, arteriovenous crossing changes), left ventricular

hypertrophy, and elevated BP. The role of these vascular changes in

kidney function is unclear. Postmortem and biopsy samples from

normotensive kidney donors demonstrate similar vessel changes associated with aging, dyslipidemia, and glucose intolerance. Although BP

reduction does slow progression of proteinuric kidney diseases and is

warranted to reduce the excessive cardiovascular risks associated with

CKD, antihypertensive therapy does not alter the course of kidney dysfunction identified specifically as hypertensive nephrosclerosis.

■ FURTHER READING

De Mast Q, Beutler JJ: The prevalence of atherosclerotic renal artery

stenosis in risk groups: A systemic literature review. J Hypertens

27:1333, 2009.

Freedman BI, Cohen AH: Hypertension-attributed nephropathy:

What’s in a name? Nat Rev Nephrol 12:27, 2016.

Herrmann SM et al: Management of atherosclerotic renovascular disease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions

(CORAL). Nephrol Dial Transplant 30:366, 2015.

Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol

12:1781 2001.

Parikh SA et al: SCAI expert consensus statement for renal artery

stenting appropriate use. Catheter Cardiovasc Interv 84:1163, 2014.

Persu A et al: European consensus on the diagnosis and management

of fibromuscular dysplasia. J Hypertens 32:1367, 2014.

Textor SC et al: Percutaneous revascularization for ischemic nephropathy: The past, present and future. Kidney Int 83:28, 2013.

Textor SC, Lerman LO: The role of hypoxia in ischemic chronic

kidney disease. Semin Nephrol 39:589, 2019.

■ EPIDEMIOLOGY

Venous thromboembolism (VTE) encompasses deep-venous thrombosis (DVT) and pulmonary embolism (PE) and causes cardiovascular

death, chronic disability, and emotional distress. In the United States,

there are an estimated 100,000–180,000 deaths attributed annually to PE.

Beginning in 2015, the life expectancy in the United States has

decreased, primarily due to more deaths among young and middle-aged

adults of all racial groups. Drug overdoses, alcoholic liver disease, and

suicides have garnered the most attention for this increase in midlife

279 Deep-Venous Thrombosis

and Pulmonary

Thromboembolism

Samuel Z. Goldhaber

2092 PART 6 Disorders of the Cardiovascular System

mortality; however, increasing deaths from heart and lung diseases, as

well as hypertension, stroke, and diabetes mellitus, help account for

this unwanted trend. The annual PE-related age-standardized mortality rate has been increasing among young and middle-aged adults

since 2007 (Fig. 279-1). Among the elderly, the rate of decrease of PErelated mortality has slowed. PE patients residing in zip codes with

lower socioeconomic status have increased in-hospital mortality. In

contrast, Canada’s and Denmark’s annual age-standardized mortality

rate with PE as the underlying cause of death has decreased across all

age groups. Europe’s age-standardized annual PE-related mortality rate

has decreased linearly since year 2000.

In 2020, COVID-19 erupted and caused a global pandemic. The most

notable clinical feature is a life-threatening acute respiratory syndrome

requiring prolonged mechanical ventilation and causing a high case–

fatality rate. This viral illness also causes extensive DVT and PE, even

when patients receive standard pharmacologic prophylaxis as soon as

they are hospitalized. At autopsy, about one-fourth of patients have

both macrovascular and microvascular PE. Arterial thrombosis also

occurs and causes myocardial infarction and stroke. The contributing

etiologies of this widespread thrombosis are excessive inflammation

with cytokine storm, platelet activation, endothelial dysfunction, and

stasis (Fig. 279-2).

In the United States, Medicare fee-for-service beneficiaries with acute

PE have a high 14% readmission rate within 30 days of hospital discharge. The reasons are uncertain, but the high rate suggests that we need

to improve the transition of care from inpatient to outpatient. In addition

to survival after PE, we now focus more attention on the quality of life

after PE. About half of PE patients report persistent dyspnea, fatigue, and

reduced exercise capacity, and about one-quarter have persistent right

ventricular dysfunction on echocardiogram following the diagnosis of

PE. This constellation of findings is being recognized more frequently

and is called the “post-PE syndrome.” These patients may subsequently

develop chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension causes breathlessness, especially with exertion. Postthrombotic syndrome (also

known as chronic venous insufficiency) damages the venous valves of

the leg and worsens the quality of life by causing ankle or calf swelling and leg aching, especially after prolonged standing. In its most

severe form, postthrombotic syndrome causes deep skin ulceration

(Fig. 279-3).

Age-standardized PE-related mortality rate

(deaths per 100,000 population)

0

20002001

2002 2003 2004

2005

2006 2007

2008 200920102011

2012

201320142015

2016

2017

Year

Women

1

2

3

4

5

6

7

8

9

10

20002001

2002 2003 2004

2005

2006

2007

2008

200920102011

201220132014

201520162017

Men

Canada United States

FIGURE 279-1 Time trends in pulmonary embolism (PE)–related age-standardized mortality in women and men in the United States and Canada from 2000 to 2017.

■ PATHOPHYSIOLOGY

Inflammation Inflammation takes center stage as a trigger of acute

PE and DVT. Inflammation-related risk factors and medical illnesses

are now linked as precipitants of VTE (Table 279-1).

Prothrombotic States The two most common autosomal dominant genetic mutations are (1) factor V Leiden, which causes resistance

to the endogenous anticoagulant activated protein C (which inactivates

clotting factors V and VIII), and (2) the prothrombin gene mutation,

which increases the plasma prothrombin concentration (Chaps. 65

and 117). Antithrombin, protein C, and protein S are naturally occurring coagulation inhibitors. Deficiencies of these inhibitors are associated with VTE but are rare. Antiphospholipid antibody syndrome is an

acquired (not genetic) thrombophilic disorder that predisposes to both

venous and arterial thrombosis. Counterintuitively, the presence of

genetic mutations such as heterozygous factor V Leiden and prothrombin

gene mutation does not appear to increase the risk of recurrent VTE.

However, patients with antiphospholipid antibody syndrome may warrant indefinite-duration anticoagulation, even if the initial VTE was

provoked by trauma or surgery.

Clinical Risk Factors Common comorbidities include cancer,

obesity, cigarette smoking, systemic arterial hypertension, chronic

obstructive pulmonary disease, chronic kidney disease, long-haul air

travel, air pollution, estrogen-containing contraceptives, pregnancy,

postmenopausal hormone replacement, surgery, and trauma. Sedentary lifestyle is increasingly prevalent. A Japanese study found that each

2 h per day increment of television watching is associated with a 40%

increased likelihood of fatal PE.

Activated Platelets Virchow’s triad of venous stasis, hypercoagulability, and endothelial injury leads to recruitment of activated

platelets, which release microparticles. These microparticles contain

proinflammatory mediators that bind neutrophils, stimulating them to

release their nuclear material and form web-like extracellular networks

called neutrophil extracellular traps. These prothrombotic networks

contain histones that stimulate platelet aggregation and promote

platelet-dependent thrombin generation. Venous thrombi form and

flourish in an environment of stasis, low oxygen tension, and upregulation of proinflammatory genes.

Deep-Venous Thrombosis and Pulmonary Thromboembolism

2093CHAPTER 279

Interaction between Venous Thromboembolism and

Atherothrombosis Carotid artery plaque doubles the risk of VTE.

This observation led to discovery of the broad interaction among VTE,

Sars-COV-2

Risk factors

Inflammatory response

Endothelial dysfunction

Superinfected

Hemostatic abnormalities Clinical outomes

A B C

Acute illness

Bed-ridden, stasis

Genetics

Fever

Diarrhea

Sepsis

Tissue factor

 TFPI

Inflammatory

cytokines

 IL-6, CRP

Lymphopenia

Liver injury

CKD

COPD

HF

Malignancy

Pulmonary microthrombi

Intravascular coagulopathy

Myocardial injury

 Cardiac biomarkers

 D-dimer, FDPs, PT

 Platelets

 Venous thromboembolism

 Myocardial infarction

 Disseminated intravascular

coagulation

FIGURE 279-2 Postulated mechanisms of coagulopathy and pathogenesis of thrombosis in COVID-19. A. Sars-COV-2 infection activates an inflammatory response,

leading to release of inflammatory mediators. Endothelial and hemostatic activation ensues, with decreased levels of TFPI and increased tissue factor. The inflammatory

response to severe infection is marked by lymphopenia and thrombocytopenia. Liver injury may lead to decreased coagulation and antithrombin formation. B. COVID-19 may

be associated with hemostatic derangement and elevated troponin. C. Increased thromboembolic state results in venous thromboembolism, myocardial infarction, or,

in case of further hemostatic derangement, disseminated intravascular coagulation. CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP,

C-reactive protein; FDP, fibrin degradation product; HF, heart failure; TFPI, tissue factor pathway inhibitor; IL, interleukin; LDH, lactate dehydrogenase; PT, prothrombin time.

(This article was published in Journal of the American College of Cardiology; 75, B Bikdeli et al: COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention,

Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review; 2950-2973. Copyright Elsevier 2020. Reproduced with permission from Elsevier.)

FIGURE 279-3 Skin ulceration in the lateral malleolus from postthrombotic

syndrome of the leg.

TABLE 279-1 Inflammation-Linked Conditions That Can Trigger

PE or DVT

Ulcerative colitis

Crohn’s disease

Rheumatoid arthritis

Psoriasis

Diabetes mellitus, type 2

Obesity/metabolic syndrome

Hypercholesterolemia, especially elevated LDL cholesterol

Lipoprotein(a)

Pneumonia

Acute coronary syndrome

Acute stroke

Cigarette smoking

Sepsis/septic shock

Erythropoiesis-stimulating agents

Blood transfusion

Cancer

Abbreviations: DVT, deep-venous thrombosis; LDL, low-density lipoprotein; PE,

pulmonary embolism.

acute coronary syndrome, and acute stroke (Fig. 279-4). These three

conditions share similar risk factors and similar pathophysiology:

inflammation, hypercoagulability, and endothelial injury. Patients who

suffer VTE are more than twice as likely to have a future myocardial

infarction or stroke. Conversely, patients with myocardial infarction or

stroke are more than twice as likely to suffer a future VTE.

Embolization When deep-venous thrombi (Fig. 279-5) detach

from their site of formation, they embolize to the vena cava, right

atrium, and right ventricle, and lodge in the pulmonary arterial circulation, thereby causing acute PE. Paradoxically, these thrombi occasionally embolize to the arterial circulation through a patent foramen ovale

2094 PART 6 Disorders of the Cardiovascular System

or atrial septal defect. Many patients with PE have no evidence of DVT

because the clot has already embolized to the lungs.

Physiology The most common gas exchange abnormalities are

arterial hypoxemia and an increased alveolar-arterial O2

 tension gradient, which represents the inefficiency of O2

 transfer across the lungs.

Anatomic dead space increases because breathed gas does not enter gas

exchange units of the lung. Physiologic dead space increases because

ventilation to gas exchange units exceeds venous blood flow through

the pulmonary capillaries (Fig. 279-6).

Other pathophysiologic abnormalities include the following:

1. Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of vasoconstricting neurohumoral agents

such as serotonin. Release of vasoactive mediators can produce

ventilation-perfusion mismatching at sites remote from the embolus,

thereby accounting for discordance between a small PE and a large

alveolar-arterial O2

 gradient.

2. Impaired gas exchange due to increased alveolar dead space from

vascular obstruction, hypoxemia from alveolar hypoventilation relative to perfusion in the nonobstructed lung, right-to-left shunting,

or impaired carbon monoxide transfer due to loss of gas exchange

surface.

3. Alveolar hyperventilation due to reflex stimulation of irritant

receptors.

4. Increased airway resistance due to constriction of airways distal to

the bronchi.

5. Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant.

Pulmonary Hypertension, Right Ventricular (RV) Dysfunction,

and RV Microinfarction Pulmonary artery obstruction and

PE

PE

MI

MI

Inflammation: A common

underlying process

Stroke

Stroke

FIGURE 279-4 Broad interaction between venous thromboembolism and

atherothrombosis. MI, myocardial infarction; PE, pulmonary embolism.

FIGURE 279-5 Deep-venous thrombosis at autopsy.

neurohumoral mediators cause a rise in pulmonary artery pressure

and in pulmonary vascular resistance. When RV wall tension rises, RV

dilation and dysfunction ensue, with release of the cardiac biomarker,

brain natriuretic peptide, due to abnormal RV stretch. The interventricular septum bulges into and compresses an intrinsically normal

left ventricle (LV). Diastolic LV dysfunction reduces LV distensibility

and impairs LV filling. Increased RV wall tension also compresses the

right coronary artery, limits myocardial oxygen supply, and precipitates

right coronary artery ischemia and RV microinfarction, with release

of cardiac biomarkers such as troponin. Underfilling of the LV may

lead to a fall in LV cardiac output and systemic arterial pressure, with

consequent circulatory collapse and death (Fig. 279-6).

■ CLASSIFICATION OF PULMONARY EMBOLISM

AND DEEP-VENOUS THROMBOSIS

Pulmonary Embolism Massive (high-risk) PE accounts for

5–10% of cases and is usually characterized by systemic arterial

hypotension and extensive thrombosis affecting at least half of the

pulmonary vasculature. Dyspnea, syncope, hypotension, and cyanosis

are hallmarks of massive PE. Patients with massive PE may present in

cardiogenic shock and can die from multisystem organ failure. Submassive (intermediate-risk) PE accounts for 20–25% of patients and

is characterized by RV dysfunction despite normal systemic arterial

pressure. The combination of right heart failure and release of cardiac

biomarkers such as troponin indicates a high risk of clinical deterioration. Low-risk PE constitutes about 65–75% of cases. These patients

have an excellent prognosis.

Deep-Venous Thrombosis Lower extremity DVT usually begins

in the calf and can propagate proximally to the popliteal, femoral, and

iliac veins. Leg DVT is ~10 times more common than upper extremity

DVT, which is often precipitated by placement of pacemakers, internal

cardiac defibrillators, or indwelling central venous catheters. The likelihood of upper extremity DVT increases as the catheter diameter and

number of lumens increase. Superficial venous thrombosis usually

presents with erythema, tenderness, and a “palpable cord.” Patients are

at risk for extension of the superficial vein thrombosis to the deepvenous system.

■ DIAGNOSIS

Clinical Evaluation PE is known as “the Great Masquerader.”

Diagnosis is difficult because symptoms and signs are nonspecific. In

the United States, there appears to be excessive ordering of computed

tomography (CT) pulmonary angiograms in patients suspected of

PE. In a study of 27 emergency departments in Indiana and DallasFort Worth, where 1.8 million patient encounters were logged, 5% of

patients underwent CT pulmonary angiography. Increased d-dimer

correlated with an increased diagnostic yield rate, varying from 1.3%

in Indiana to 4.8% in Dallas-Fort Worth.

RV pressure

overload

RV wall

tension

RV dysfunction RV ischemia

or infarction

LV preload Coronary

perfusion

LV Cardiac

output

Systemic

pressure

FIGURE 279-6 Pathophysiology of pulmonary embolism (PE). LV, left ventricular; RV,

right ventricular.

Deep-Venous Thrombosis and Pulmonary Thromboembolism

2095CHAPTER 279

The standard upper of limit of a d-dimer is 500 ng/mL. However,

guidelines now recommend use of an age-adjusted d-dimer when

ruling out acute PE. The age-adjusted d-dimer applies to patients older

than 50 years of age with low or intermediate clinical probability of PE.

To calculate the upper limit of normal d-dimer in these patients, multiply the age by 10. For example, a 70-year-old patient suspected of PE

would have 700 ng/mL as the upper limit of normal. The age-adjusted

d-dimer does not apply to patients suspected of acute DVT. In validation studies, implementing routine use of the age-adjusted d-dimer

may reduce the number of CT pulmonary angiograms that are ordered

by about one-third.

The most common symptom of PE is unexplained breathlessness.

When occult PE occurs concomitantly with overt congestive heart

failure or pneumonia, clinical improvement often fails to ensue despite

standard medical treatment of the concomitant illness. This scenario

presents a clinical clue to the possible coexistence of PE.

With DVT, the most common symptom is a cramp or “charley

horse” in the lower calf that persists and intensifies over several days.

Wells Point Score criteria help estimate the clinical likelihood of DVT

and PE (Table 279-2). Patients with a low likelihood of DVT or a

low-to-moderate likelihood of PE should undergo initial diagnostic

evaluation with d-dimer testing alone (see “Blood Tests”) without

obligatory imaging tests if the d-dimer test result is negative (Fig. 279-7).

However, patients with a high clinical likelihood of VTE should skip

d-dimer testing and undergo imaging as the next step in the diagnostic

algorithm.

Clinical Pearls Not all leg pain is due to DVT, and not all dyspnea

is due to PE (Table 279-3). Sudden, severe calf discomfort suggests a

ruptured Baker’s cyst. Fever and chills usually herald cellulitis rather

than DVT. Physical findings, if present, may consist only of mild palpation discomfort in the lower calf. However, massive DVT often presents

with marked thigh swelling, tenderness, and erythema. Recurrent left

thigh edema especially in young women raises the possibility of MayThurner syndrome, with right proximal iliac artery compression of the

left proximal iliac vein. If a leg is diffusely edematous, DVT is unlikely.

More probable is an acute exacerbation of venous insufficiency due to

postthrombotic syndrome. Upper extremity venous thrombosis may

present with asymmetry in the supraclavicular fossa or in the circumference of the upper arms.

TABLE 279-2 Clinical Decision Rules

Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate

Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater

CLINICAL VARIABLE DVT SCORE

Active cancer 1

Paralysis, paresis, or recent cast 1

Bedridden for >3 days; major surgery <12 weeks 1

Tenderness along distribution of deep veins 1

Entire leg swelling 1

Unilateral calf swelling >3 cm 1

Pitting edema 1

Collateral superficial nonvaricose veins 1

Alternative diagnosis at least as likely as DVT –2

High Clinical Likelihood of PE if Point Score Exceeds 4

CLINICAL VARIABLE PE SCORE

Signs and symptoms of DVT 3.0

Alternative diagnosis less likely than PE 3.0

Heart rate >100/min 1.5

Immobilization >3 days; surgery within 4 weeks 1.5

Prior PE or DVT 1.5

Hemoptysis 1.0

Cancer 1.0

Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism.

Suspect DVT or PE

Assess clinical likelihood

Low

D-dimer D-dimer

Normal

No DVT Imaging test needed No PE Imaging test needed

High Normal High

Not low Not high High

DVT PE

FIGURE 279-7 How to decide whether diagnostic imaging is needed. For

assessment of clinical likelihood, see Table 279-2. DVT, deep-venous thrombosis;

PE, pulmonary embolism.

TABLE 279-3 Differential Diagnosis of DVT and PE

DVT

Ruptured Baker’s cyst

Muscle strain/injury

Cellulitis

Acute postthrombotic syndrome/venous insufficiency

PE

Pneumonia, asthma, chronic obstructive pulmonary disease

Congestive heart failure

Pericarditis

Pleurisy: “viral syndrome,” costochondritis, musculoskeletal discomfort

Rib fracture, pneumothorax

Acute coronary syndrome

Anxiety

Vasovagal syncope

Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism.

Pulmonary infarction usually indicates a small PE. This condition is

exquisitely painful because the thrombus lodges peripherally, near the

innervation of pleural nerves. Nonthrombotic PE etiologies include fat

embolism after pelvic or long bone fracture, tumor embolism, bone

marrow, and air embolism. Cement embolism and bony fragment

embolism can occur after total hip or knee replacement. Intravenous

drug users may inject themselves with a wide array of substances that

can embolize, such as hair, talc, and cotton. Amniotic fluid embolism

occurs when fetal membranes leak or tear at the placental margin.

Nonimaging Diagnostic Modalities • BLOOD TESTS The

quantitative plasma d-dimer enzyme-linked immunosorbent assay

(ELISA) rises in the presence of DVT or PE because of the breakdown

of fibrin by plasmin. Elevation of d-dimer indicates endogenous

although often clinically ineffective thrombolysis. The sensitivity of

the d-dimer is >80% for DVT (including isolated calf DVT) and >95%

for PE. The d-dimer is less sensitive for DVT than for PE because the

DVT thrombus size is smaller. A normal d-dimer is a useful “rule out”

test for PE. However, the d-dimer assay is not specific. Levels increase

in patients with myocardial infarction, pneumonia, sepsis, cancer, the

postoperative state, and those in the second or third trimester of pregnancy. Therefore, d-dimer rarely has a useful role among hospitalized

patients, because levels are frequently elevated due to systemic illness.

2096 PART 6 Disorders of the Cardiovascular System

ELEVATED CARDIAC BIOMARKERS Serum troponin and plasma hearttype fatty acid–binding protein levels increase because of RV microinfarction. Myocardial stretch causes release of brain natriuretic peptide

or NT-pro-brain natriuretic peptide.

ELECTROCARDIOGRAM The most frequently cited abnormality, in

addition to sinus tachycardia, is the S1Q3T3 sign: an S wave in lead I, a

Q wave in lead III, and an inverted T wave in lead III (Chap. 240). This

finding is relatively specific but insensitive. RV strain and ischemia

cause the most common abnormality, T-wave inversion in leads V1

 to

V4 (Fig. 279-8).

Noninvasive Imaging Modalities • VENOUS ULTRASONOGRAPHY

Ultrasonography of the deep-venous system relies on loss of vein compressibility as the primary diagnostic criterion for DVT. When a normal

vein is imaged in cross-section, it readily collapses with gentle manual

pressure on the ultrasound transducer. This creates the illusion of a

“wink.” With acute DVT, the vein loses its compressibility because of passive distention by acute thrombus. The diagnosis of acute DVT is even

more secure when thrombus is directly visualized. It appears homogeneous and has low echogenicity (Fig. 279-9). The vein itself often appears

mildly dilated, and collateral channels may be absent.

Venous flow dynamics can be examined with Doppler imaging.

Normally, manual calf compression causes augmentation of the Doppler flow pattern. Loss of normal respiratory variation is caused by an

obstructing DVT or by any obstructive process within the pelvis. For

patients with a technically poor or nondiagnostic venous ultrasound,

one should consider alternative imaging modalities for DVT, such as

CT and magnetic resonance imaging.

CHEST ROENTGENOGRAPHY A normal or nearly normal chest x-ray

often occurs in PE. Well-established abnormalities include focal

oligemia (Westermark’s sign), a peripheral wedge-shaped density

usually located at the pleural base (Hampton’s hump), and an enlarged

right descending pulmonary artery (Palla’s sign).

CHEST CT CT of the chest with intravenous contrast is the principal

imaging test for the diagnosis of PE (Fig. 279-10A). Thin-cut chest CT

I

II

III

II

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

FIGURE 279-8 Electrocardiogram with both the S1Q3T3 sign and T-wave inversions in leads V1

-V4

—typical of an anatomically large pulmonary embolism. This patient’s

CT pulmonary angiogram is shown as Figures 279-10A and B.

Compression

CFV

CFA

CFV

CFA

No Compression

FIGURE 279-9 Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left.

Deep-Venous Thrombosis and Pulmonary Thromboembolism

2097CHAPTER 279

FIGURE 279-10 A. Massive bilateral proximal pulmonary embolism on an axial chest

CT image in a 53-year-old man (whose electrocardiogram is shown in Fig. 279-8)

with filling defects in the right and left main pulmonary arteries (white arrows).

B. Four-chamber view in the same patient showing the right ventricle (RV) larger

than the left ventricle (LV).

A

B

RV

LV

segmental perfusion defects in the presence of normal ventilation.

The diagnosis of PE is very unlikely in patients with normal and

nearly normal scans and, in contrast, is ~90% certain in patients with

high-probability scans.

MAGNETIC RESONANCE (MR) (CONTRAST-ENHANCED) IMAGING

When ultrasound is equivocal, MR venography with gadolinium contrast is an excellent imaging modality to diagnose DVT. MR pulmonary angiography may detect large proximal PE but is not reliable for

smaller segmental and subsegmental PE.

ECHOCARDIOGRAPHY Echocardiography is not a reliable diagnostic

imaging tool for acute PE because most patients with PE have normal

echocardiograms. However, echocardiography is a very useful diagnostic tool for detecting conditions that may mimic PE, such as acute

myocardial infarction, pericardial tamponade, and aortic dissection.

Transthoracic echocardiography rarely images thrombus directly. The

best-known indirect sign of PE on transthoracic echocardiography

is McConnell’s sign: hypokinesis of the RV free wall with normal or

hyperkinetic motion of the RV apex. One should consider transesophageal echocardiography when CT scanning facilities are not available

or when a patient has renal failure or severe contrast allergy that

precludes administration of contrast despite premedication with highdose steroids. This imaging modality can identify saddle, right main,

or left main PE.

Invasive Diagnostic Modalities • PULMONARY ANGIOGRAPHY

Chest CT with contrast (see above) has virtually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for patients with technically unsatisfactory

chest CTs and for those in whom an interventional procedure such as

catheter-directed thrombolysis is planned. A definitive diagnosis of PE

requires visualization of an intraluminal filling defect in more than one

projection. Secondary signs of PE include abrupt occlusion (“cut-off ”)

of vessels, segmental oligemia or avascularity, and a prolonged arterial

phase with slow filling, and tortuous, tapering peripheral vessels.

CONTRAST PHLEBOGRAPHY Venous ultrasonography has virtually

replaced contrast phlebography as the principal diagnostic test for

suspected DVT. However, contrast phlebography is used when an

interventional procedure is planned.

Integrated Diagnostic Approach An integrated diagnostic

approach streamlines the workup of suspected DVT and PE (Fig. 279-11).

TREATMENT

Deep-Venous Thrombosis

PRIMARY THERAPY

Primary therapy consists of clot dissolution with pharmacomechanical therapy using low-dose catheter-directed thrombolysis. The

open vein hypothesis postulates that patients who receive primary

therapy will sustain less long-term damage to venous valves, with

consequent lower rates of postthrombotic syndrome. However, the

ATTRACT trial randomized 692 patients with femoral or iliofemoral DVT to catheter-directed thrombolysis versus usual care with

anticoagulation alone. After 2 years of follow-up, there was no

overall reduction in postthrombotic syndrome in the thrombolysis

group. Nevertheless, there was a trend toward less postthrombotic

syndrome 2 years after randomization among patients with iliofemoral DVT (compared with only femoral DVT) who received catheterdirected thrombolysis compared with anticoagulation alone.

Asymptomatic DVT In the primary prevention APEX trial substudy of patients with asymptomatic DVT, 299 patients with asymptomatic DVT were compared with 5898 patients with no DVT.

Those with asymptomatic DVT had a threefold higher mortality

rate.

Upper Extremity DVT As peripherally inserted central catheter

(PICC) use has increased, so has the rate of upper extremity DVT.

images can provide exquisite detail, with ≤1 mm of resolution during a

short breath hold. Sixth-order branches can be visualized with resolution superior to that of conventional invasive contrast pulmonary angiography. The CT scan also provides an excellent four-chamber view of

the heart (Fig. 279-10B). RV enlargement on chest CT indicates an

increased likelihood of death within the next 30 days compared with

PE patients who have normal RV size. In patients without PE, the lung

parenchymal images may establish alternative diagnoses not apparent

on chest x-ray that explain the presenting symptoms and signs, such

as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, and

aortic pathology.

LUNG SCANNING Lung scanning has become a second-line diagnostic test for PE, used mostly for patients who cannot tolerate

intravenous contrast. Small particulate aggregates of albumin labeled

with a gamma-emitting radionuclide are injected intravenously and

are trapped in the pulmonary capillary bed. The perfusion scan

defect indicates absent or decreased blood flow, possibly due to PE.

Ventilation scans, obtained with a radiolabeled inhaled gas such

as xenon or krypton, improve the specificity of the perfusion scan.

Abnormal ventilation scans indicate abnormal nonventilated lung,

thereby providing possible explanations for perfusion defects other

than acute PE, such as asthma and chronic obstructive pulmonary

disease. A high-probability scan for PE is defined as two or more