Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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CRITICAL CARE OF VASCULAR DISEASE & EMERGENCIES

637

therapeutic window when combined with thrombolytic ther-

apy. Table 29–5 details the currently available thrombin

inhibitors. Lepirudin and argatroban are approved for the

treatment of thrombosis in patients with heparin-induced

thrombocytopenia. There are no currently agents available for

reversing the effects of the direct thrombin inhibitors.

E. Thrombolytic Agents—Thrombolytic agents such as

urokinase, streptokinase, and recombinant tissue plasmino-

gen activator (rt-PA; alteplase) have been evaluated in

numerous clinical trials for safety and efficacy and in com-

parison with operative management. Initially, an intense

thrombolytic state was induced with systemic therapy sus-

tained by constant intravenous infusion. In 10 uncontrolled

studies involving 1800 patients, best results were obtained

within 72 hours of onset of symptoms. Lysis was observed in

40%, with no difference in success rates between embolic or

thrombotic occlusions. Unfortunately, serious hemorrhagic

complications occurred in one-third of patients.

Regional or intraarterial thrombolysis has become an alter-

native to systemic therapy. The rate of successful reperfusion

(50–85%) appears to be higher than what is reported with sys-

temic infusion. Local infusion coupled with arteriography

conferred an additional advantage in delineating the cause of

the arterial occlusion (thrombosis versus embolus). Vessel wall

morphologic characteristics that may lead to early recurrent

thrombosis also were unmasked and further directed appro-

priate management (surgery versus angioplasty). Prolonged

arterial catheterization (hours to days) resulting in major

bleeding (6–20%) remains the main disadvantage of this

approach. Current thrombolytic agents include streptokinase,

urokinase, alteplase, reteplase, and tenecteplase.

Urokinase, a relatively inexpensive trypsin-like protease,

converts plasminogen directly to plasmin. Initially, the main

advantages of urokinase over streptokinase were its direct

action on plasminogen and its nonantigenicity. However,

pyretic reactions have been observed and attributed to inter-

leukins present during the manufacturing process. As a result,

urokinase is currently not available in the United States.

Alteplase is now the only thrombolytic agent available for

peripheral arterial thrombolysis. A naturally occurring acti-

vator of plasminogen, it is produced and released by the

endothelium. Manufactured through recombinant DNA

techniques, it is nonantigenic, has a half-life of 3.5–4 min-

utes, and has a high affinity for fibrin, which enhances lysis at

the thrombus level. Similar to urokinase, the primary route

of metabolism is hepatic.

Reteplase is a new plasminogen activator approved for

treatment of acute myocardial infarction and is used anecdo-

tally in the peripheral vasculature. Designed for use as bolus

therapy through recombinant DNA technology, experience

with reteplase in arterial and venous thromboembolic dis-

ease is limited.

An inert zymogen activated by the presence of fibrin clot,

prourokinase is converted to an active two-chain urokinase

that is highly fibrin-specific. Availability of this agent is also

limited.

Tenecteplase, a genetically engineered variant of alteplase,

has a prolonged half-life, increased fibrin specificity, and

higher resistance to inhibition by circulating plasminogen

activator inhibitor-1. A three-amino-acid substitution

resulted in a 14–19-minute half-life and more specific fibri-

nolysis in comparison with alteplase. Pending approval by

the Food and Drug Administration (FDA) for treatment of

acute myocardial infarction, the role of tenecteplase in the

management of peripheral arterial and venous thrombotic

occlusion has yet to be explored.

Because of the lack of evidence demonstrating the bene-

fits of improved limb salvage, lower mortality, or cost-

effectiveness, thrombolytic therapy cannot be regarded as

Drug

Dose

∗

Duration Notes

Lepirudin Load: 0.4 mg/kg IV then

0.15 mg/kg/hr

2–10 days Keep aPTT between 1.5 and 2.5 times normal.

Indicated for use in patients with HIT.

Bivalirudin Load: 1.0 mg/kg IV, followed

by 2.5 mg/kg/h for 4 h, then

0.2 mg/kg/h

20 h Has only been studied with concomitant aspirin

treatment.

Argatroban Initial dose 2 μg/kg/min IV Indicated as an anticoagulant in heparin-induced

thrombocytopenias. Monitor aPTT beginning 2 h

after start of infusion—steady state should be

1.5–3 times initial baseline.

∗

Check current prescribing information. Doses may need to be adjusted in the presence of comorbidites such as hepatic and/or renal failure.

Table 29–5. Currently available thrombin inhibitors.

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CHAPTER 29

638

first-line treatment in the management of acute limb

ischemia. However, it remains a reasonable alternative in a

select group of patients, especially those with distal throm-

boembolic occlusions in surgically inaccessible small arteries

of the hands and feet and in patients who are at high risk for

surgery (Table 29–6).

F. Surgery—Operation is the best treatment of acute extrem-

ity ischemia, achieving both life and limb salvage. Adequate

preoperative support is essential. In the presence of active

cardiac risk, use of local anesthesia must be considered and

adequate intravenous hydration provided to minimize renal

insufficiency. At the time of surgery, placement of the inci-

sion is guided by the cause of occlusion, the presence of a

palpable pulse, and a history of previous revascularization.

In patients with embolic occlusion, exploration of the

femoral artery is considered in the presence of femoral and

distal pulses. A below-the-knee approach is preferred in

patients presenting with a palpable popliteal pulse and dis-

tal embolization. Patients with acute ischemia and a previ-

ous bypass graft usually are explored through the distal

anastomosis.

A transverse incision is often sufficient for passage of a

Fogarty catheter. Longitudinal arteriotomy is considered if

the cause is not known for certain or if bypass is necessary.

Removal of the entire embolic material is essential, and suc-

cess is confirmed through an intraoperative arteriogram to

ensure patency of the arterial runoff distal to the embolus.

Approximately 35–40% of completion angiograms will iden-

tify residual thrombus.

Although highly successful in embolic occlusion, blind

thromboembolectomy in patients with acute on chronic

thrombosis is highly dangerous and risks further intimal dis-

ruption to an already diseased vessel. Often these patients

require further surgical revascularization (eg, bypass or

endarterectomy) or endovascular management (eg, thrombol-

ysis, angioplasty, or stent placement in debilitated patients).

Intraoperative lytic therapy has been reported in several

series for the following indications: residual thrombus on

angiography, slow flow despite the absence of an angiographic

defect, prolonged ischemia with evidence of thickened blood

on retrograde bleeding, and persistent ischemia despite

restoration of sufficient proximal inflow. In a series of 78

patients, limb salvage was achieved in 73% of the 67%

treated successfully.

A new approach to intraoperative thrombolysis undergo-

ing recent investigation is high-dose isolated limb perfusion.

Surgical cutdowns of the femoral vessels are performed, with

intraarterial insertion of standard infusion pumps. A tourni-

quet is applied proximal to the exposed vessels, and venous

effluent is drained by gravity or through the use of extracor-

poreal pump support with concomitant dialysis.

Fasciotomy should be considered in all patients following

successful revascularization in the setting of prolonged

ischemia. Common clinical indications are pain out of pro-

portion to findings, pain on passive stretch, tense muscular

compartments with elevated pressures, and compartmental

hypesthesia and paralysis.

G. Supportive Care—Perioperative care of the patient fol-

lowing revascularization of an acutely ischemic limb can

vary from simple to extremely complex. Reperfusion of an

ischemic extremity can lead to the release of toxic cellular

products, the generation of oxygen-free radicals, hyper-

kalemia, increased intracellular calcium overload, myoglo-

binuria, and altered arachidonic acid metabolism. Critical

care therefore is directed toward ameliorating the damage

done by cellular breakdown.

Appropriate hemodynamic monitoring is essential.

Correction of electrolyte abnormalities and prompt treat-

ment of hyperkalemia through brisk diuresis and adminis-

tration of insulin and glucose can prevent fatal cardiac

arrhythmias. Adequate fluid volume and the administration

of mannitol—a free-radical scavenger and osmotic

diuretic—is the best strategy to correct acidosis and to pre-

vent acute renal failure caused by myoglobin precipitates.

Local mechanical factors are also important to prevent

skin and soft tissue breakdown. The extremity should be kept

warm but must not be heated in an effort to restore flow

because this will increase the metabolic rate, further the lac-

tic acidosis, and contribute to tissue destruction. Similarly,

cooling is inappropriate. Care must be taken to prevent

Drug Half-Life Intravenous Dose Intraarterial Dose

Altepase (t-PA) 3.5 min 50 mg over 2 h, followed by 0.05–0.1 unit/kg/h

Reteplase 14 min 10 units over 2 min, then 10 0.25–1 unit/h

Tenectplase 15 min 0.5 mg/kg Unknown

Data from Schmittling ZC, Hodgson KJ: Thrombolysis and mechanical thrombectomy for arterial disease. Surg Clin North Am 2004;84:1237–66.

Table 29–6. Thrombolytic agents.

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CRITICAL CARE OF VASCULAR DISEASE & EMERGENCIES

639

pressure on an ischemic extremity. Heel pads and cushions

should be used as needed. Other vascular precautions

include keeping linens suspended with a bed cradle and posi-

tioning the patient in reverse Trendelenburg.

In patients who have not undergone fasciotomy, fre-

quent and careful assessment of the lower extremities is

warranted. In the event that a compartment syndrome is

diagnosed, prompt decompression is required to preserve

tissue viability.

Pain control typically requires high doses of an opioid

such as morphine. Analgesia must not be increased to the

point that symptoms are masked and a reliable neurologic

examination cannot be obtained. Short-acting intravenous

agents such as fentanyl have been used with success, pro-

vided that the dose is regulated so as not to obscure worsen-

ing of symptoms.

Prognosis

Despite recent advances in perioperative critical care, the

mortality rate after acute leg ischemia remains relatively

high. Both the mortality rate and the need for amputation

are directly related to the duration of ischemia. A recent

study found that no amputations were required when sur-

gery was undertaken within 2 hours compared with a 44%

amputation rate when operation was delayed up to 7 days.

The mortality rate was 10% in patients with symptoms pres-

ent for less than 2 hours and 32% in those whose symptoms

were present for up to 8 hours. Coexisting cardiopulmonary

complications were the underlying cause of most fatalities,

especially in patients with acute arterial thrombosis in con-

trast to peripheral embolism.

Current Controversies and Unresolved Issues

The cause of ischemic injury remains unclear. While it is

logical to assume that hypoxia is the culprit, investigations

have shown that most of the tissue damage actually occurs

during the time of reperfusion. Even short periods of

ischemia followed by reperfusion can cause cell damage. A

recent canine study found that 3 hours of partial ischemia

resulted in more tissue damage than the same period of

complete ischemia. Furthermore, the extent of postreperfu-

sion damage can be decreased by graded reflow. These inves-

tigations suggest that scavengers of free radicals may be

useful in the treatment of acute vascular insufficiency.

Although numerous investigations have been under-

taken, little improvement has been made over the last 2

decades in morbidity and mortality associated with surgical

thrombectomy in this fragile patient group. The advantage of

surgery stems from rapid restoration of blood flow. On the

contrary, pharmacologic thrombolysis is much less invasive.

The main disadvantage is the time lag involved for revascu-

larization. What is needed is an ideal therapeutic option that

achieves rapid blood flow and is minimally invasive. The

advent of endovascular surgery has spurred the development

of percutaneous mechanical thrombectomy devices to

answer this need. Current devices in various stages of clinical

trials include rheolytic, clot aspiration, and microfragmenta-

tion catheters.

Andersen JC: Advances in anticoagulation therapy: The role of

selective inhibitors of factor Xa and thrombin in thrombopro-

phylaxis after major orthopedic surgery. Semin Thromb

Hemost 2004;30:609–47. [PMID: 15630666]

Comerota AJ, Schmieder FA: Intraoperative lytic therapy: Agents

and methods of administration. Semin Vasc Surg 2001;14:

132–42. [PMID: 11400089]

Eslami MH, Ricotta JJ: Operation for acute peripheral arterial

occlusion: Is it still the gold standard? Semin Vasc Surg

2001;14:93–9. [PMID: 11400084]

Friedl HP et al: Ischemia-reperfusion in humans: Appearance of

xanthine oxidase activity. Am J Pathol 1990;136:491–5. [PMID:

2316621]

Greenberg RK, Ouriel K: Arterial thromboembolism. In

Rutherford R (ed), Vascular Surgery, 15th ed. Philadelphia:

Saunders, 2000.

Jackson MR, Clagett GP: Antithrombotic therapy in peripheral

arterial occlusive disease. Chest 2001;119:283–9S. [PMID:

11157655]

Kubaska SM, Greenberg RK: Techniques for percutaneous treat-

ment of acute arterial occlusion. Semin Vasc Surg 2001;14:

114–22. [PMID: 11400087]

Kasirajan K, Marek JM, Langsfeld M: Mechanical thrombectomy

as first-line treatment for arterial occlusion. Semin Vasc Surg

2001;14:123–31. [PMID: 11400088]

Lyden SP, Shortell CK, Illig KA: Reperfusion and compartment

syndromes: Strategies for prevention and treatment. Semin Vasc

Surg 2001;14:107–13. [PMID: 11400086]

Ouriel K, Vieth FJ: Acute lower limb ischemia: Determinants of

outcome. Surgery 1998;124:336–41. [PMID: 9706157]

Ouriel K, Veith FJ, Sasahara AA: A comparison of recombinant

urokinase with vascular surgery as initial treatment for acute

arterial occlusion of the legs. Thrombolysis or Peripheral

Arterial Surgery (TOPAS) investigators. N Engl J Med

1998;338:1105–11. [PMID: 9545358]

Patrono C et al: Platelet-active drugs: The relationship among

dose, effectiveness, and side effects. Chest 2001;119:

39–63S.

Schmittling ZC, Hodgson KJ: Thrombolysis and mechanical

thrombectomy for arterial disease. Surg Clin North Am

2004;84:1237–66. [PMID: 15364553]

Singh S et al: Thromboembolectomy and thrombolytic therapy in

acute lower limb ischemia: A five-year experience. Int Angiol

1996;15:6–8.

Working Party on Thrombolysis in the Management of Limb

Ischemia: Thrombolysis in the management of lower limb

peripheral arterial occlusion: A consensus document. Am J

Cardiol 1998;81:207–18. [PMID: 9591906]

Weaver FA et al: Surgical revascularization versus thrombolysis for

nonembolic lower extremity native artery occlusions: Results of

a prospective, randomized trial evaluating surgery versus

thrombolysis for ischemia of the lower extremity. The STILE

Investigators. J Vasc Surg 1996;24:513–21.

Weitz JI, Hirsh J: New anticoagulant drugs. Chest 2001;119:

95–107S. [PMID: 11157644]

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

Deep Venous Thrombosis

ESSENTIALS OF DIAGNOSIS

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Multiple risk factors.

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Aching pain exaggerated by motion.

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Calf and thigh swelling.

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Tenderness to palpation and dorsiflexion.

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Erythema, cyanosis, or venous distention.

General Considerations

Three factors (Virchow’s triad) contribute to the develop-

ment of venous thrombosis: stasis, increased coagulabil-

ity, and vessel wall damage. Contrary to former belief,

low flow alone is not sufficient to cause thrombosis.

Thrombophlebitis is venous thrombosis that follows inflam-

mation of the vessel wall. Because of underlying intimal

irregularities, the clot adheres firmly and is unlikely to

become dislodged. Phlebothrombosis occurs without vessel

wall injury and results in minimal clot adherence.

Patients at risk for the development of deep venous

thrombosis may be divided into three groups: (1) Low-risk

patients are under 40 years of age and are free of systemic

disease. Surgery lasts less than 60 minutes and is uncompli-

cated. Overall risk for the development of deep venous

thrombosis is less than 2%, and the chance of proximal pro-

gression is less than 1%. (2) Moderate-risk patients are over

age 40 and have undergone general anesthesia for more than

60 minutes. They also may have risk factors such as cancer,

obesity, varicose veins, bed rest, or cardiac failure. If prophy-

laxis is not given, the risk for development of deep venous

thrombosis is between 10% and 40% and that of proximal

propagation is between 2% and 8%. The risk of fatal pul-

monary embolism is almost 1%. (3) High-risk patients have

a history of deep venous thrombosis or of pulmonary

embolism. They undergo extensive abdominal or pelvic pro-

cedures for advanced disease or for some orthopedic indica-

tion. The risk of calf vein thrombosis is between 40% and

80% without prophylaxis. Proximal extension occurs in

10–20%, leading to fatal pulmonary embolism in up to 5%.

Risk factors for the development of venous thrombi and rec-

ommended prophylaxis are listed in Table 29–7. Most deep

venous thrombi are initiated by platelet adhesion either to

endothelial tissue or to exposed collagen of damaged vascular

Low Risk Moderate Risk High Risk

Event or condition

General surgery

Age <40 years or time <60 minutes Age >40 years or time >60 minutes Age >40 years or time >60 minutes

plus risk factor

Orthopedic surgery — — Elective hip or knee surgery

Trauma — — Extensive soft tissue injury; major

fractures; multiple trauma

Medical conditions Pregnancy Myocardial infarction postpartum,

especially with previous deep

venous thrombosis; estrogen use;

varicose veins

Stroke, paraplegia, spine fracture,

prolonged bed rest, burns, hyperco-

agulable state, obesity

Incidence of thromboembolism without prophylaxis (%)

Distal calf veins 2

10–40 40–80

Proximal veins (pelvis, thigh,

popliteal veins)

0.4 2–8 10–20

Symptomatic pulmonary embolism 0.2 1–8 5–10

Fatal pulmonary embolism 0.002 0.1–0.4 1–5

Recommended prophylaxis Graduated compression stockings;

early ambulation

Heparin (5000 units SC twice daily),

LMWH, external or pneumatic

compression

Heparin (5000 units SC three times

daily), LMWH, external pneumatic

compression, inferior vena caval

filter, warfarin

Adapted from Colman RW et al (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: Lippincott, 1994.

Table 29–7. Risk stratification for venous thrombosis and recommended prophylaxis.

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CRITICAL CARE OF VASCULAR DISEASE & EMERGENCIES

641

walls. As platelet aggregation continues, the clot becomes

organized and begins to trap circulating white and red blood

cells. Deposition of fibrin organizes the clot and allows it to

build a stable matrix.

Activation of either the intrinsic or the extrinsic clotting

system contributes to thrombus formation. Adhesion of fac-

tor XII to exposed endothelium results in progressive activa-

tion of factor X. Activated factor X (Xa), along with factor V,

converts prothrombin to thrombin and fibrinogen to fibrin,

producing an insoluble clot. Platelets accumulate within the

matrix and provide a surface for further fibrin deposition.

Thromboxane A

, produced and released by platelets, aids

the process by contributing to vasoconstriction and further

platelet aggregation. Prostacyclin, which is produced by vas-

cular intima, limits the process by causing vascular dilation

and by inhibiting platelet aggregation. Antithrombin III

inhibits the action of factors IX, X, XI, and XII. Proteins C

and S, produced by the liver, inhibit coagulation by destroy-

ing factors V and VII and provide negative feedback to con-

trol the generation of thrombin (Figure 29–1).

The velocity of blood flow is inversely proportional to the

propensity for intravascular clotting. However, the threshold

for thrombus formation is decreased in the face of vascular

endothelial injury. Such injury may be caused by catheters,

infection, or external influences. In normal veins, the

endothelium is well supplied with prostacyclin and plas-

minogen, which prevent thrombus formation even at low

flow rates. However, when intimal damage is present—or in

the face of a hypercoagulable state—thrombus accumulates

rapidly. Red clots predominate in the venous system and

consist of platelets, red blood cells, and fibrin. White

thrombi, which contain chiefly platelets, are usually found in

the arterial system.

Hypercoagulable states are common in postoperative

critical care patients. The plasma concentration of clotting

factors rises after surgery. Maximum procoagulant activity

corresponds temporally with the peak incidence of throm-

boembolism. Detection of hypercoagulability remains diffi-

cult except in certain pathologic conditions such as

decreased concentrations of antithrombin III, protein C, and



Figure 29–1. Factors involved in arrest of hemorrhage. Injury to the blood vessel wall initiates a series of reactions

that arrest hemorrhage. The exposed subendothelial collagen initiates formation of the platelet plug (primary hemo-

stasis). The coagulation system is activated, leading to production of fibrin, which interacts with the platelet aggregate

to form a hemostatic seal. These relationships are also involved in spontaneous thrombus formation, although the

inciting event is usually not identifiable. (Reproduced, with permission, from Way LW (ed), Current Surgical Diagnosis &

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CHAPTER 29

642

protein S. Use of some medications, such as oral contracep-

tives, is known to increase the risk of thromboembolic dis-

ease. Ill-defined alterations in the clotting mechanism that

predispose to clotting accompany some severe systemic dis-

eases such as cancer and sepsis.

Most deep venous thrombi begin in the veins of the calf.

When limited to this location, they are usually asymptomatic

except for mild calf pain and minimal swelling. Extension

into the deep venous system of the thigh produces more

swelling, pain, and purpura. Proximal propagation involves

the veins of the pelvis (iliofemoral thrombosis). As outflow is

restricted, the lower extremity swells and causes obstruction

of lymphatic channels, producing a blanched “milk leg”

(phlegmasia alba dolens). If patency is not restored, cyanosis

and venous gangrene result. This condition, known as phleg-

masia cerulea dolens (“blue leg”), is more common in the left

lower extremity than in the right from compression of the left

iliac vein as it passes under the right iliac artery. Phlegmasia

cerulea dolens is usually associated with disseminated malig-

nancies or sepsis. It is accompanied by hypotension and

hypovolemia, which result from venous pooling in the leg.

Thrombosis of the deep veins of the thigh and pelvis dra-

matically increases the risk of pulmonary embolism.

Approximately 85% of clinically significant pulmonary

emboli arise from the thighs and pelvis. Eighty percent of

deep venous thrombi remain confined to the calf, whereas

20% extend proximally. In the latter group, 40–50% will

result in pulmonary embolism if not treated appropriately.

Unfortunately, only 30% of those with confirmed pul-

monary embolism have objective signs consistent with deep

venous thrombosis.

Venous thrombosis of the upper extremities is becoming

increasingly prevalent in the ICU as a result of chronic

indwelling central venous catheters. Patients being main-

tained on long-term parenteral nutrition, hemodialysis,

antibiotics, or chemotherapy or those with poor peripheral

access are some of those at risk. Other predisposing factors

include exertion, thoracic outlet syndrome, congenital mal-

formations, and trauma (Table 29–8). Approximately 3–6%

of all pulmonary emboli and 1–2% of fatal pulmonary

emboli have been reported to originate from clots in the deep

veins of the upper extremity.

Superficial venous thrombi typically present as a small

lump or cord. These are usually of no systemic significance

except in the saphenous vein of the thigh, where they can

propagate through the saphenofemoral junction and gain

access to the deep iliofemoral system. When such proximal

extension is noted, ligation of the saphenous vein just distal

to its origin is warranted.

Clinical Features

A. Symptoms and Signs—Patients may complain of a

vague aching sensation or tightness in the calf or thigh. This

is worsened by active motion of the calf or foot. When super-

ficial thrombosis is present, localized tenderness is usually

also present.

Physical examination is notoriously unreliable for deep

venous thrombosis and accurately detects only 50% of cases.

Areas with increased tenderness to palpation include the

sole, the region deep to Achilles’ tendon, the groove between

the tibia and fibula, the regions over the soleus and gastroc-

nemius muscles, in the popliteal fossa, over the adductor

muscles of the thigh, and at the femoral vein near the

inguinal ligament. Tenderness induced by compression of

the calf muscles anteriorly against the interosseous mem-

brane or with passive dorsiflexion of the ankle (Homans’

sign) is present in less than 30% of patients. Inflation of a

sphygmomanometer cuff (40 mm Hg) placed above the knee

may provoke pain at the site of the thrombosis. A difference

of 1.5 cm in diameter between the swollen and the contralat-

eral leg supports the diagnosis.

Deep venous thrombosis of the axillary and subclavian

veins of the upper extremity results in swelling of the entire

arm. Pitting edema is usually absent. Percussion over the

clavicle and the course of the axillary vein often elicits

tenderness.

B. Noninvasive Diagnostic Techniques—Hand-held

continuous-wave Doppler devices test for continuity

between the deep system of the leg and the intrathoracic vena

cava. The probe is placed initially at the popliteal fossa and

subsequently over the femoral vein. The patient is instructed

to inspire, at which time an augmentation of flow should be

heard. The increased flow is due to transmission of the neg-

ative intrathoracic pressure to the deep system. This is a use-

ful screening test that can be performed at the bedside, but it

has a sensitivity of only about 75% when compared with

venography. Duplex scans and color-coded Doppler exami-

nations have accuracy rates between 90% and 100% for

detecting large thrombi of the femoral veins in symptomatic

patients. The sensitivity decreases to 59%, although the sen-

sitivity remains at 98%, in asymptomatic patients. Accuracy

also diminishes when examining the distal veins of the calf

owing to poor visualization. Isolated instances of iliac vein

thrombosis are also not detectable by ultrasound imaging

but may be diagnosed by simple Doppler examination.

Source Incidence (%)

Catheter-associated

Spontaneous (effort-induced)

Miscellaneous

Intravenous drug use

Thoracic tumors

Trauma

Radiation

30–40

20–30

30–40

Table 29–8. Etiology of upper extremity venous

thrombosis.

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CRITICAL CARE OF VASCULAR DISEASE & EMERGENCIES

643

Multiple studies have shown that repeat duplex scanning has

an improved negative predictive value in patients suspected

of deep vein thrombosis but who have negative initial scans.

Pressure on the underlying vein by the ultrasound probe

helps to establish the age of the clot because fresh thrombi

are poorly organized and easily compressible. This is the

diagnostic test of choice for most patients, although it

requires an experienced technician to perform and interpret.

Impedance plethysmography relies on changes in electri-

cal resistance associated with alteration in limb volume. Deep

venous thrombosis impedes venous outflow and causes a

slower change in impedance when a proximally occluding

cuff is deflated. This technique is very accurate in ambulatory

patients but should be interpreted cautiously in those with

congestive heart failure or hypervolemia. It is more sensitive

for iliac and femoral vein thrombosis than for calf thrombi

and generally cannot be used in patients with fractures or

bandages that prevent proper electrode positioning. A posi-

tive test correctly indicates the presence of thrombosis in 90%

of patients. Recently, however, the sensitivity for plethysmog-

raphy in symptomatic patients was found to be much less

than earlier studies reported. In asymptomatic patients, the

specificity also falls. Impedance plethysmography can over-

look sizable thrombi that are not totally occlusive and can

interpret any pelvic venous outflow obstruction (eg, enlarged

nodes or pregnancy) as a venous thrombus. It also may be

falsely negative in patients with well-developed collaterals.

CT scanning and MR venography have successfully

diagnosed thrombi in the proximal veins and have proved

to be superior to conventional phlebography in visualizing

the great veins, identifying intraluminal thrombi, distin-

guishing new thrombi, and delineating adjacent abnormal-

ities. Ongoing prospective trials are confirming these initial

findings.

C. Invasive Diagnostic Studies—Contrast venography is

the “gold standard” with which all noninvasive modalities are

compared. It is the most reliable technique for detecting

thrombi in any location. Positive findings on venography

include constant filling defects, abrupt termination of the

dye column, nonfilling of the entire deep venous system or

portions thereof, and diversion of flow through collaterals.

The venogram catheter may be exchanged for one capable of

delivering thrombolytic agents if that therapeutic route is

chosen. Overall accuracy is better than 90%. A negative study

virtually eliminates the possibility of venous thrombosis.

Complications include foot pain at the site of injection and a

2–3% incidence of thrombosis owing to contrast

material–induced endothelial cell injury. Not routinely used

for primary diagnosis, phlebography has been advocated in

the diagnosis of symptomatic recurrent venous thrombosis

and after hip operations in suspected patients in whom non-

invasive means lack sensitivity.

D. Laboratory Findings—Several blood tests are available

that detect activation of the clotting cascade, including meas-

urement of fibrinopeptide A, fibrin monomers, and fibrin

degradation products. Plasma D-dimer, a degradation prod-

uct of plasmin digestion of mature cross-linked fibrin, is ele-

vated in patients with venous thrombosis. The sensitivity

measured by enzyme-linked immunosorbent assay

approaches 97%. Although highly accurate, confirmation of

venous thrombosis with an elevated D-dimer concentration

is necessary with objective imaging tests.

Differential Diagnosis

See Table 29–9.

Prevention

All critically ill patients should be considered for throm-

boembolic prophylaxis. Particular attention should be paid

to those with preexisting risk factors (see Table 29–7).

A. Physical Measures—Early ambulation or exercise of the

lower extremity muscles is probably the best and most cost-

effective prophylactic measure for preventing subsequent

venous thrombosis. Lower extremity elevation and active

flexion-extension exercises of the ankle will prevent stasis.

Prolonged standing in one position should be discouraged

because it promotes venous pooling. Use of thigh-high

antiembolism stockings is encouraged when they are fitted

properly. Casual application of stockings that extend only to

the knee are unlikely to be of value.

Of the compression techniques available, intermittent

compression garments are best. Garments with single com-

partments for the calves or multiple sequential compart-

ments are available. Maximum benefit is realized when they

are applied prior to surgery. Direct sequential compression

promotes blood flow and also stimulates systemic fibri-

nolytic activity. Therefore, benefit still accrues even with only

unilateral application can be achieved because of bandages

or casts. Studies have shown a reduction in the incidence of

thrombosis from 23–7% in patients so treated.

B. Anticoagulation—When used properly, preoperative

anticoagulation decreases the incidence of postoperative deep

venous thrombosis and secondary pulmonary embolism.

Lymphatic obstruction

Cellulitis

Baker’s cyst

Traumatic contusion

Tendon rupture

Congestive heart failure

Nephrosis

Arterial occlusion

Table 29–9. Differential diagnosis of deep venous

thrombosis.



CHAPTER 29

644

1. Warfarin—Coumarin derivatives act by suppressing the

formation of vitamin K–dependent clotting factors (II,VII, IX,

and X). When these agents are initiated before and continued

after operation, they are safe and effective. Coumarins require

several days to reach full effect because of the time interval

required for clearance of normal coagulation factors. These

agents are usually started after the patient has already been sys-

temically anticoagulated with unfractionated heparin.

Initiation of therapy with warfarin alone can have deleterious

effects. Protein C and protein S—natural anticoagulants—are

similarly reduced (especially protein C) with factor VII,

thereby shifting the hemostatic balance toward coagulation. In

patients with underlying protein C and protein S deficiency,

warfarin-induced skin necrosis can occur from thrombotic

occlusion of small vessels in the subcutaneous tissue. This

effect is manifested within 3–8 days of administration of the

initial dose. Patients with protein C and protein S deficiency

should not receive a loading dose of warfarin, and heparin

should be continued until the international normalization

ratio (INR) is therapeutic for 2 consecutive days.

Several drug interactions are known to occur with war-

farin. Of particular importance are those that increase

hepatic degradation (eg, barbiturates) and those that dis-

place warfarin from albumin (eg, aspirin and nonsteroidal

anti-inflammatory agents). Coumarins are also teratogenic

and should not be given to pregnant patients.

2. Heparin—Unfractionated heparin binds with antithrom-

bin III to prevent the conversion of prothrombin to throm-

bin. A “low dose”unfractionated heparin (LDUH) regimen is

used customarily prior to surgery and in the postoperative

period while the patient is still at risk. The postulated mech-

anism of action is enhancement of antithrombin III. The

usual regimen consists of 5000 units given subcutaneously

2 hours before surgery and every 8–12 hours during the

postoperative period. No changes in the usual coagulation

parameters can be detected at this dosing level. Increased

bleeding at the time of surgery generally does not occur.

Heparin prophylaxis is unlikely to be effective when started

in the postoperative period. It is not effective for patients

undergoing hip surgery and should not be used in those with

bleeding disorders or for scheduled intracerebral procedures.

An adjusted-dose heparin regimen has been described for

patients undergoing total hip replacement. Two days prior to

surgery, the patient receives 3500 units of heparin subcuta-

neously every 8 hours, with the dose adjusted to elevate the

aPTT to the high-normal range. This regimen has been

shown to reduce the incidence of deep venous thrombosis in

hip replacement patients from 39–13%.

3. Low-molecular-weight heparin (LMWH)—LMWHs

are produced by depolymerization of unfractionated

heparin. They have a more uniform molecular weight, longer

half-life, and more predictable pharmacokinetics. Significantly,

when compared with unfractionated heparin, they have a

higher ration of anti–factor Xa activity to anti–factor IIa

activity and are less likely to lead to heparin-induced

thrombocytopenia. LMWH has several clinical advantages

over unfractionated heparin. First evaluated in the 1980s in

high-risk surgical patients, one daily dose administered sub-

cutaneously is as effective as two or three doses of unfrac-

tionated heparin for deep vein thrombosis prophylaxis. It has

become the anticoagulant of choice for preventing deep vein

thrombosis in most orthopedic procedures. Its long half-life

precludes the need for laboratory monitoring, and it is more

effective than unfractionated heparin in preventing recur-

rence of venous thrombosis. Inpatient and outpatient uses of

LMWH have equivalent safety and efficacy. LMWH and

LDUH appear to be equally effective in reducing the inci-

dence of deep vein thrombosis in general surgical patients.

Studies have reported contradictory results with regard to

the incidence of wound hematomas and bleeding complica-

tions when comparing LMWH and LDUH likely because of

the doses used. Higher doses of LMWH are associated with

more bleeding, whereas lower doses are equivalent to LDUH

in preventing venous thromboembolism in moderate-risk

patients and have a lower rate of bleeding complications.

Currently, two LMWH preparations are approved in the

United States for the prevention of deep venous thrombosis

(Table 29–11). Enoxaparin is approved for use in patients

undergoing abdominal surgery as well as hip and knee sur-

gery. It is also approved for use in medical patients who are

at risk owing to severely restricted mobility during acute ill-

ness. The usual dose of enoxaparin in abdominal surgical

patients is 40 mg by subcutaneous injection given once daily.

The first dose should be administered 2 hours prior to sur-

gery, and the drug should be continued for 7–12 days after

surgery. The same dosing regimen applies to medical patients

with the exception that the drug should be started at the time

of immobilization. Dalteparin is approved for use in patients

undergoing hip replacement surgery and those undergoing

abdominal surgery who are at risk for thromboembolic com-

plications. The dose for abdominal surgical patients is 2500

IU given by subcutaneous injection starting 1–2 hours prior

to surgery, and then the drug is given once daily for 5–10

days. Neither of the LMWH preparations requires routine

monitoring of coagulation parameters during its use. Careful

monitoring for bleeding complications is mandatory. The

dose of LMWH may need to be reduced in older patients and

in those with renal and/or hepatic impairment.

4. Low-molecular-weight dextran—Dextran 40 acts by

coating platelet surfaces to reduce adhesion. It also increases

plasma volume and decreases the viscosity of blood. An

important mechanism of action may be the prevention of

platelet adhesion to venous valve cusps. The usual dose of

dextran 40 is 100–200 mL as an intravenous bolus (intra-

operatively), followed by 30–40 mL/h for 2–3 days after

surgery. Because dextran 40 is a volume expander, patients

with congestive heart failure or respiratory distress should

be monitored carefully for hypervolemia. Dextran potenti-

ates the effects of heparin, reducing the dosing requirements

of the latter by up to 50%.



CRITICAL CARE OF VASCULAR DISEASE & EMERGENCIES

645

5. Factor Xa Inhibitors—Fondaparinux is a synthetic

molecule that is an indirect inhibitor of factor Xa. It acts by

potentiating the anti–factor Xa activity of antithrombin.

Fondaparinux has no platelet effect, nor does it modulate

primary hemostasis. It is currently approved in the United

States for deep vein thrombosis prophylaxis in patients

undergoing hip fracture or replacement surgery and knee

replacement surgery. Fondaparinux has no effect on routine

coagulation studies, and monitoring is not necessary. The

usual dose is 2.5 mg given subcutaneously starting 6–8 hours

after surgery. Administration either prior to surgery or soon

after surgery is associated with an increased risk of major

bleeding.

Management of Deep Vein Thrombosis

The objectives of treatment are to limit further accumulation

of thrombus, prevent embolization, and minimize injury to

venous valves.

A. Supportive Therapy—Treatment of calf vein thrombi

remains largely controversial, with most centers recommend-

ing supportive care. In several large trials, anticoagulation was

withheld safely in patients with suspected deep vein thrombo-

sis and normal results on serial examinations with compres-

sion ultrasonography. Only supportive therapy is required,

consisting of bed rest, leg elevation, and mild analgesics.

Although some advocate the use of warm soaks, this measure

can macerate the overlying skin and promote infection. Early

ambulation should be encouraged, with elastic stockings as

required. Anticoagulation is indicated in patients with symp-

tomatic deep vein thrombosis identified by duplex scanning

and those with recurrent venous thrombosis.

B. Anticoagulation—Thrombi of the proximal veins (ie,

popliteal vein, femoral vein, and iliac veins) or of the axillary

and subclavian veins requires anticoagulation. Heparin,

either unfractionated or low-molecular weight, is the agent of

choice because it limits further propagation of the thrombus.

A recent consensus conference found that there is no differ-

ence between them regarding their efficacy or safety.

However, because of the advantages of convenient dosing,

facilitation of outpatient therapy, and a potentially lower risk

for recurrent deep vein thrombosis, some prefer the use of

LMWH over unfractionated heparin (UFH). Additionally,

there may be a survival advantage favoring the use of LMWH

in venous thromboembolic disease associated with malig-

nancy. For most patients, an initial bolus dose of 100 units/kg

(UFH) followed by a continuous infusion of 10 units/kg per

hour is adequate. Larger doses (200 units/kg as bolus injec-

tion) may be given if the clot extends into the iliac or femoral

system, if there is profound edema of the leg, or if imaging

studies indicate the presence of a long tail extending proxi-

mally. Anticoagulation should be assessed by monitoring

either the aPTT or the activated clotting time (ACT). The

heparin infusion should be titrated to keep the aPTT

between 1.5 and 2.5 times normal. Failure to achieve a

therapeutic level of anticoagulation within 24 hours carries a

25% risk of recurrent deep venous thrombosis. Bleeding

complications are reduced if dosage is regulated by monitor-

ing of anticoagulation and if the heparin is given by continu-

ous infusion rather than by intermittent bolus administration.

Five days of intravenous heparin therapy followed by oral

warfarin is usually effective and generally is regarded as con-

ventional therapy.

Although warfarin therapy can be started concomitantly

with heparin, most prefer to wait several days before starting

oral anticoagulation. Titration of the dose to achieve an INR

of 2.0–3.0 is adequate. Oral anticoagulation is continued for

3–6 months following discharge from the hospital based on

risk factors (Table 29–10).

Platelet counts should be obtained initially and every

other day to detect the development of heparin-induced

antiplatelet antibodies. Immune heparin-induced thrombo-

cytopenia (HIT) is suspected when the platelet count falls

below 100,000/μL or less than 50% of the baseline value. This

IgG-mediated platelet deficiency is seen in 3% of patients

and occurs 5–15 days after heparin therapy is initiated.

Management of patients with persistent thrombosis and HIT

can be difficult. Two agents, argatroban and lepirudin, have

been approved for patients with HIT needing anticoagulant

therapy. Argatroban is begun with a continuous intravenous

infusion at 2 μg/kg per minute and titrated to keep the

aPTT 1.5–3 times the initial baseline. Lepirudin (recombi-

nant hirudin) achieves rapid anticoagulation with a loading

dose of 0.4 mg/kg followed by an infusion of 0.15 mg/kg per

hour. It is adjusted to maintain an aPTT 1.5–3 times normal.

Oral warfarin then is instituted for the appropriate duration.

Approximately 3% of patients receiving oral anticoagula-

tion will present with recurrent deep venous thrombosis.

These patients should be assessed for a deficiency in

antithrombin III and proteins C and S. Bleeding is the major

complication of anticoagulation and occurs in 5–10% of

patients. This often presents as oozing from wounds, melena,

or a heme-positive gastric aspirate. If bleeding continues

despite discontinuation of heparin, protamine sulfate, a

heparin inhibitor, may be required. Infusion of fresh-frozen

plasma and vitamin K can counteract the effects of warfarin.

When LMWH is employed, the dose used depends on the

preparation (Table 29-11). Meta-analysis has failed to find a

clear advantage of one LMWH over the others with regard to

both safety and efficacy. Once-daily administration appears

as safe and effective as twice-daily use. Although anticoagu-

lation monitoring generally is unnecessary, anti–factor Xa

levels may be followed for 4 hours after injection, with a

desirable therapeutic range of 0.6–1.0 units/mL for twice-

daily administration and 1.0–2.0 units/mL for once-daily

administration. Monitoring is recommended for patients

with renal impairment because of the risk of accumulation

of anti–factor Xa activity.

C. Thrombolytic Therapy—There are currently two throm-

bolytic agents available for use in venous thrombosis.



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646

Multiple investigations have determined that streptokinase

and recombinant tissue plasminogen activator (rt-PA;

alteplase) are superior to intravenous heparin in preserving

venous patency and valvular function. Approximately 50% of

patients treated with thrombolytic agents retain valve func-

tion compared with 7% of those treated with heparin alone.

If complete thrombolysis is achieved, the incidence of post-

phlebitic syndrome is reduced. However, owing to the vari-

able nature of this syndrome, further investigation is

warranted to confirm these early findings.

Thrombolytic agents followed by heparin result in more

rapid resolution of lower extremity and pulmonary emboli,

restoring hemodynamic homeostasis. The main disadvantage

is the additional 1–2% risk of intracranial hemorrhage.

Because the incidence and mortality of pulmonary embolism

are the same in the two treatment modalities, systemic throm-

bolysis is reserved for acute massive pulmonary embolus in an

unstable patient with no bleeding dyscrasias. Young patients

with massive ileofemoral venous thrombosis (eg, phlegmasia

cerulea dolens) also may benefit from thrombolysis.

Neither streptokinase nor alteplase directly dissolves the

clot but rather requires activation of the fibrinolytic system.

Absolute contraindications to the use of lytic therapy include

active bleeding, recent (<2 months) cerebrovascular acci-

dent, or intracranial disease. Major contraindications include

recent surgery and evidence of GI hemorrhage. Prior to insti-

tution of therapy, the fibrinogen level, thrombin time, PT

and aPTT, platelet count, and hematocrit should be deter-

mined. Heparin administration should be discontinued.

Dosing regimens vary widely, but common doses are as fol-

lows: (1) streptokinase, 250,000 units over 30 minutes, fol-

lowed by an infusion of 100,000 units/h up to 72 hours, or

(2) alteplase, 100 mg infused over 2 hours. Within 4 hours of

commencing therapy, thrombin time, fibrinogen level, and

fibrin degradation products should be assessed. A lytic state

is documented by an elevated thrombin time and the pres-

ence of fibrin degradation products. Hematocrit should be

assessed every 6 hours. Elevation of fibrin degradation

products is anticipated. Infusion for more than 24 hours sel-

dom produces additional results. Lytic therapy should be

Patient Characteristic Recommendation

Calf vein thrombosis Up to 3 months of anticoagulant therapy

Proximal venous thrombosis or pulmonary embolus without previous

episode

a. Transient clinical risk factor—major orthopedic surgery or trauma

b. Metastatic cancer

c. Hypercoagulable risk factors

∗

Idiopathic thromboembolism

Anticoagulant therapy for 4–6 weeks or until risk factor is resolved and

patient is mobile, whichever is later.

Long-term anticoagulation (indefinite)

Either 3–6 months of therapy

Lifelong anticoagulation

Recurrent venous thromboembolism 1 year or lifelong anticoagulation

Any venous thromboembolism during pregnancy Unfractionated intravenous heparin for 5 days, followed by adjusted-dose

subcutaneous heparin every 12 hours

†

or low-molecular-weight heparin

until delivery followed by oral warfarin for 4–6 weeks.

∗

Hypercoagulable risk factors include protein C and S, antithrombin III, plasminogen deficiencies; resistance to activated protein C; hyper-

homocystinemia, and antiphospholipid antibodies.

†

aPTT should be checked 6 hours after initial subcutaneous dosing.

Adapted from Ginsberg JS: Management of venous thromboembolism. N Engl J Med 1996;335:1816.

Table 29–10. Recommendations for long-term management of venous thromboembolism.

Drug Name

Subcutaneous Dose for Treatment of

Venous Thromboembolism

Enoxaparin

100 anti-Xa units/kg every 12 h*,

†

or 150

anti-Xa units/kg every 24 h

‡

Dalteparin

100 anti-Xa units/kg twice daily

‡

or 200

anti-Xa units/kg once daily

‡

Tinzaparin

175 anti-Xa U/kg once daily

†

∗

For enoxaparin, 100 anti-Xa units/kg corresponds to a dose of

100 mg/kg.

†

FDA approved for this indication.

‡

FDA approved for this indication.

Data from McRae SJ, Ginsberg JS: Initial treatment of venous throm-

boembolism. Circulation 2004;110;I3–I9.

Table 29–11. Low-molecular weight heparins.