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CHAPTER 39: Pulmonary Embolic Disorders: Thrombus, Air, and Fat 327

a positive sPESI score (≥1 point), a positive troponin was associated Xa, IXa, XIa, and XIIa. It also inhibits the activation of factors V and VIII
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with a higher risk of mortality or PE recurrence at 1 month. 73,74 Plasma by thrombin. Heparin is cleared rapidly from the plasma by binding to cell
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N-terminal pro-brain natriuretic peptide (NTproBNP) also seems a surface receptors on endothelial cells and reticuloendothelial elements, and
helpful prognostic indicator; among normotensive patients with PE, its clearance is unaffected by renal or hepatic insufficiency. 81
normal NTproBNP is positively associated with survival, whereas when In dosing heparin, a singular concept emerges: one must give enough
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elevated, the marker was associated with increased risk of both short- heparin to surpass a minimal level of anticoagulation in order to prevent
term and long-term recurrence or death. 75,76 Echocardiographic evidence further thromboembolism, and this therapeutic level should be reached
of right ventricular dysfunction also clearly identifies a subgroup of quickly. This threshold level appears to be doses at which the activated
patients with PE at high risk of shock or death, and patients manifesting partial thromboplastin time (aPTT) is at least 1.5 times baseline (or alter-
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right ventricular dysfunction warrant ICU observation. 38 natively at which a heparin level of 0.2-0.4 U/mL by the protamine sulfate
It is tempting to alter therapy based on the knowledge that adverse assay or 0.3-0.6 IU/mL by amidolytic anti-Xa study), and this therapeutic
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prognostic indicators exist, though to date, no study has shown a level should be reached as quickly as possible. 41,85 Two observational studies
decreased mortality or decreased recurrence of thromboembolic events have shown an increase in recurrent PE and death when the time to thera-
by adopting a more aggressive treatment strategy for patients deemed to peutic aPTT took more than 24 hours, and in one trial, receipt of heparin
be high risk. As discussed below in the section on thrombolytic therapy, in the emergency department rather than after admission to the ward was
a retrospective review of normotensive PE registry patients who received associated with decreased mortality. 84,85 Rapid, adequate anticoagulation
thrombolytic therapy found an increased risk of mortality, compared to is facilitated by a weight-based nomogram, and each institution’s aPTT
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a propensity—matched patients receiving heparin alone. The lack of targets should be adjusted based heparin activity assays in the clinical labo-
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proven benefit of such a strategy, combined with the clearly increased ratory. A typical initial dosing regimen for UFH uses a bolus of 80 U/kg
risk of thrombolysis, against using thrombolytic medications based on followed by a continuous infusion of 18 U/kg per hour. For most patients,
troponin, NTproBNP, or echocardiographic criteria of right ventricular oral anticoagulation—coumadin—should begin soon after initiating hepa-
dysfunction in normotensive patients. However, it seems prudent to use rin, though the acute agent (UFH, LMWH, or fondaparinux) should
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a careful risk assessment of death, recurrence, or major bleeding when continue for at least 5 days and until coumadin activity is therapeutic (inter-
contemplating which patients may benefit from outpatient therapy, treat- national normalized ratio >2.0). 41,87
ment on the general ward, or surveillance in an ICU. While the evidence supporting a lower therapeutic limit for heparin
■ SUPPORTIVE CARE of 1.5 times control as judged by the aPTT is quite strong, the conven-
tional upper limit (2.5 times control) is relatively arbitrary. For years it
Oxygen and Bed Rest: Patients typically present with hypoxemia which had been assumed that the risk of hemorrhage was significantly related
responds well to oxygen therapy since the underlying pathophysiol- to the level of the aPTT, but data supporting this belief are lacking. In
ogy is usually V/Q mismatch. Bed rest, once advocated as the standard general, bleeding risk appears more likely to be related to underlying
of care in treating venous thromboembolic disease, has recently been clinical risk factors such as recent surgery, previous hemorrhage, ulcer
called into question by two randomized prospective studies. 78,79 Both disease, or comorbidities (cancer or major organ failure) rather than
studies found that allowing patients with DVT to ambulate on day 2— to supratherapeutic aPTT. In one trial, almost 50% of subjects spent
compared to imposed strict bed rest for between 4 and 10 days— at least 24 hours with a supratherapeutic aPTT, defined as ≥2.5 times
failed to increase the incidence of PE as detected by V/Q scanning. control, yet the bleeding risk was not higher than for patients who never
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Ambulating patients wore thigh-length compression stockings, and had a supratherapeutic aPTT. These findings refute an association
walked up to 4 hours per day. Admittedly, the applicability of these between modestly elevated aPTT and hemorrhage and, combined with
studies to an ICU population may be problematic, as patients were the importance of prompt, adequate anticoagulation, suggest the value
excluded if they had clinically overt PE, free-floating thrombus, of an approach that aims to ensure enough heparin in the first hours of
pregnancy, renal insufficiency, or were unable to ambulate. Many of treatment, rather than to avoid too much.
our ICU patients, and all patients with symptomatic PE, would have Complications of Heparin Complications of heparin, in addition to hemor-
failed to qualify for these studies. Bed rest may have advantages to rhage, include heparin-induced thrombocytopenia (HIT), osteoporo-
the critically ill patient beyond the theoretical advantage of reducing sis, hypersensitivity, and (rarely) hyperkalemia. The most important
clot dislodgement. Given the imperative to reduce oxygen consump- complication of heparin is bleeding. Several meta-analyses of clinical
) and thus maximize a limited Q ˙ t for patients in shock, bed trials report that in the setting of VTE, heparin therapy is associated
tion (V O 2
rest—combined with sedation and mechanical ventilation in selected with a 2% to 3% incidence of major bleeding (bleeding >1 L, bleed-
patients—is clearly indicated for patients with PE and shock. ing requiring blood transfusion, intracerebral bleeding). 88,89 When the
■ SPECIFIC THERAPIES definition is broadened to include any clinical bleeding, clinical trials
have reported rates of 8% to 12% while receiving UFH.
Hemorrhage
87,90
Anticoagulation typically occurs from the gastrointestinal or urinary tract, or from
surgical incisions. Less common sites of serious bleeding include the
Unfractionated Heparin (UFH) Heparin has long been the mainstay of therapy for retroperitoneum, adrenal glands, soft tissues, nose, and pleural space.
PE, although it is no longer the preferred first-line treatment for confirmed Intracranial hemorrhage is uncommon in patients anticoagulated with
PE in stable patients. Unfractionated heparin is a mixture of acidic gly- heparin, though it is frequently fatal.
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cosaminoglycans typically extracted from porcine intestinal mucosa, with a The approach to treatment of the patient who bleeds on heparin
variable molecular weight of between 5000 and 30,000 daltons depending depends on the severity of bleeding. When bleeding is minor, simply stop-
on its clinical preparation. 80,81 Along with a coumarin derivative, it was the ping the heparin may be sufficient. Bleeding related to needle sticks may
first anticoagulant to be prospectively shown to decrease mortality and respond to sustained direct pressure. If hemorrhage endangers life or organ
recurrent PE, decreasing mortality by 25%. While effective, heparin ther- function, a more aggressive approach is mandatory. Transfusion of fresh
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apy requires monitoring of coagulation parameters as well as dose adjust- frozen plasma is usually ineffective since circulating heparin inhibits the
ment due to unpredictable plasma levels even within individuals. Given function of transfused factors. Protamine sulfate is an antidote to heparin.
subcutaneously twice daily, UFH seems to be equally efficacious and safe to The dose of protamine depends on heparin levels, and is therefore related
continuous intravenous dosing, although common practice seems to favor to dose, route of administration, and time since the last dose. When
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continuous drips, functionally restricting heparin’s use to the inpatient hos- hemorrhage immediately follows a bolus of heparin, sufficient protamine
pital setting. Heparin catalyzes the effect of antithrombin to rapidly inhibit to completely neutralize the heparin (1 mg protamine per 100 units
several members of the intrinsic and common coagulation pathways: factors heparin) should be administered. In the more usual situation where

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