凝晨algorithm as outlined in the previous section and,if PE is con?rmed,
primary pharmacological (or,alternatively,surgical or interventional)reperfusion therapy.
Patients without shock or hypotension are not at high risk of an adverse early outcome.Further risk strati?cation should be considered after the diagnosis of PE has been con?rmed,as this may in?uence the therapeutic strategy and the duration of the hospi-talization (see Section 5.8).In these patients,risk assessment should begin with a validated clinical prognostic score,preferably the PESI or sPESI,its simpli?ed version,to distinguish between intermediate and low risk.Around one-third of PE patients are at low risk of an early adverse outcome as indicated by a PESI Class I or II,or a simpli?ed PESI,of 0.On the other hand,in registries and cohort studies,patients in PESI Class III–V had a 30-day mortality rate of up to 24.5%,214and those with a simpli?ed PESI ≥1up to 11%.218Accordingly,normoten-sive patients in PESI Class ≥III ora simpli?ed PESI of ≥1are considered to constitute an intermediate-risk group.Within this category,further risk assessment should be considered,focusing on the status of the RV in response to the PE-induced acute pressure overload.Patients
who display evidence of both RV dysfunction (by echocardiography
or CT angiography)and elevated cardiac biomarker levels in the circu-
lation (particularly a positive cardiac troponin test)should be classi?ed
into an intermediate-high-risk category.As discussed in more detail in the following section,close monitoring is recommended in these cases to permit early detection of haemodynamic decompensation and the need for initiation of rescue reperfusion therapy.253On the other hand,patients in whom the RV is normal on echocardiography or CT angiography,and/or have normal cardiac biomarker levels,belong to an intermediate-low-risk group.
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Data from registries and cohort studies suggest that patients in PESI Class I–II,or with sPESI of0,but with elevated cardiac biomarkers or signs of RV dysfunction on imaging tests,should also be classi?ed into the intermediate-low-risk category.76,222,262Never-theless,routine performance of imaging or laboratory tests in the presence of a low PESI or a simpli?ed PESI of0is not considered necessary at present as,in these cases,it has not been shown to have therapeutic implications.
Recommendations for prognostic assessment
Recommendations Class a Level b Ref c
Initial risk stratification of
suspected or confirmed PE—
based on the presence of shock
or persistent hypotension—is
recommended to identify
patients at high risk of early
mortality.
I B47, 48
In patients not at high risk, use of
a validated clinical risk prediction
score, preferably the PESI or sPESI, should be considered to distinguish between low-and intermediate-risk PE. IIa B
214,
218
In patients at intermediate risk,
assessment of the right ventricle
with echocardiography or CT,
and of myocardial injury using a
laboratory biomarker, should be
considered for further risk
stratification.
IIa B253
CT?computed tomographic(pulmonary angiography);PE?pulmonary embolism;PESI?pulmonary embolism severity index;sPESI?simpli?ed pulmonary embolism severity index.
a Class of recommendation.
b Level of evidence.
c References.
5.Treatment in the acute phase 5.1Haemodynamic and respiratory support
Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE.Therefore,supportive treatment is vital in patients with PE and RV failure.Experimental studies indicate that aggressive volume expansion is of no bene?t and may even worsen RV function by causing mechanical overstretch, or by re?ex mechanisms that depress contractility.263On the other hand,modest(500mL)?uid challenge may help to increase cardiac index in patients with PE,low cardiac index,and normal BP.264 Use of vasopressors is often necessary,in parallel with(or while waiting for)pharmacological,surgical,or interventional reperfusion treatment.Norepinephrine appears to improve RV function via a direct positive inotropic effect,while also improving RV coronary perfusion by peripheral vascular alpha-receptor stimulation and the increase in systemic BP.Its use should probably be limited to hypo-tensive patients.Based on the results of small series,the use of dobu-tamine and/or dopamine may be considered for patients with PE,low cardiac index,and normal BP;however,raising the cardiac index above physiological values may aggravate the ventilation–perfusion mismatch by further redistributing?ow from(partly)obstructed to unobstructed vessels.265Epinephrine combines the bene?cial prop-erties of norepinephrine and dobutamine,without the systemic vaso-dilatory effects of the latter.It may therefore exert bene?cial effects in patients with PE and shock.
Vasodilators decrease pulmonary arterial pressure and pulmonary vascular resistance,but the main concern is the lack of speci?city of these drugs for the pulmonary vasculature after systemic(intraven-ous)administration.According to data from small clinical studies,in-halation of nitric oxide may improve the haemodynamic status and gas exchange of patients with PE.266,267Preliminary data suggest that levosimendan may restore right ventricular–pulmonary arterial coupling in acute PE by combining pulmonary vasodilation with an in-crease in RV contractility.268
Hypoxaemia and hypocapnia are frequently encountered in patients with PE,but they are of moderate severity in most cases.
A patent foramen ovale may aggravate hypoxaemia due to shunting when right atrial-exceeds left atrial pressure.80Hypoxaemia is usually reversed with administration of oxygen.When mechanical ventilation is required,care should be taken to limit its adverse haemodynamic effects.In particular,the positive intrathoracic pres-sure induced by mechanical ventilation may reduce venous return and worsen RV failure in patients with massive PE;therefore,positive end-expiratory pressure should be applied with caution.Low tidal volumes(approximately6mL/kg lean body weight)should be used in an attempt to keep the end-inspiratory plateau pressure ,30cm H2O.
Experimental evidence suggests that extracorporeal cardiopul-monary support can be an effective procedure in massive PE.269 This notion is supported by occasional case reports and patient series.270–272
5.2Anticoagulation
In patients with acute PE,anticoagulation is recommended,with the objective of preventing both early death and recurrent symptomatic or fatal VTE.The standard duration of anticoagulation should cover at least3months(also see Section6).Within this period,acute-phase treatment consists of administering parenteral anticoagulation [unfractionated heparin(UFH),LMWH or fondaparinux]over the ?rst5–10days.Parenteral heparin should overlap with the initiation of a vitamin K antagonist(VKA);alternatively,it can be followed by administration of one of the new oral anticoagulants:dabigatran or edoxaban.If rivaroxaban or apixaban is given instead,oral treatment with one of these agents should be started directly or after a1–2day administration of UFH,LMWH or fondaparinux.In this latter case, acute-phase treatment consists of an increased dose of the oral anti-coagulant over the?rst3weeks(for rivaroxaban),or over the?rst7 days(for apixaban).
In some cases,extended anticoagulation beyond the?rst3 months,or even inde?nitely,may be necessary for secondary preven-tion,after weighing the inpidual patient’s risk of recurrence vs. bleeding risk.
5.2.1Parenteral anticoagulation
In patients with high or intermediate clinical probability for PE(see Section3),parenteral anticoagulation should be initiated whilst awaiting the results of diagnostic tests.Immediate anticoagulation
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can be achieved with parenteral anticoagulants such as intravenous UFH,subcutaneous low-molecular-weight heparin (LMWH),or sub-cutaneous fondaparinux.LMWH or fondaparinux are preferred over UFH for initial anticoagulation in PE,as they carry a lower risk of in-ducing major bleeding and heparin-induced thrombocytopenia (HIT).273–276On the other hand,UFH is recommended for patients in whom primary reperfusion is considered,as well as for those with serious renal impairment (creatinine clearance ,30mL/min),or severe obesity.These recommendations are based on the short half-life of UFH,the ease of monitoring its anticoagulant effects,and its rapid reversal by protamine.The dosing of UFH is adjusted,based on the activated partial thromboplastin time (aPTT;Web Addenda Table II ).277
The LMWHs approved for the treatment of acute PE are listed in Table 10.LMWH needs no routine monitoring,but periodic mea-surement of anti-factor Xa activity (anti-Xa levels)may be considered during pregnancy.279Peak values of anti-factor Xa activity should be measured 4hours after the last injection and trough values just before the next dose of LMWH would be due;the target range is 0.6–1.0IU/mL for twice-daily administration,and 1.0–2.0IU/mL for once-daily administration.280
Fondaparinux is a selective factor Xa inhibitor administered once daily by subcutaneous injection at weight-adjusted doses,without the need for monitoring (Table 10).In patients with acute PE and no indi-cation for thrombolytic therapy,fondaparinux was associated with recurrent VTE and major bleeding rates similar to those obtained with intravenous UFH.281No proven cases of HIT have been
reported with fondaparinux.282Subcutaneous fondaparinux is con-traindicated in patients with severe renal insuf?ciency (creatinine clearance ,30mL/min)because it will accumulate and increase the risk of haemorrhage.Accumulation also occurs in patients with moderate renal insuf?ciency (clearance 30–50mL/min)and,there-fore,the dose should be reduced by 50%in these patients.2835.2.2Vitamin K antagonists
