pulmonary%20thromboembolism
PULMONARY THROMBOEMBOLISM
Pulmonary embolism is the blockage of the blood vessels in the lungs usually due to blood clots from the veins, especially the veins in the legs and pelvis.
Dyspnea, chest pain, syncope or tachypnea (respiratory rate of ≥20/min) occur in most cases of pulmonary embolism.
Pleuritic chest pain with or without dyspnea is one of the most frequent presentations of this disease.
Syncope or shock are the hallmark signs of central pulmonary embolism and usually result in severe hemodynamic repercussions.
Signs of hemodynamic compromise and reduced heart flow are also usually present.

Principles of Therapy

Inpatient Versus Outpatient Management

  • Intermediate- to high-risk patients w/ the following features should be managed in a hospital setting
    • Hemodynamic instability
    • Oxygen saturation (O2 sat) <90%
    • Active bleeding or at risk for major bleeding
    • Currently on full-dose anticoagulants during assessment
    • Severe pain
    • With comorbidities requiring hospital confinement
    • With chronic kidney disease stage 4/5 or severe hepatic disease
    • Socioeconomic reasons eg unfavorable living conditions, concern over treatment compliance
  • Low-risk PE patients without abovementioned criteria should be considered for home treatment or early discharge
  • Patients w/ symptomatic PE should initially be treated in the hospital because of:
    • Decreased cardiorespiratory reserve
    • Complications
    • Monitoring of INR to guide Warfarin therapy

Parenteral Anticoagulants

  • Heparin should be administered in patients w/ intermediate or high clinical probability of PE before imaging studies are performed & in low probability patients once PE is confirmed
  • If PE occurs postoperatively, Heparin therapy should not be started until 12-24 hours after major surgery & after consultation w/ surgeon
    • Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site
  • Both subcutaneous low molecular weight heparin (SC LMWH) or intravenous unfractionated heparin (UFH) short course treatments are recommended for objectively confirmed non-massive PE
    • Either LMWH or UFH is appropriate for the initial treatment of PE

Thrombolysis

General Therapeutic Principles

  • Studies have shown a more rapid improvement in radiographic & hemodynamic abnormalities in acute massive PE patients who received thrombolytic agents & anticoagulant agents over conventional anticoagulant agents alone
    • There was no clinically relevant outcomes for death rate or for the resolution of symptoms

Massive PE

  • The use of thrombolytic therapy in PE should be individualized
    • Patients w/ hemodynamically unstable PE who are at low risk of bleeding are the most appropriate candidates
  • Thrombolytic therapy is recommended in high-risk PE presenting w/ cardiogenic shock &/or persistent arterial hypotension
  • Thrombolytic therapy may also be considered in patients w/
    • Compromised oxygenation
    • Free-floating right ventricular thrombus or patent foramen ovale documented by echocardiography
    • Massive hemodynamically significant PE without systemic hypotension or profound hypoxemia

Non-massive PE

  • The use of thrombolytic therapy in non-high-risk patients (hemodynamically stable patients w/ echocardiographic evidence of RV dysfunction) is controversial
    • Further studies are needed to show a clinically relevant improvement in the benefit-risk ratio of thrombolytic treatment over traditional anticoagulant therapy in these patients
  • Thrombolytic therapy should not be used in patients w/ low-risk PE

Pharmacotherapy

Adrenergic Agonists

  • Should be considered for patients w/ low cardiac index & normal blood pressure (BP) or w/ impending hypotension

Dobutamine

  • Considered 1st-line agent to treat right-sided heart failure & cardiogenic shock
  • Affects vasodilatation of both systemic & pulmonary vascular beds, increases myocardial contractility while decreasing right-sided filling pressures

Dopamine

  • Has also been used for hemodynamic support in pulmonary embolism (PE) patients
  • Use may be limited by the development of tachycardia

Epinephrine

  • May be effective when shock complicates acute PE
  • Vasoconstrictor effect similar to Norepinephrine, inotropic effect more due to potent beta1 stimulation rather than beta2 effect, accounting for improved pulmonary vascular resistance

Norepinephrine

  • May be appropriate in acute massive PE when there is profound hypotension
  • Stimulates both alpha-adrenergic (inducing vasoconstriction) & beta1-adrenergic receptors (augmenting cardiac contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, & right ventricular pressure
  • Combination w/ other vasoactive agents such as Dobutamine needs further evaluation

Nitric Oxide Inhalation

  • May be indicated in patients w/ pulmonary hypertension & a patent foramen ovale
  • Based on clinical studies, may improve the hemodynamic status & gas exchange in patients w/ PE

Parenteral Anticoagulants

Unfractionated Heparin (UFH)

  • Intravenous (IV) UFH treatment in PE is well-established
  • UFH should be considered as a 1st dose bolus & when rapid reversal of effect may be required, as in patients w/ high-risk of bleeding
  • Should be given as initial anticoagulation for patients w/ PE presenting w/ shock or hypotension, also referred to as high-risk PE or clinically massive PE
  • Preferred over LMWH in patients w/ severe renal failure
  • IV UFH has been proven effective in the therapy of PE & deep vein thrombosis (DVT)
    • Studies have shown a reduced mortality rate when UFH has been used to treat VTE disease
    • Recurrence of VTE is unusual when UFH is infused at a rate that prolongs the aPTT >1.5 times the control value & when adequate levels are reached within 24 hours
  • IV UFH typically requires hospitalization w/ frequent monitoring & dose adjustment
    • aPTT should be measured 4-6 hours after bolus injection, then 3 hours after each dose adjustment, or once daily when the target therapeutic dose has been attained
  • Heparin-induced thrombocytopenia is a rare but serious complication

Low-molecular-weight heparin (LMWH)

  • Eg Dalteparin, Enoxaparin, Nadroparin, Tinzaparin 
  • LMWH is now preferred over UFH in patients w/ acute non-massive PE
  • A number of studies have shown that LMWH has equal efficacy to UFH in patients w/ non-massive PE
  • Patients w/ symptomatic PE should initially be treated in the hospital because of:
    • Decreased cardiorespiratory reserve
    • Complications
    • Monitoring of international normalized ratio (INR) to guide Warfarin therapy
  • The use of LMWH is safe, effective, may shorten hospital stay & improve the quality of life for patients
  • Monitoring of platelet count is necessary before treatment initiation & on the 5th day, then every 2-3 days if LMWH treatment is continued
  • LMWH is not recommended for high-risk PE w/ hemodynamic instability

Fondaparinux

  • Also a preferred initial treatment for PE
  • Heparin assay (anti-factor Xa) has been used to monitor effects of Fondaparinux
  • Obtain a platelet count prior to the start of therapy & periodically to check for any bleeding
  • Not recommended for high-risk PE w/ hemodynamic instability & those w/ severe renal impairment
  • Recommended for patients w/ known history of heparin-induced thrombocytopenia

Duration of Therapy

  • Acute phase treatment w/ UFH, LMWH, or Fondaparinux should be continued for at least 5-7 days after the initiation of Warfarin & until therapeutic INR is stable & ≥2 (range: 2.0-3.0) for 2 consecutive days

Non-Vitamin K Oral Anticoagulants (NOACs)

  • Eg Apixaban, Edoxaban, Rivaroxaban, Dabigatran etexilate
  • Long-term anticoagulant treatment of PE is for prevention of fatal & nonfatal recurrent venous thromboembolic events & complications

Apixaban

  • A direct factor Xa inhibitor that effectively prevents thrombin generation
  • W/ significantly lower bleeding risk compared to Warfarin & other vitamin K antagonists

Dabigatran etexilate

  • A direct thrombin inhibitor that effectively prevents thrombin generation
  • Studies have shown that Dabigatran is comparable to Warfarin for the treatment of PE
    • Dabigatran also effectively prevents recurrence of DVT w/ or w/o PE, & bleeding incidences

Edoxaban

  • A direct factor Xa inhibitor that effectively prevents thrombin generation
  • May be used for treatment PE in patients treated w/ parenteral anticoagulant for 5-10 days

Rivaroxaban

  • A direct factor Xa inhibitor that effectively prevents thrombin generation
  • An alternative treatment for parenteral anticoagulants in the initial treatment of patients w/ high clinical pretest probability
  • Studies have shown that Rivaroxaban is comparable to Warfarin for the prevention of PE

Warfarin

  • Should be started only when VTE has been reliably confirmed
    • Start on day 1 of Heparin therapy, except in patients w/ suspected hypercoagulable state (Protein C or Protein S deficiency) wherein adequate anticoagulation w/ Heparin is needed before start of treatment to prevent Warfarin-induced skin necrosis or other transient hypercoagulable complications
  • Bolus dose is not effective, therefore it requires at least 5 days to achieve its full effect
    • Thus, it is recommended that Warfarin therapy overlap w/ Heparin at least 5 days until therapeutic INR is stable & ≥2 x 2 consecutive days
  • Therapy w/ Warfarin remains unsatisfactory
    • High rate of major bleeding despite optimal attempts at dose adjustment by INR

Thrombolysis

Antithrombotics

  • Eg Alteplase (r-tPA), Reteplase, Streptokinase, Urokinase
  • Alteplase (r-tPA)
    • Has comparable thrombolytic capacity to Streptokinase & Urokinase but can be administered for a shorter duration (2 hours)
    • Preferred thrombolytic agent because of its shorter administration time
  • Streptokinase or Urokinase
    • These 2 agents have similar thrombolytic effects in PE & have been shown to resolve PE comparatively at 24 hours & 3x that as seen w/ Heparin alone
    • 12 hours of Urokinase has equivalent thrombolytic efficacy to 24 hours of Streptokinase

Investigational Drugs

  • Tenecteplase is a tissue plasminogen activator that is approved for acute myocardial infarction & is currently being studied for PE in the context that it has better half life & fibrin specificity compared to Alteplase

Non-Pharmacological Therapy

  • A considerable number of deaths occur within the 1st few hours after massive pulmonary embolism (PE) & therefore appropriate supportive therapy could have a major role in pulmonary embolism (PE) w/ circulatory failure

O2 Supplementation

  • May be necessary in patients w/ hypoxemia
  • Consider monitoring of O2 saturation & give supplementary O2 if necessary

Mechanical Ventilation

  • May be needed temporarily in patients who appear toxic & hypoxic
  • Care should be taken to limit its hemodynamic adverse effects
    • Positive intrathoracic pressures induced by mechanical ventilation, may reduce venous return & worsen right ventricular (RV) failure

Hemodynamic Support

Fluid Loading

  • Fluids may be administered initially & cautiously, but other vasoactive therapy should promptly follow
  • Aggressive fluid challenge is not recommended
    • May worsen RV function by causing ventricular overstretch, leading to decreased contractility

Evaluation of Contraindications to Thrombolysis

  • Absolute contraindications to thrombolysis in a life-threatening situation are rarely a factor for treatment

Absolute Contraindications to Thrombolysis

  • Hemorrhagic stroke or stroke of unknown origin
  • Ischemic stroke within the last 6 months
  • Presence of benign/malignant tumor or damage within the CNS
  • Major surgery, trauma, or injury within the past 3 weeks
  • GI bleeding within the last 30 days
  • Known bleeding risk

Relative Contraindications

  • Transient ischemic attack within the past 6 months
  • On oral anticoagulants
  • Uncontrolled severe hypertension (SBP >180 mmHg, DBP >100 mmHg)
  • Pregnancy or within 1 week postpartum
  • Recent traumatic CPR
  • Infective endocarditis
  • Advanced liver disease
  • Active peptic ulcer
  • Puncture of a non-compressible vessel
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