Pulmonary Arterial Hypertension Management

Aka: Pulmonary Arterial Hypertension Management, Pulmonary Hypertension Management

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II. Precautions

  1. Management strategies below are specific for Pulmonary Arterial Hypertension (WHO Group 1)
  2. Other Pulmonary Hypertension Causes should be specifically treated
    1. Pulmonary Hypertension associated with left heart disease
      1. Treat significant valvular disease (e.g. Mitral Stenosis)
      2. Afterload reduction for Left Ventricular Dysfunction
      3. Manage Fluid Overload with Diuretics
      4. Avoid vasodilators
    2. Pulmonary Hypertension associated with lung disease, Hypoxemia or both
      1. Screen for Sleep Apnea
        1. CPAP for Obstructive Sleep Apnea
      2. Maximize COPD Management
      3. Supplemental Oxygen for PaO2 <60 mmHg (<90% Oxygen Saturation)
      4. Avoid vasodilators
    3. Pulmonary Hypertension associated with chronic thromboembolic disease (WHO Group 4)
      1. Pulmonary endarterectomy (if surgical candidate, first-line if done at major center)
      2. Lifelong Anticoagulation
    4. Miscellaneous Pulmonary Hypertension (WHO Group 5)
      1. Maximize treatment of underlying cause (e.g. Sarcoidosis, pulmonary vessel compression)
      2. Sickle Cell Anemia may respond to Hydroxyurea, chronic transfusions

III. Management: Acute Presentation

  1. See Pulmonary Arterial Hypertension Crisis

IV. Management: Chronic General Measures

  1. Prevent and promptly treat respiratory infections
  2. Regular symptom-limited Exercise
    1. Consider supervised Exercise rehabilitation
    2. Improves 6 Minute Walk Test and functional capacity
  3. Avoid pregnancy (12% mortality)
    1. Use reliable Contraception
    2. Endothelin receptor Antagonists (e.g. Bosentan) may reduce Hormonal Contraception efficacy and are Teratogenic
    3. Refer to maternal fetal medicine if pregnancy does occur
  4. Immunizations
    1. Influenza Vaccine annually
    2. Pneumococcal Vaccine
    3. Covid Vaccine
  5. Perioperative Evaluation
    1. Consider surgical alternatives
    2. Preoperative Echocardiogram, Electrocardiogram, lab testing
    3. Evaluate functional status (e.g. 6 Minute Walk Test)
    4. Consult specialty care
      1. Decision to approve the surgery
      2. Optimization for at least 2-4 weeks before elective surgery
      3. Consideration of right heart catheterization before surgery
      4. Arranging surgery at specialty medical center (skilled in the complex care of Pulmonary Hypertension)
  6. Advanced Directives
    1. Consider Palliative Care or Hospice Referral
    2. Address Code Status
      1. Cardiac Arrest in Pulmonary Hypertension has a very high mortality even for witnessed in hospital events
  7. Address Mental health
    1. Major Depression and Anxiety Disorder are common after Pulmonary Hypertension Diagnosis

V. Management: Chronic Medications

  1. Anticoagulation
    1. Coumadin to keep INR between 1.7 to 2.2
  2. Cardiac Output maximization
    1. Consider Digoxin to increase Cardiac Output or for tachyarrhythmias
    2. Consider Parenteral inotropic medications in refractory inpatients
  3. Decrease Preload
    1. Follow low-salt diet
    2. Diuretics to reduce volume retention
  4. Treat Hypoxia
    1. Oxygen Supplementation to keep Oxygen Saturation >90-92% (60 mmHg)
    2. Supplemental Oxygen is recommended on plane flights (and consider for travel to high altitude)
  5. Pulmonary Arterial Hypertension medications
    1. Low risk patient
      1. See Vasodilators below
      2. PDE-5 Inhibitors (Sildenafil) or
      3. Endothelin receptor Antagonists (Bosentan, Ambrisentan)
    2. High risk patient (or low risk patient protocol fails)
      1. Epoprostenol (Flolan) IV or
      2. Selexipag (Uptravi) oral
      3. Treprostinil (Remodulin, Orenitram) Oral, IV or SQ
      4. Iloprost (Ventavis) Inhaled
  6. High Dose Calcium Channel Blockers (vasoreactivity positive PAH)
    1. Indicated only if positive vasoreactivity test during right heart catheterization (<5-20% of patients)
  7. Other medical management
    1. Experimental options
      1. Nitric oxide
  8. Surgery (if refractory to medical management)
    1. Lung Transplantation
      1. Patients who survive first year after lung transplant, have a 10 year median survival
    2. Other measures
      1. Balloon Atrial Septoplasty

VI. Management: Vasodilators (reduce vascular resistance) - Specific PAH Treatments

  1. Endothelin receptor Antagonists
    1. Precautions
      1. FDA pregnancy category X (and may reduce OCP efficacy)
      2. Liver Function Testing monthly (due to hepatotoxicity risk)
      3. Drug Interaction with Warfarin (increased INR)
    2. Medications
      1. Bosentan (Tracleer) Start 62.5 mg orally twice daily (may increase to 125 mg twice daily)
      2. Ambrisentan (Letairis) Start 5 mg daily (may increase to 10 mg daily)
      3. Macitentan (Opsumit) 10 mg orally daily
      4. Sitaxsentan
  2. Phosphodiesterase-5 Inhibitors (PDE-5 Inhibitors) and Other Nitrous Oxide Pathway Mediators
    1. Precautions
      1. Avoid with nitrates (precipitous Hypotension risk)
      2. Avoid with CYP3A4 inhibitors (Clarithromycin, Itraconazole)
    2. Adverse effects
      1. Headache
      2. Flushing
      3. Epistaxis
    3. Mechanism
      1. Cyclic guanosine monophosphate (cGMP) is a vasodilator
      2. cGMP is rapidly degraded by PDE5 (Phosphodiesterase 5), present in the right ventricle of PAH patients
    4. PDE-5 Inhibitors
      1. Sildenafil (Revatio) 20 mg orally three times daily
      2. Tedalafil (Adcirca) 40 mg orally daily
    5. Soluble cGMP Stimulators
      1. Riociguat (Adempas) 2.5 mg orally three times daily
  3. Prostenoids (Prostacyclins)
    1. Efficacy
      1. Highly effective in improving symptoms, functional capacity and mortality
    2. Precautions
      1. Avoid stopping abruptly (risk of rebound Pulmonary Arterial Hypertension)
    3. Adverse effects
      1. Jaw pain
      2. Diarrhea
      3. Peripheral Edema
      4. Headache
    4. Mechanism
      1. Prostacyclins reduce Platelet aggregation and causes vasodilation
      2. Prostacylcins are reduced in PAH
    5. Prostacyclin Analogs
      1. Epoprostenol (Flolan)
        1. Start 2 ng/kg/min IV
        2. Titrate 1-2 ng/kg/min every 15 min as needed
        3. Maximum 30 mg/kg/min
      2. Iloprost (Ventavis)
        1. Dose 2.5 to 5 mcg nebulized every 2-4 hours (up to 9 doses per day)
      3. Treprostinil (Remodulin)
        1. IV/SQ: 1.25 ng/kg/min titrated once weekly
        2. Inhaled: 18 mcg (3 breaths from 1.74 mg/2.9 ml Inhaler) four times daily
          1. Increased by 18 mcg/dose (3 breaths) every 1-2 weeks
          2. Maximum of 54 mcg/dose (9 breaths/dose)
      4. Beraprost
        1. Start 20 mcg three times daily
        2. Titrate up to maximum 60 mcg, over several weeks
    6. Prostacyclin Receptor Agonists
      1. Selexipag (Uptravi)
        1. Start 200 mcg orally twice daily
        2. May titrate by 200 mcg per dose on up to a weekly basis
        3. Maximum: 1600 mcg orally twice daily

VII. Management: Calcium Channel Blockers

  1. Indicated only if positive vasoreactivity test during right heart catheterization (<5-20% of patients)
    1. Do not use in non-vasodilator responders
    2. Risk of Hypotension, Syncope and Right Ventricular Failure
  2. Effective longterm in only 5-20%
    1. Effectiveness wanes over time
  3. Requires vasodilation test as above (use only if responder)
    1. If non-responder, then do not use Calcium Channel Blocker (use other vasodilators listed above)
  4. Determine if patient responds to vasodilation (vasoreactivity study)
    1. Perform right heart catheterization (mandatory prior to using Calcium Channel Blocker)
    2. Administer vasodilator (e.g. Adenosine, epoprostenol)
    3. Responder criteria
      1. Pulmonary Artery Pressure decreases >10 mmHg and <40 mmHg
      2. Cardiac Output does not change or increases
    4. Use responder status to direct therapy
      1. Responder: Calcium Channel Blocker
      2. Non-responder: Use other vasodilators listed above
  5. Preparations (use very high dose)
    1. Amlodipine 15 to 30 mg orally once daily
    2. Felodipine 15 to 30 mg orally once daily
    3. Diltiazem ER 120 to 360 mg orally twice daily

VIII. Complications

  1. See Pulmonary Arterial Hypertension Crisis (PAH Crisis)

IX. References

  1. Meter (2013) Crit Dec Emerg Med 27(5): 2-10
  2. Dunlap (2016) Am Fam Physician 94(6):463-9 [PubMed]
  3. Gaine (2000) JAMA 284:3160-8 [PubMed]
  4. Galie (2009) Eur Heart J 30(20): 2493-537 [PubMed]
  5. Latimer (2024) Am Fam Physician 110(2): 183-91 [PubMed]
  6. Nauser (2001) Am Fam Physician 63(9):1789-98 [PubMed]
  7. Rubin (1997) N Engl J Med 336:111-7 [PubMed]
  8. Rubin (1993) Chest 104:236-50 [PubMed]
  9. Ryerson (2010) Respir Res 11:12 [PubMed]
  10. McLaughlin (2009) Circulation 119(16): 2250-94 [PubMed]
  11. Stringham (2010) Am Fam Physician 82(4): 370-7 [PubMed]

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