Pulmonary Hypertension 

1. Definition 

Pulmonary Hypertension (PH)

  • Mean Pulmonary Artery Pressure (mPAP) ≥ 20 mmHg at rest (Right heart catheterization)
  • Pre-capillary PH:(Problem is in pulmonary arteries (before capillaries)
    • mPAP ≥ 20 mmHg
    • PAWP ≤ 15 mmHg
    • PVR ≥ 3 Wood units
  • Post-capillary PH:(Problem is in left heart → backward transmission)
    • PAWP > 15 mmHg

Further classification of Post-capillary PH

1. Isolated post-capillary PH (IpcPH)

  • PVR ≤ 2 WU

2. Combined pre + post-capillary PH (CpcPH)

  • PVR > 2 WU

 Important exam point: CpcPH behaves worse and mimics pre-capillary physiology

 Pathophysiology 

 Pre-capillary PH

  • Pulmonary arteriolar vasoconstriction + remodeling
  • Endothelial dysfunction (↓ NO, ↑ endothelin)
  • Progressive ↑ PVR → RV pressure overload → RV failure

– Idiopathic PAH 

– Chronic thromboembolic pulmonary hypertension

– COPD, ILD 

– Hypoxia 

– Connective tissue disease


 Post-capillary PH

  • Elevated left atrial pressure
  • Backward transmission → pulmonary veins → capillaries
  • Leads to pulmonary congestion + edema
  • Chronic cases → secondary vascular remodeling → CpcPH

– Heart failure with reduced ejection fraction

– Heart failure with preserved ejection fraction

– Mitral stenosis

– Mitral regurgitation


2. WHO Classification 

Group

Cause

ICU relevance

Group 1

Pulmonary arterial hypertension (PAH)

Vasodilator therapy, RV failure

Group 2

Left heart disease

Commonest in ICU

Group 3

Lung disease / hypoxia

ARDS, COPD

Group 4

CTEPH

Thrombolysis, surgery

Group 5

Multifactorial

Sepsis, sarcoidosis

 ICU admissions most often: Group 2, 3, acute decompensation of Group 1


3. Pathophysiology (Why ICU patients crash)

Core problem

↑ PVR → ↑ RV afterload → RV dilation → RV ischemia → ↓ LV filling → shock

Vicious cycle

  • RV dilation → septal shift → ↓ LV preload
  • ↓ Coronary perfusion of RV
  • Tricuspid regurgitation
  • Systemic hypotension → further RV ischemia

 PH is primarily a RIGHT HEART disease


4. Triggers for ICU Decompensation 

  • Infection / sepsis
  • Hypoxia, hypercapnia
  • Acidosis
  • Pulmonary embolism
  • Arrhythmias (AF, SVT)
  • Excessive fluids
  • Withdrawal of PAH drugs
  • Mechanical ventilation (↑ PEEP)


5. Clinical Features in ICU

Symptoms

  • Acute dyspnea most common 
  • Syncope
  • Chest pain
  • Fatigue

Signs

  • Hypotension
  • Raised JVP
  • RV heave
  • Loud P2
  • Hepatomegaly
  • Peripheral edema
  • Shock with preserved lungs


6.LABORATORY EVALUATION IN PAH 

1. ROUTINE BASELINE LABS (ALL PATIENTS)

These are done in every suspected PAH patient:

  • CBC:
    • Polycythemia → chronic hypoxia
    • Anemia → worsens dyspnea & prognosis
    • Thrombocytopenia → advanced disease / drug-related


  • Urea, creatinine
  • LFT:
    • Elevated bilirubin/AST/ALT → hepatic congestion (RV failure)


  • Especially Na⁺ → hyponatremia = poor prognostic sign

 2. CARDIAC BIOMARKERS 

 Natriuretic peptides

  • BNP / NT-proBNP:
    • Reflect right ventricular (RV) strain
    • Used for:
      • Risk stratification
      • Follow-up
  • High levels → worse prognosis

 Troponin

  • Elevated in advanced PAH
  • Indicates RV ischemia / failure


 3. AUTOIMMUNE & CONNECTIVE TISSUE SCREEN

Must be done in all PAH cases (to detect secondary causes)

  • ANA
  • Anti-centromere
  • Anti-Scl-70
  • Anti-RNP

 To diagnose:

  • Systemic sclerosis
  • Systemic lupus erythematosus
  • Mixed connective tissue disease


 4. INFECTIOUS SCREENING

Mandatory:

  • HIV ELISA
  • Hepatitis B & C

Important causes:

  • HIV-associated pulmonary arterial hypertension
  • Portal hypertension-related PAH (porto-pulmonary)


 5. THROMBOEMBOLIC WORKUP

  • D-dimer (screening only, not definitive)
  • Thrombophilia profile (selected cases):
    • Protein C, S
    • Antithrombin III
    • Antiphospholipid antibodies

 To evaluate:

  • Chronic thromboembolic pulmonary hypertension

 6. THYROID FUNCTION TESTS

  • TSH, T3, T4

 Association:

  • Hyperthyroidism
  • Hypothyroidism

 7. GENETIC TESTING (SELECTED)

  • BMPR2 mutation
  • ALK1 mutation

 Indicated in:

  • Familial PAH
  • Idiopathic PAH (young patients)

 8. ARTERIAL BLOOD GAS (ABG)

  • Mild hypoxemia
  • ↓ PaCO₂ (hyperventilation)

 Severe hypoxemia suggests:

  • Not pure PAH → think:
    • Lung disease
    • Shunt

7. Echocardiography 

Key findings

  • Dilated RV
  • RV/LV ratio > 1
  • Septal flattening (D-shaped LV)
  • Reduced TAPSE (< 17 mm)
  • TR jet → estimate PASP
  • IVC dilated, non-collapsing

 Echo guides fluids, inotropes, vasopressors

8. Radiological

 1. CHEST X-RAY (INITIAL SCREENING)

  • Enlarged main pulmonary artery
  • Pruning of peripheral vessels
  • Right ventricular enlargement

 In thromboembolic disease:

  • Regional oligemia (Westermark-like areas)
  • Asymmetrical vascularity

 Limitation:

  • Normal CXR does NOT exclude PH or CTEPH


 2. CT CHEST (HRCT + CT PULMONARY ANGIOGRAPHY)

 A. HRCT (Parenchymal assessment)

  • Rule out lung diseases (Group 3 PH)

Findings:

  • ILD → fibrosis, honeycombing
  • COPD → emphysema
  • Mosaic attenuation → vascular disease / CTEPH

 B. CT Pulmonary Angiography (CTPA)

  • Detect chronic thromboembolic lesions

Typical CTEPH findings:

  • Webs and bands
  • Eccentric thrombus
  • Abrupt vessel cutoff
  • Post-stenotic dilatation

 Important:

  • CTPA can miss distal disease
  • Normal CTPA ≠ rule out CTEPH

 3. GOLD STANDARD SCREENING: V/Q SCAN (MOST IMPORTANT)

  • Most sensitive test for CTEPH
  • Recommended in ALL PH patients


4. DIAGNOSTIC ALGORITHM 

Stepwise approach:

  1. Suspected PH → Echo suggests PH
  2. Perform:
    • CXR
    • HRCT
  1. Mandatory: V/Q scan

 If V/Q normal → CTEPH excluded → think PAH

 If V/Q abnormal →
→ Do CTPA ± Pulmonary angiography
→ Refer to CTEPH center


5. WHY THIS MATTERS (CLINICAL IMPACT)

  • Chronic thromboembolic pulmonary hypertension is:
    • Potentially CURABLE (pulmonary endarterectomy)
  • Missing it → catastrophic mistake

8. VASOREACTIVITY TESTING

Acute testing during RHC to assess reversible pulmonary vasoconstriction


 Agents used

  • Inhaled nitric oxide (preferred)
  • IV epoprostenol
  • IV adenosine


 POSITIVE TEST (STRICT CRITERIA)

  • Fall in mPAP ≥ 10 mmHg
  • Absolute mPAP ≤ 40 mmHg
  • Cardiac output unchanged or increased

 Why it matters?— Identifies patients who benefit from high-dose calcium channel blockers (CCBs)

 CCB responders (only small subset!)

  • ~5–10% of idiopathic PAH
  • Drugs:
    • Amlodipine
    • Nifedipine
    • Diltiazem

 These patients have excellent long-term prognosis

When NOT to do vasoreactivity testing

  • Not indicated in:
    • Chronic thromboembolic pulmonary hypertension
    • PH due to left heart disease
    • Lung disease-associated PH

 Only for:

  • Idiopathic PAH
  • Heritable PAH
  • Drug-induced PAH


 CRITICAL PITFALLS 

 Do NOT give CCB without vasoreactivity test
→ Can cause hemodynamic collapse

 Negative test ≠ no treatment
→ These patients need PAH-specific therapy

 8.Management 

 GENERAL CARE IN PAH (GUIDELINE-ORIENTED)

 1. ANTICOAGULATION (WARFARIN)

  • In situ thrombosis occurs in pulmonary arteries due to:
    • Low flow
    • Endothelial dysfunction

 Indications (selective, not routine for all)

  • Idiopathic PAH (controversial but often considered)
  • Heritable PAH
  • Stronger indication in:
    • Chronic thromboembolic pulmonary hypertension → mandatory lifelong


  • Target INR:Often 2–3 (current practice)

 Cautions

  • Avoid in:
    • High bleeding risk
    • Portal hypertension (porto-pulmonary PAH)
  • Evidence is mixed → individualized decision (ESC Class IIb)


 2. OXYGEN THERAPY

 Indications

  • Resting hypoxemia (SpO₂ < 90% or PaO₂ < 60 mmHg)
  • Sleep-related desaturation
  • High altitude exposure

Goals-Maintain SpO₂ > 90%

 Mechanism

  • Prevents hypoxic pulmonary vasoconstriction
  • Reduces PVR progression


 Key point-Not routinely required in all PAH → only if hypoxic

 3. DIURETICS

Indication-Right heart failure with volume overload

  • Reduce:
    • Peripheral edema
    • Ascites
    • Hepatic congestion

Monitoring

  • Electrolytes (K⁺, Na⁺)
  • Renal function
  • Avoid over-diuresis → ↓ preload → ↓ cardiac output

 4. DIGOXIN  Indications

  • Right heart failure with low output
  • Atrial arrhythmias (AF)

 5. VACCINATION 

  • Influenza (annual)
  • Pneumococcal vaccine

 Why?

  • Respiratory infections → precipitate RV failure & decompensation

6.ADDITIONAL GENERAL MEASURES 

  • Salt restriction (for volume control)
  • Avoid pregnancy (high maternal mortality)
  • Supervised exercise (NOT complete rest)
  • Avoid high altitude

7. VASOREACTIVITY TESTING → CCB PATHWAY

 If positive (rare: 5–10%)

  • Start high-dose CCBs:
    • Amlodipine
    • Nifedipine
    • Diltiazem

 Only in:

  • Idiopathic PAH
  • Heritable PAH

 Reassess after 3–6 months
→ Continue only if sustained response


8. TARGETED PAH THERAPY (MAIN PILLARS)

PAH is driven by imbalance in 3 pathways:


 PROSTACYCLIN PATHWAY

Drug/Class

Route

Adverse Effects / Limitations / Special Points

Epoprostenol

Continuous IV infusion (central line)

Headache, flushing, jaw pain (with mastication), diarrhea, nausea, blotchy erythematous rash, musculoskeletal pain (legs/feet); dose-dependent side effects; overdose → systemic hypotension (acute), high-output cardiac failure (chronic); abrupt interruption → rebound PH, deterioration, death; complications: line infection, catheter thrombosis, systemic hypotension, thrombocytopenia, ascites

Treprostinil

SC, IV, inhaled (18–54 µg QID)

Headache, diarrhea, nausea, rash, jaw pain; infusion-site pain (85%), erythema/induration (83%)

Iloprost

Inhaled (6–9 times/day; total 15–45 µg/day)

Mild cough, headache, jaw pain; major limitation = short duration → frequent dosing

Beraprost

Oral

Benefits may diminish over time (shown in RCTs)

Selexipag

Oral (nonprostanoid prostacyclin receptor agonist)

Headache, diarrhea, nausea, jaw pain


 ENDOTHELIN PATHWAY (ERA)

Drug/Class

Mechanism

Adverse Effects / Special Points

Bosentan

Dual ERA

Hepatotoxicity (↑ AST/ALT, dose-dependent → monthly LFT required); anemia (usually mild → monitor Hb/Hct)

Ambrisentan

Selective ETA antagonist

Class effects: edema, hepatotoxicity, teratogenicity

Macitentan

Dual ERA

Peripheral edema; low incidence liver dysfunction; anemia, headache, nasopharyngitis

 NITRIC OXIDE–cGMP PATHWAY

Drug/Class

Mechanism

Adverse Effects / Special Points

Sildenafil

Inhibits PDE5 → ↑ cGMP

Headache, dyspepsia, flushing; may worsen gas exchange due to V/Q mismatch in lung disease

Tadalafil

Same (longer acting)

Similar side effects; advantage = once daily dosing

Riociguat

Stimulates sGC → ↑ cGMP

Headache, dyspepsia, dizziness; contraindicated with PDE inhibitors (hypotension risk); teratogenic

 NITRIC OXIDE (INHALED)

Therapy

Mechanism

Uses / Effects

Limitations

Inhaled Nitric Oxide

Activates sGC → ↑ cGMP → vasodilation

Potent selective pulmonary vasodilator; used in vasoreactivity testing; effective in neonatal PH, congenital heart disease, ARDS, post-op PH, lung transplant

FDA-approved mainly for neonatal hypoxemic respiratory failure; mainly short-term ICU use

 COMBINATION THERAPY

Strategy

Regimen

Effects

Initial combination therapy

Ambrisentan + Tadalafil

↓ disease progression; ↓ NT-proBNP; ↑ exercise capacity

Add-on therapy

Selexipag added to ERA/PDE

Additional reduction in progression/hospitalization

 9. INITIAL THERAPY (ESC GUIDELINE)

 Low–Intermediate risk- Initial dual combination therapy

  • ERA + PDE5 inhibitor
    (e.g., Ambrisentan + Sildenafil)


 High-risk patients- Initial triple therapy including IV prostacyclin

  • ERA + PDE5i + IV Epoprostenol


10. FOLLOW-UP & ESCALATION

  • Reassess at 3–6 months
  • If not low-risk → escalate:

Step

Action

Dual →

Add prostacyclin

Triple →

Consider transplant


 11. ADVANCED / REFRACTORY OPTIONS

 Lung transplantation

  • Indicated in:
    • Refractory PAH
    • Progressive RV failure


 Atrial septostomy

  • Creates right-to-left shunt
  • Used as bridge therapy

12. ICU MANAGEMENT (DECOMPENSATED PAH / RV FAILURE)

Principles:

  • Maintain preload (avoid over-diuresis)
  • Reduce RV afterload
  • Improve contractility

 Drugs:

  • Vasopressors:
    • Norepinephrine (preferred)
  • Inotropes:
    • Dobutamine
  • Pulmonary vasodilators:
    • Inhaled NO
    • IV prostacyclin

 Avoid:

  • Hypoxia
  • Hypercapnia
  • Acidosis
    → all increase PVR

 13. WHAT NOT TO DO 

  • Do NOT give PAH drugs in post-capillary PH
  • Do NOT start CCB without vasoreactivity test
  • Do NOT rely on monotherapy in most patients