2025 PACUPrep BCCCP Preparatory Course Pulmonary Hypertension (Acute and Chronic severe pulmonary hypertension) Foundational Principles & Classification of Pulmonary Hypertension
Foundational Concepts and WHO Classification of Pulmonary Hypertension

Foundational Concepts and WHO Classification of Pulmonary Hypertension

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Learning Objective

  • Describe foundational principles of pulmonary hypertension, including epidemiology, risk factors, classification, pathophysiology, and clinical presentation.

1. Definition and Epidemiology

Pulmonary hypertension (PH) is defined by invasive hemodynamic criteria that guide diagnosis and management. Recognition of its prevalence and the shift to lower diagnostic thresholds drives earlier identification in the ICU.

Diagnostic Criteria (Right Heart Catheterization)

Hemodynamic Definitions of Pulmonary Hypertension
Parameter Value Notes
Mean Pulmonary Artery Pressure (mPAP) ≥20 mmHg Required for PH diagnosis.
Pulmonary Vascular Resistance (PVR) >2 Wood units (WU) Indicates precapillary component.
Pulmonary Artery Wedge Pressure (PAWP) ≤15 mmHg Defines precapillary PH when PVR >2 WU.

Hemodynamic Subtypes

  • Isolated Postcapillary PH (IpcPH): mPAP ≥20 mmHg, PAWP >15 mmHg, PVR ≤2 WU.
  • Combined Pre- and Postcapillary PH (CpcPH): mPAP ≥20 mmHg, PAWP >15 mmHg, PVR >2 WU.

ICU Prevalence

  • PH detected in approximately 10–25% of critically ill patients, varying by cohort and screening method.
  • Often underdiagnosed amidst confounding factors like sepsis, ARDS, and significant volume shifts.
Key Point Icon A lightbulb, symbolizing a key point or insight. Key Point: Lowered mPAP Threshold

The mPAP threshold for diagnosing PH was lowered from ≥25 mmHg to ≥20 mmHg. This change aims to capture “borderline” PH, which is linked to worse outcomes, and to prompt earlier evaluation and intervention.

2. WHO Classification of Pulmonary Hypertension

The World Health Organization (WHO) grouping system categorizes PH based on etiology and underlying pathophysiology. This classification is crucial as it guides targeted therapies; currently, only Group 1 (Pulmonary Arterial Hypertension) has evidence-based vasodilator regimens.

Group 1: Pulmonary Arterial Hypertension (PAH)

Examples: Idiopathic, heritable (e.g., BMPR2 mutations), drug/toxin-induced, associated with connective tissue disease (CTD), HIV infection, portal hypertension.

Pathophysiology: Characterized by precapillary vasculopathy, endothelial dysfunction, and the development of plexiform lesions.

Group 2: PH due to Left Heart Disease

Examples: Left ventricular systolic or diastolic dysfunction, valvular heart disease.

Pathophysiology: Postcapillary PH resulting from elevated left-sided filling pressures transmitted backward to the pulmonary circulation.

Group 3: PH due to Lung Disease and/or Hypoxia

Examples: COPD, interstitial lung disease (ILD), sleep apnea syndromes, chronic hypoventilation disorders, chronic exposure to high altitude.

Pathophysiology: Primarily driven by hypoxic vasoconstriction, destruction of the pulmonary vascular bed, and vascular remodeling.

Group 4: PH due to Pulmonary Artery Obstructions

Examples: Chronic thromboembolic pulmonary hypertension (CTEPH), other pulmonary artery obstructions (e.g., angiosarcoma, tumors, arteritis, congenital stenoses).

Pathophysiology: Mechanical obstruction from organized thrombi combined with secondary microvascular remodeling in non-obstructed areas.

Group 5: PH with Unclear and/or Multifactorial Mechanisms

Examples: Hematologic disorders (e.g., sickle cell disease, chronic hemolytic anemia, myeloproliferative disorders), systemic disorders (e.g., sarcoidosis, neurofibromatosis), metabolic disorders (e.g., glycogen storage disease), complex congenital heart disease.

Pathophysiology: Heterogeneous; mechanisms vary widely and may involve multiple contributing factors.

Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Mixed Phenotypes

Patients presenting with mixed phenotypes (e.g., mild underlying lung disease but disproportionately severe PH) require careful multidisciplinary evaluation. Misclassification, particularly failing to identify a significant Group 1 PAH component, may preclude access to beneficial PAH-specific therapies.

3. Risk Factors in ICU Populations

Critically ill patients often harbor a combination of chronic predisposing conditions and acute precipitating factors for PH. Awareness of these drivers is key to early detection and appropriate intervention in the ICU setting.

Non-Modifiable Risk Factors

  • Heritable PAH (e.g., due to BMPR2 mutations)
  • Connective tissue diseases (especially systemic sclerosis)
  • HIV infection
  • Congenital heart disease (repaired or unrepaired)

Acquired/Chronic Risk Factors

  • Left heart disease (HFpEF/HFrEF, valvular pathologies)
  • Chronic lung diseases (COPD, ILD)
  • Chronic thromboembolic pulmonary hypertension (CTEPH)

Acute Precipitants in the ICU

  • Massive or submassive pulmonary embolism
  • Sepsis and Acute Respiratory Distress Syndrome (ARDS)
  • Fluid overload leading to pulmonary venous congestion
  • Arrhythmias (e.g., atrial fibrillation with rapid ventricular response)
  • Medication nonadherence (in patients with known PH)
Decision Point Icon A branching path, indicating a clinical decision point. Clinical Decision Point: Unstable Patient with RV Dilation

In an unstable ICU patient presenting with new or worsened right ventricular (RV) dilation on echocardiography and hypotension, it is crucial to systematically assess for acute triggers. Before attributing these changes solely to an exacerbation of chronic PH, actively investigate and rule out acute pulmonary embolism, sepsis-induced myocardial dysfunction, or severe hypoxemia as potential primary or contributing causes.

4. Pathophysiologic Mechanisms

Both chronic and acute increases in pulmonary vascular resistance (PVR) are central to the pathophysiology of PH, leading to right ventricular (RV) overload and eventual failure. Cellular remodeling processes contribute to the establishment and progression of the disease.

Increased Pulmonary Vascular Resistance (PVR)

  • Endothelial Injury and Dysfunction: Leads to an imbalance with decreased production of vasodilators (e.g., nitric oxide, prostacyclin) and increased production of vasoconstrictors (e.g., endothelin-1, thromboxane A2), promoting sustained vasoconstriction.
  • In Situ Thrombosis and Impaired Fibrinolysis: Particularly prominent in CTEPH (Group 4) but can contribute to microvascular disease in other PH forms.

RV Overload and Remodeling

  • Acute RV Overload: A rapid increase in afterload (e.g., from massive PE) causes acute RV dilation, interventricular septal flattening/bowing towards the LV, and a decrease in cardiac output.
  • Chronic RV Overload: Initially, the RV adapts through hypertrophy. Over time, this can become maladaptive, leading to RV dilation, fibrosis, impaired contractility, and ultimately RV failure. Tricuspid regurgitation often worsens due to annular dilation.

Vascular Remodeling

  • Structural Changes: Proliferation of pulmonary artery smooth muscle cells, intimal proliferation and fibrosis, and adventitial thickening are common features.
  • Plexiform Lesions: These complex vascular lesions, characterized by a network of capillary-like channels, are a hallmark of severe, advanced PAH (Group 1) and contribute significantly to increased PVR.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Key Pearl: RV-Pulmonary Artery Coupling

The relationship between RV contractility and pulmonary artery afterload, known as RV-PA coupling, is a critical determinant of functional capacity, response to therapy, and overall prognosis in PH. While invasive pressure-volume loop analysis provides the most direct assessment of RV-PA coupling, it remains primarily a research tool and is not routinely performed in the ICU. Non-invasive echocardiographic parameters are more commonly used to estimate RV function and its response to afterload.

5. Clinical and Hemodynamic Features

Distinguishing between an acute decompensation of PH and the presentation of chronic, compensated PH is vital for tailoring management strategies in the ICU. Symptoms often reflect the severity of RV dysfunction and the degree of PVR elevation.

Acute Decompensation of Pulmonary Hypertension

  • Symptoms: Sudden onset or worsening of dyspnea (often at rest), syncope or presyncope, chest discomfort (angina-like, due to RV ischemia), oliguria, and signs of low cardiac output.
  • Physical Exam Findings: Hypotension, cool extremities, elevated jugular venous pressure (JVP), often with clear lung fields (unless concomitant left heart failure or pulmonary edema from other causes). A new or louder tricuspid regurgitation murmur may be present.
  • Hemodynamics: Characterized by a rapid rise in right atrial (RA) pressure, a significant drop in cardiac index (CI), and often a marked spike in PVR. Mixed venous oxygen saturation (SvO₂) will be low.

Chronic Severe Pulmonary Hypertension

  • Symptoms: Progressive dyspnea on exertion, fatigue, lethargy, peripheral edema, abdominal distension (ascites), and exertional chest pain or syncope in advanced stages.
  • Physical Exam Findings: Loud P2 component of the second heart sound, RV heave or lift, JVD, hepatomegaly, ascites, peripheral edema. Cyanosis may be present in severe cases with right-to-left shunting.
  • Hemodynamics: Sustained elevation of mPAP and PVR. Cardiac output may be preserved or even elevated in early stages due to compensatory mechanisms but declines as RV failure progresses. RA pressure is typically elevated.
Pearl Icon A shield with an exclamation mark, indicating a clinical pearl. Clinical Pearl: Echocardiographic Screening vs. RHC

Echocardiographic estimation of pulmonary artery systolic pressure (PASP) using the tricuspid regurgitation velocity (TRV) is a valuable non-invasive screening tool for PH. It is sensitive but can be nonspecific and may overestimate or underestimate true pulmonary pressures. When clinical suspicion for PH is high, or when PH-specific therapies are being considered, right heart catheterization (RHC) remains the gold standard for confirming the diagnosis, assessing severity, determining vasoreactivity, and guiding management.

6. Differential Diagnosis of RV Failure

Right ventricular (RV) dysfunction and failure can result from various etiologies beyond chronic PH. Accurate differentiation is crucial as management strategies differ significantly and misdiagnosis can lead to inappropriate or harmful therapies.

Acute Pulmonary Embolism (PE)

  • Presentation: Often sudden hemodynamic collapse or instability, acute dyspnea, pleuritic chest pain.
  • Key Findings: RV dilation and dysfunction on echocardiography are common. Diagnosis is confirmed by CT pulmonary angiography (CTPA).
  • Biomarkers: Elevated troponin and BNP/NT-proBNP levels reflect acute RV strain and myocardial injury.

Left Heart Disease (WHO Group 2 PH)

  • Mechanism: RV dysfunction secondary to elevated left-sided filling pressures (high PAWP).
  • Key Findings: Echocardiography shows evidence of left ventricular systolic or diastolic dysfunction, or significant valvular disease. PAWP on RHC is >15 mmHg.
  • Note: Postcapillary PVR is typically low (≤2 WU) unless a combined pre- and postcapillary PH (CpcPH) develops due to reactive pulmonary vasoconstriction or remodeling.

Other Causes of RV Dysfunction/Failure

  • Restrictive Cardiomyopathy: Characterized by impaired diastolic filling of one or both ventricles. Echocardiography shows typical diastolic filling patterns.
  • Constrictive Pericarditis: Impaired diastolic filling due to a rigid pericardium. May present with a pericardial knock on auscultation and characteristic respiratory discordance in ventricular pressures on hemodynamics.
  • Arrhythmogenic Right Ventricular Dysplasia (ARVD): A genetic cardiomyopathy characterized by fibrofatty replacement of RV myocardium.
  • RV Infarction: Usually occurs in the context of an inferior myocardial infarction involving the right coronary artery.

7. Prognostic Indicators and Risk Stratification

A comprehensive assessment integrating hemodynamic parameters, biomarkers, functional status, and validated risk scores is essential for determining prognosis and guiding triage decisions in patients with pulmonary hypertension, particularly those who are critically ill.

Key Hemodynamic Predictors of Poor Outcome

  • Right atrial pressure (RAP) >15 mmHg
  • Cardiac index (CI) <2.0 L/min/m²
  • Mixed venous oxygen saturation (SvO₂) <60%
  • Pulmonary vascular resistance (PVR) significantly elevated (e.g., >10 WU)

Biomarkers Indicating RV Stress and Hypoperfusion

  • NT-proBNP/BNP: Elevated levels (e.g., NT-proBNP >300 pg/mL, though higher thresholds often used for risk stratification) correlate with RV wall stress and dysfunction. Serial measurements are valuable.
  • High-Sensitivity Troponin: Elevation indicates RV myocardial injury or ischemia.
  • Serum Lactate: Rising lactate levels are a critical sign of tissue hypoperfusion and impending circulatory collapse.

Risk Scores

  • REVEAL Score (Registry to Evaluate Early and Long-Term PAH Disease Management): Integrates multiple variables including demographics, functional class, 6-minute walk distance (6MWD), BNP levels, PFTs, echocardiographic findings, and hemodynamics.
  • Other Scores: Various other risk stratification tools exist, often tailored to specific PH subgroups (e.g., COMPERA, FPHR).
  • ICU Application: While many scores are validated primarily in stable outpatient PAH populations, their components (e.g., RAP, CI, SvO₂, biomarkers) are highly relevant in assessing severity and prognosis in critically ill PH patients.
Key Point Icon A lightbulb, symbolizing a key point or insight. Key Point: Serial Assessment is Crucial

No single parameter in isolation is sufficient for comprehensive risk stratification or prognostication in PH. Serial assessment, tracking trends in clinical status, hemodynamics (if invasively monitored), biomarkers (especially NT-proBNP and lactate), and RV function (via echocardiography), is crucial for guiding therapeutic escalation, de-escalation, and determining candidacy for advanced therapies such as mechanical circulatory support or lung transplantation.

References

  1. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(36):3618–3731.
  2. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913.
  3. Johnson S, Singh S, Kholdani C, et al. Pulmonary Hypertension: A Contemporary Review. Am J Respir Crit Care Med. 2023;208(5):528–548.
  4. Maron BA, Hess E, McLaughlin VV. Redefining pulmonary hypertension. Lancet Respir Med. 2018;6(3):168–170.
  5. Sysol JR, Machado RF. Classification and Pathophysiology of Pulmonary Hypertension. Contemporary Cardiology Education. 2018;4:2–12.
  6. Fayyaz AU, Tuder RM, Pinsky MR, et al. Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure. Circulation. 2018;137(17):1796–1810.
  7. Benza RL, Miller DP, Gomberg-Maitland M, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141(2):354–362.
  8. Brener MI, Houston BA, Goya JA, et al. Invasive Right Ventricular Pressure-Volume Analysis: Principles and Applications. Circ Heart Fail. 2022;15(7):e009101.
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