Respiratory

Pulmonary hypertension: classification and workup

Clinical Overview and When to Suspect Pulmonary Hypertension

— Pre-capillary PH: mPAP >20, PAWP ≤15, PVR >2 Wood units

— Post-capillary PH: mPAP >20, PAWP >15 (left heart disease)

— Combined pre- and post-capillary: both elevated

— Group 1: Pulmonary arterial hypertension (PAH) — idiopathic, heritable (BMPR2), drug/toxin (methamphetamine, fenfluramine, dasatinib), connective tissue disease (scleroderma), HIV, portal HTN, congenital heart disease, schistosomiasis

— Group 2: Left heart disease (HFpEF, HFrEF, valvular) — most common cause in US

— Group 3: Lung disease/hypoxia (COPD, ILD, OSA, high altitude)

— Group 4: Chronic thromboembolic PH (CTEPH)

— Group 5: Multifactorial/unclear (sarcoid, sickle cell, chronic hemolytic anemia, CKD on dialysis)

— Unexplained progressive dyspnea on exertion + normal or near-normal CXR/PFTs

— Exertional syncope or presyncope (ominous — implies fixed cardiac output)

— New right-sided heart failure signs (JVD, hepatomegaly, ascites, edema)

— Scleroderma, HIV, portopulmonary, prior PE, or family history of PAH → annual screening echo in selected patients

Board pearl: A scleroderma patient with progressive dyspnea and a normal CXR — get a transthoracic echo. Annual screening echo + DLCO is standard in systemic sclerosis even when asymptomatic; a falling DLCO out of proportion to lung volumes is an early PAH clue.

Definition (2022 ESC/ERS, adopted in US practice): Pulmonary hypertension (PH) = mean pulmonary artery pressure (mPAP) >20 mmHg at rest by right heart catheterization (RHC). Prior threshold was ≥25 mmHg — Step 3 stems may use either.

WHO Group classification (must memorize):

When to suspect:

Epidemiology pearls: Idiopathic PAH skews young women (30s–40s). Group 2 PH dominates the older outpatient population.

Presentation Patterns and Key History

— Early: fatigue, decreased exercise tolerance, atypical chest pressure

— Intermediate: palpitations, lightheadedness on exertion

— Advanced: exertional syncope (RV cannot augment output), hemoptysis, hoarseness (Ortner syndrome — enlarged PA compressing left recurrent laryngeal nerve), abdominal distension, lower extremity edema, early satiety from hepatic congestion

— Drug/toxin exposure: methamphetamine, cocaine, anorexigens (fen-phen, aminorex), dasatinib, interferon, leflunomide

— Connective tissue disease: Raynaud, sclerodactyly, dysphagia, sicca symptoms, rash → think scleroderma, MCTD, lupus

— VTE history: unprovoked PE, recurrent DVT, antiphospholipid syndrome → CTEPH (Group 4)

— Liver disease/portal HTN: suggests portopulmonary HTN

— HIV status and ART history

— Sleep history: snoring, witnessed apnea, daytime somnolence, BMI → OSA-driven Group 3

— Altitude exposure, cabin pressurization symptoms

— Family history: BMPR2, heritable PAH (autosomal dominant, incomplete penetrance, anticipation)

— Cardiac history: HFpEF risk (HTN, DM, obesity, AFib) — points to Group 2

— Class I: no limitation

— Class II: slight limitation, comfortable at rest

— Class III: marked limitation, less-than-ordinary activity causes symptoms

— Class IV: symptoms at rest or with any activity, signs of RV failure

Step 3 management: On the first outpatient visit for suspected PH, document WHO functional class, 6-minute walk distance, and order TTE, BNP/NT-proBNP, and basic CTD serologies before subspecialty referral.

Cardinal symptom: Exertional dyspnea — present in >95% at diagnosis. Insidious onset, often misattributed to deconditioning or asthma for 2+ years before diagnosis (a tested delay-to-diagnosis fact).

Other symptoms by severity:

Targeted history must capture:

Functional class (WHO/NYHA): Document at every visit — drives prognosis and therapy escalation.

Physical Exam Findings (and Hemodynamic Assessment)

— Resting tachycardia, narrow pulse pressure

— Resting or exertional hypoxemia — SpO₂ drop with ambulation is a key clinic-room maneuver

— Central cyanosis (advanced or with right-to-left shunt via PFO)

— Left parasternal heave (RV lift) at the lower sternal border

— Palpable P₂

— Loud P₂ — the single most reliable auscultatory sign

— Fixed or narrowly split S₂

— Right-sided S₄ (early), right-sided S₃ (late, RV failure)

— Holosystolic murmur of tricuspid regurgitation at the left lower sternal border, increases with inspiration (Carvallo sign)

— Early diastolic decrescendo murmur of pulmonic regurgitation (Graham Steell murmur) at the left upper sternal border

— Pulsatile hepatomegaly (TR), hepatojugular reflux

— Ascites, lower extremity edema

— Clubbing → suggests congenital heart disease, ILD, or right-to-left shunt rather than idiopathic PAH

— Sclerodactyly, telangiectasias, calcinosis → systemic sclerosis

— Spider angiomata, palmar erythema, caput medusae → portopulmonary

— Kyphoscoliosis or thoracoplasty scars → restrictive Group 3

— Measure RA pressure, RV pressure, PA pressure, PAWP, cardiac output (thermodilution or Fick), and PVR

— Vasoreactivity testing with inhaled nitric oxide in idiopathic/heritable/drug-induced PAH: positive = mPAP drop ≥10 mmHg to absolute <40, with preserved CO → eligible for high-dose CCB therapy

Board pearl: A loud P₂ + RV heave + elevated JVP in a dyspneic patient with a clear CXR should trigger an immediate echo — not another round of inhalers.

Inspection and vitals:

Neck: Elevated JVP with prominent a wave (forceful RA contraction against stiff RV); large v wave if functional tricuspid regurgitation develops.

Precordium:

Abdomen and extremities:

Skin/MSK clues to etiology:

Hemodynamic assessment by RHC (gold standard, required for Group 1 diagnosis):

Diagnostic Workup — Initial Labs, Imaging, ECG, Biomarkers

— Right axis deviation

— Right ventricular hypertrophy (R/S >1 in V1, deep S in V5/V6)

— Right atrial enlargement (P pulmonale, P ≥2.5 mm in II)

— RBBB or incomplete RBBB

— New AFib or atrial flutter heralds clinical deterioration

— Enlarged central pulmonary arteries with peripheral pruning

— RA/RV enlargement (filling of the retrosternal space on lateral)

— Look for parenchymal disease (Group 3) or Kerley B lines/cardiomegaly (Group 2)

— Estimate PASP from tricuspid regurgitation jet velocity using modified Bernoulli (4v² + RA pressure)

— TR velocity >2.8 m/s or estimated PASP >35 mmHg suggests PH and warrants further workup

— Assess RV size/function (TAPSE <17 mm = RV dysfunction), septal flattening ("D-shaped" LV in systole = pressure overload; in diastole = volume overload), RA dilation, pericardial effusion (poor prognosis)

— Bubble study to detect intracardiac shunt

— BNP/NT-proBNP — elevated; prognostic and trended longitudinally

— Troponin — elevation in advanced RV strain portends worse outcome

— CBC, CMP (liver/kidney), TSH (thyroid disease frequently coexists)

— HIV antibody

— ANA, anti-centromere, anti-Scl-70, anti-RNP → CTD

— Hepatitis B/C serologies, LFTs → portopulmonary

— Iron studies (often deficient, treatable)

— BNP/NT-proBNP baseline

Step 3 management: Echo is the screening test; right heart catheterization is required to confirm PAH and to characterize hemodynamics before initiating Group 1–specific therapy. Do not start PAH-specific drugs based on echo alone.

ECG (low sensitivity, but classic patterns):

CXR:

Transthoracic echocardiogram — the screening test of choice:

Biomarkers:

Initial labs (etiology hunt):

Diagnostic Workup — Advanced and Confirmatory Studies

— Always exclude CTEPH (Group 4) in every PH workup

— V/Q is more sensitive than CT pulmonary angiogram for chronic clot

— Normal/low-probability scan effectively rules out CTEPH

— Mismatched segmental perfusion defects → proceed to CTPA and digital subtraction pulmonary angiography

— Missing this step is a classic Step 3 trap — CTEPH is potentially curable with pulmonary thromboendarterectomy (PTE)

— Obstruction → COPD (Group 3)

— Restriction with low DLCO and low TLC → ILD (Group 3)

— Isolated low DLCO with preserved volumes → suggests PAH or pulmonary vascular disease, especially in scleroderma

— Identifies ILD, emphysema, mosaic perfusion (CTEPH), enlarged PA (PA diameter >29 mm or PA:aorta ratio >1)

— Mediastinal adenopathy → sarcoid (Group 5)

— Baseline functional capacity (<165 m at diagnosis = poor prognosis)

— Desaturation pattern guides oxygen prescription

— Quantify mPAP, PAWP, PVR, CO, mixed venous O₂ saturation

— Vasoreactivity testing with inhaled NO (or adenosine, epoprostenol) only in suspected idiopathic, heritable, or drug-induced PAH

— Do not test vasoreactivity in Groups 2, 3, 4, or 5

— Positive responders (~10%) → trial high-dose CCB; long-term responders are an even smaller subset (~5%)

Key distinction: V/Q scan — not CTPA — is the screening test of choice for CTEPH. CTPA can miss distal chronic thrombi.

V/Q scan — mandatory step:

Pulmonary function tests + DLCO:

High-resolution chest CT:

Polysomnography: If clinical suspicion for OSA or obesity hypoventilation.

Arterial blood gas + 6-minute walk test:

Cardiac MRI: Best modality for RV volumes, mass, and function; increasingly used for prognosis.

Right heart catheterization (gold standard, confirms diagnosis):

Genetic testing/counseling: Offer when heritable PAH suspected (BMPR2, ALK1, ENG, SMAD9, CAV1, KCNK3).

Risk Stratification and First-Line Management Logic

— WHO functional class (I/II vs III vs IV)

— 6-minute walk distance (>440 m low, 165–440 intermediate, <165 high risk)

— BNP/NT-proBNP (BNP <50, 50–800, >800 pg/mL strata)

— RA area, pericardial effusion, TAPSE on echo

— RHC: RA pressure, cardiac index, mixed venous O₂ saturation

— Signs of right heart failure, syncope

— Group 1 (PAH): PAH-specific vasodilator therapy at a PH center (endothelin receptor antagonists, PDE-5 inhibitors, prostacyclins, sGC stimulators) ± high-dose CCB only if vasoreactive

— Group 2 (left heart disease): Do NOT use PAH-specific therapy — treat the underlying LV disease (HFrEF GDMT, HFpEF risk factor control, valvular surgery). Pulmonary vasodilators can precipitate flash pulmonary edema.

— Group 3 (lung disease/hypoxia): Treat underlying disease, supplemental O₂ if SpO₂ ≤88%, pulmonary rehab; inhaled treprostinil approved for PH-ILD

— Group 4 (CTEPH): Lifelong anticoagulation + referral for pulmonary thromboendarterectomy (PTE) — potentially curative; riociguat or balloon pulmonary angioplasty for inoperable/residual disease

— Group 5: Treat underlying disorder

— Diuretics for RV volume overload

— Supplemental O₂ to keep SpO₂ ≥90%

— Influenza, pneumococcal, and COVID-19 vaccination

— Supervised exercise/pulmonary rehab

— Avoid pregnancy in PAH (high maternal mortality)

— Avoid high-altitude travel without supplemental O₂

Step 3 management: Always classify before treating. Misclassifying Group 2 PH as Group 1 and starting a PDE-5 inhibitor is a tested error that can precipitate pulmonary edema.

Once PAH (Group 1) confirmed by RHC, stratify risk using a multiparameter approach (ESC/ERS 4-strata or REVEAL 2.0). Risk re-assessed every 3–6 months and after each therapy change.

Key risk variables:

Low-risk: <5% 1-year mortality; intermediate-low/high: 5–20%; high-risk: >20%.

Management logic by WHO group — extremely high yield:

General supportive measures for all groups:

Pharmacotherapy — First-Line Drug Regimen (Group 1 PAH)

— Nifedipine, diltiazem, amlodipine; titrate to maximum tolerated dose

— Avoid verapamil (negative inotrope on stressed RV)

— Reassess in 3–6 months; if not WHO class I/II with near-normal hemodynamics, switch to standard PAH therapy

— Low/intermediate risk: Initial dual oral combination — endothelin receptor antagonist (ERA) + PDE-5 inhibitor

— High risk: Initial triple therapy including a parenteral prostacyclin

— Ambrisentan, macitentan, bosentan

— Adverse: peripheral edema, anemia, hepatotoxicity (monthly LFTs with bosentan), teratogenic — Category X, REMS program with monthly pregnancy testing in women of reproductive age, mandatory contraception

— Sildenafil, tadalafil — enhance NO–cGMP pathway

— Riociguat (sGC stimulator) — first-line in CTEPH (Group 4); never combine with PDE-5 inhibitor or nitrates (severe hypotension)

— Adverse: headache, flushing, hypotension, visual changes, hearing loss; contraindicated with nitrates

— IV epoprostenol — gold standard for advanced disease; continuous infusion via central line (half-life 3–5 min — abrupt interruption can be fatal); known to improve survival

— Treprostinil (IV, SC, inhaled, oral)

— Iloprost (inhaled)

— Selexipag — oral IP receptor agonist

— Adverse: jaw pain, flushing, diarrhea, line infections (parenteral)

— Loop diuretics for RV volume overload

— Anticoagulation: routinely indicated only in CTEPH and considered selectively in idiopathic PAH

— Iron repletion if deficient

— Digoxin in atrial arrhythmias with RV failure

Board pearl: Riociguat + sildenafil = forbidden combination. Same NO-cGMP pathway, additive hypotension. Tested as a "next step is to stop the drug" item.

Vasoreactive (~5% long-term responders) — high-dose CCBs:

Non-vasoreactive (95%) — combination therapy is now standard:

Endothelin receptor antagonists (ERAs):

PDE-5 inhibitors / sGC stimulators:

Prostacyclin pathway agents:

Adjunctive:

Procedures and Invasive Management

— Open surgical endarterectomy under deep hypothermic circulatory arrest

— Performed at specialized centers

— Every CTEPH patient should be evaluated by a multidisciplinary team for surgical candidacy

— 5-year survival ~80% post-PTE; can normalize hemodynamics

— Persistent PH post-PTE → riociguat or balloon pulmonary angioplasty

— For inoperable distal CTEPH or persistent PH after PTE

— Multiple staged sessions; risk of reperfusion pulmonary edema and vessel injury

— Palliative — creates a right-to-left shunt to decompress failing RV and augment LV preload

— Bridge to transplant in selected refractory class IV patients

— Trade-off: systemic desaturation

— Indicated for WHO class III/IV PAH refractory to maximal medical therapy including parenteral prostacyclins

— Bilateral lung transplant preferred; heart-lung reserved for Eisenmenger or severe RV failure unlikely to recover

— Refer early — waitlist mortality is high

— Used selectively in ICU for hemodynamic monitoring in decompensated RV failure or post-cardiac surgery PH

— Inhaled nitric oxide and inhaled epoprostenol for acute RV failure or right heart catheter vasoreactivity testing

— Selective pulmonary vasodilation without systemic hypotension

— General anesthesia carries high mortality — avoid elective surgery

— Avoid hypoxia, hypercarbia, acidosis, hypotension (all increase PVR)

— Maintain preload but avoid volume overload

— Continue PAH-specific therapy uninterrupted perioperatively

— Regional anesthesia preferred when feasible; arterial line monitoring routine

CCS pearl: For a CTEPH patient — order V/Q scan → CTPA → digital subtraction pulmonary angiography → refer to PTE-capable center; start lifelong anticoagulation immediately upon CTEPH diagnosis.

Pulmonary thromboendarterectomy (PTE / PEA) — curative for CTEPH:

Balloon pulmonary angioplasty (BPA):

Atrial septostomy:

Lung or heart-lung transplantation:

Pulmonary artery catheter / Swan-Ganz:

Inhaled pulmonary vasodilators:

Procedural cautions in any PH patient (Step 3 perioperative pearl):

Special Populations — Elderly and Renal/Hepatic Impairment

— Group 2 PH from HFpEF dominates — careful PAWP interpretation is essential before labeling a patient as PAH

— Misdiagnosis risk: HFpEF can mimic PAH on echo; exercise RHC may unmask occult left heart disease (PAWP rises >25 mmHg with exercise)

— Avoid PAH-specific vasodilators when PAWP elevated — risk of flash pulmonary edema and death

— Comorbidities (DM, HTN, CKD, AFib, obesity) drive prognosis as much as PH itself

— Drug interactions more frequent (sildenafil + alpha-blockers, ERAs + warfarin metabolism)

— Polypharmacy — review for nitrates before PDE-5 inhibitor prescription

— Lower starting doses, slower titration; monitor orthostatic hypotension, falls

— Common in advanced PH from venous congestion (cardiorenal physiology) and diuretic use

— Macitentan, ambrisentan: no dose adjustment in renal impairment

— Sildenafil: caution in CrCl <30; tadalafil — avoid in CrCl <30

— Riociguat: caution in CrCl <30; no data in dialysis

— Selexipag: titrate cautiously

— Loop diuretics may need dose escalation; monitor electrolytes (hypokalemia, hyponatremia)

— Avoid NSAIDs (renal vasoconstriction worsens RV preload mismatch and renal function)

— Portopulmonary HTN is a distinct entity — screen with TTE before liver transplant evaluation

— Bosentan: contraindicated in moderate-severe hepatic impairment (Child-Pugh B/C); monthly LFTs even in mild

— Macitentan: avoid in severe hepatic impairment

— Ambrisentan: less hepatotoxic but still monitor

— Riociguat: avoid in Child-Pugh C

— Tadalafil: avoid in severe hepatic impairment

Step 3 management: In an older patient with dyspnea, AFib, HTN, DM, and obesity who has "PH" on echo, the next step is usually a diastolic stress echo or RHC with provocation, not empiric PAH therapy. Treat HFpEF first.

Elderly (>65 years):

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Maternal mortality 30–50% historically; even with modern care, 10–25%

— PAH is a clear contraindication to pregnancy (WHO Class IV cardiac risk)

— Counsel reliable contraception at every visit — IUDs or progestin-only methods preferred; avoid combined estrogen contraceptives (thrombotic risk)

— If unintended pregnancy: offer therapeutic abortion counseling

— If patient elects to continue: manage at a tertiary center with multidisciplinary team (PH cardiology, MFM, OB anesthesia)

— Switch from ERAs and riociguat (teratogenic) to PDE-5 inhibitors ± inhaled/IV prostacyclins

— Highest risk: peripartum and first 4–6 weeks postpartum (volume shifts, hypercoagulability)

— Cesarean under regional anesthesia, invasive monitoring, avoid Valsalva

— Postpartum hemorrhage and PE drive late mortality

— Often associated with congenital heart disease (Eisenmenger physiology from unrepaired VSD, ASD, PDA, AV canal)

— Heritable PAH presents earlier with BMPR2 mutations; genetic counseling

— Early repair of left-to-right shunts prevents progression

— Sildenafil and bosentan have pediatric indications

— Treat with ART regardless of CD4

— PAH-specific therapy same as idiopathic; watch protease inhibitor–sildenafil interactions (use lowest sildenafil dose; tadalafil preferred)

— Worst prognosis among Group 1; screen annually with echo + DLCO

— Earlier escalation to combination therapy and prostacyclins

— Elevated TR velocity >2.5 m/s on echo predicts mortality

— Manage with hydroxyurea, transfusion to lower HbS, treat OSA; PAH-specific therapy has limited efficacy

Board pearl: A PAH patient asking about pregnancy → counsel against it, offer effective contraception, and avoid estrogen-containing methods. This is the single most tested PAH-pregnancy item.

Pregnancy in PAH — high-yield, high-mortality:

Pediatric PAH:

HIV-associated PAH:

Connective tissue disease (especially scleroderma):

Sickle cell disease (Group 5):

Complications and Adverse Outcomes

— Progressive RV dilation → tricuspid annular dilation → functional TR → further RV volume overload (vicious cycle)

— Systemic congestion: JVD, hepatic congestion, ascites, edema, cardiorenal syndrome

— Decreased LV filling via interventricular dependence → low cardiac output, hypotension, end-organ hypoperfusion

— Atrial flutter and AFib in 25% over 5 years — often precipitate clinical decompensation

— Rate control alone is poorly tolerated (RV depends on sinus rhythm and atrial kick)

— Pursue rhythm control (cardioversion, ablation) aggressively

— Avoid AV nodal–blocking agents that depress RV (verapamil, high-dose beta-blockers in decompensated patients)

— From bronchial artery hypertrophy and rupture

— Can be life-threatening; consider bronchial artery embolization

— Central line–associated bloodstream infection (parenteral prostacyclins)

— Abrupt prostacyclin interruption → rebound PH crisis and death within minutes

— PDE-5 + nitrate hypotension

— Diuretic overdiuresis → preload-dependent RV collapse and hypotension

— Anesthesia-related mortality (up to 7% for noncardiac surgery)

Key distinction: In acute decompensation of PH, fluid resuscitation can worsen RV failure. Unlike LV-driven shock, the failing RV is preload-intolerant — give small, cautious boluses and start vasopressors/inotropes (norepinephrine, dobutamine, milrinone) early.

Right heart failure (RHF) — the dominant cause of morbidity and mortality:

Arrhythmias:

Hemoptysis:

Pulmonary artery aneurysm/dissection: Rare but catastrophic in long-standing severe PH.

Sudden cardiac death: From RV ischemia (RV pressure exceeds coronary perfusion pressure during exertion), arrhythmia, or PE.

Hepatic dysfunction: Congestive hepatopathy → cardiac cirrhosis in advanced cases.

In-situ pulmonary thrombosis: Distinct from CTEPH; stagnant flow predisposes to clot.

Syncope and sudden death with exertion or Valsalva — driven by fixed cardiac output and inability to augment with demand.

Iatrogenic complications:

When to Escalate Care — ICU, Consult, and Inpatient Triage

— All suspected or confirmed Group 1 PAH

— All suspected CTEPH (for PTE evaluation)

— Any patient who deteriorates on therapy

— Pregnancy in a PH patient

— Pre-transplant evaluation

— Pediatric PAH

— New WHO class IV symptoms

— Syncope

— Rapidly progressive edema or ascites despite oral diuretics

— Hemoptysis

— New atrial arrhythmia

— Suspected pulmonary embolism or sepsis in known PAH

— Initiating IV prostacyclin therapy (typically inpatient)

— Hemodynamic instability, hypotension (SBP <90), oliguria

— Lactic acidosis or rising lactate

— Hypoxemia refractory to supplemental O₂

— Acute RV failure (rising RA pressure, falling cardiac index)

— Decompensation requiring inotropes (dobutamine, milrinone) or vasopressors (norepinephrine — preferred over phenylephrine, which raises PVR less favorably and is purely alpha)

— Need for inhaled nitric oxide or inhaled epoprostenol

— Mechanical support consideration: VA-ECMO as bridge to recovery, decision, or transplant

— Identify and reverse the trigger: sepsis, PE, arrhythmia, missed prostacyclin dose, anemia, hypoxia

— Optimize preload: small, careful diuresis if congested; small fluid bolus only if dry

— Maintain coronary perfusion: norepinephrine to keep MAP > PA pressure

— Augment RV contractility: dobutamine or milrinone (milrinone also reduces PVR but can drop SVR)

— Reduce PVR: inhaled NO, inhaled epoprostenol; correct hypoxia/acidosis

— Avoid intubation if possible; if needed, etomidate induction, avoid propofol bolus, avoid PEEP escalation

CCS pearl: In an ICU CCS case of decompensated PH — order continuous telemetry, arterial line, central venous access, lactate, BNP, troponin, ABG, echo, and consult pulmonary hypertension and cardiothoracic surgery for ECMO consideration; do not delay calling the PH center.

Refer to a PH expert center early:

Admit to hospital:

ICU admission indications:

Management priorities in PH crisis (treat the RV):

Key Differentials — Same-Category Causes (Within PH)

— Young woman, dyspnea, normal CXR/PFTs, low DLCO out of proportion

— Scleroderma features, HIV, methamphetamine use, family history (BMPR2)

— RHC: mPAP >20, PAWP ≤15, PVR >2 WU

— Echo: D-shaped LV, dilated RA/RV, normal LA size

— Older, obese, HTN, DM, AFib, CKD

— Orthopnea, PND, S3, basilar crackles

— Echo: LA enlargement, LVH, diastolic dysfunction, mitral/aortic valve disease

— RHC: mPAP >20, PAWP >15

— BNP elevated, but diuresis improves symptoms dramatically

— Smoking history, occupational exposure

— Hypoxemia, abnormal PFTs (obstructive, restrictive, or mixed)

— Imaging: emphysema, fibrosis, mosaicism

— Polysomnography for OSA

— PH typically mild-to-moderate; severe PH out of proportion to lung disease warrants specialist evaluation

— History of acute PE (only 25% recall it), antiphospholipid syndrome, splenectomy, indwelling lines, inflammatory bowel disease, thyroid replacement

— V/Q scan with segmental mismatched defects

— CTPA confirms chronic clot

— Treatable — and missing it is malpractice on the exam

— Sarcoidosis (hilar adenopathy, ACE elevation, granulomas on biopsy)

— Sickle cell disease

— Chronic hemolytic anemia

— End-stage renal disease on dialysis

— Fibrosing mediastinitis

— Glycogen storage diseases

Key distinction: PAWP is the single most important variable to separate pre-capillary (Group 1, 3, 4) from post-capillary (Group 2) PH. PAWP ≤15 = pre-capillary; PAWP >15 = post-capillary. Mismeasuring PAWP (catheter not wedged, or wedged in zone 1) leads to misclassification — always verify with simultaneous LVEDP or oximetry.

The most common Step 3 task is distinguishing among PH groups, because management diverges sharply.

Group 1 (PAH) clues:

Group 2 (left heart disease) clues — most common cause overall:

Group 3 (lung disease/hypoxia):

Group 4 (CTEPH):

Group 5 (multifactorial):

Key Differentials — Other-Category Causes of Dyspnea/Right Heart Strain

— Sudden-onset dyspnea, pleuritic chest pain, tachycardia, hypoxemia

— Elevated D-dimer, RV strain on echo, CTPA confirms

— Distinguish from chronic CTEPH by acuity and clot morphology

— Inferior STEMI with V4R ST elevation

— Hypotension with clear lungs, elevated JVD

— Cath shows RCA occlusion proximal to RV branch

— Fluid-responsive (unlike chronic PH)

— Beck triad, pulsus paradoxus, electrical alternans

— Echo: RA/RV diastolic collapse, plethoric IVC

— Differs from PH by pericardial physiology

— Equalization of diastolic pressures, square-root sign on RHC

— Pericardial calcification, prior TB/cardiac surgery/radiation

— Kussmaul sign, pericardial knock

— Bi-atrial enlargement, low voltage QRS with thick walls on echo (apical sparing in amyloid)

— Pyrophosphate scan, free light chains, cardiac MRI

— Subtype of Group 1' — distinct pathophysiology

— Clue: pulmonary edema after initiating PAH vasodilators, low DLCO, septal lines and centrilobular ground-glass nodules on HRCT, normal PAWP (occlusion is post-capillary at venule level)

— Requires urgent lung transplant referral

Board pearl: A PAH patient who develops pulmonary edema after starting a vasodilator — think PVOD. Stop the drug, evaluate for transplant.

Acute pulmonary embolism:

Acute coronary syndrome with RV infarct:

Cardiac tamponade:

Constrictive pericarditis:

Restrictive cardiomyopathy (amyloid, hemochromatosis, sarcoid):

Hyperthyroidism / high-output failure: Anemia, AV fistula, thyrotoxicosis, beriberi, Paget disease — wide pulse pressure, warm extremities, bounding pulses.

Anxiety/hyperventilation syndrome: Diagnosis of exclusion; normal echo and exercise testing.

Deconditioning, obesity hypoventilation syndrome: Common confounders.

Pulmonary veno-occlusive disease (PVOD) / pulmonary capillary hemangiomatosis:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Never interrupt parenteral prostacyclins — abrupt cessation causes rebound PH crisis. Educate patient and family on pump troubleshooting, backup cassette, 24/7 hotline

— Refill PAH medications via specialty pharmacy; verify insurance authorization before discharge

— Document REMS compliance (monthly pregnancy testing for ERAs in reproductive-age women)

— Treat HTN, DM, dyslipidemia per guidelines

— Smoking cessation — every visit

— Weight management; OSA evaluation if BMI elevated or symptoms

— CTEPH: lifelong anticoagulation (DOAC or warfarin per shared decision)

— Idiopathic PAH: selective use based on individual risk-benefit

— Group 2, 3, 5: no routine anticoagulation unless other indication (AFib, VTE)

— Loop diuretic (furosemide, torsemide) titrated to euvolemia; daily weights at home

— Add spironolactone for diuretic resistance or hypokalemia; monitor K and Cr

— Continuous O₂ if resting SpO₂ ≤88% or PaO₂ ≤55 mmHg

— Nocturnal O₂ if desaturation during sleep

— Ambulatory O₂ for exertional desaturation

— Annual influenza

— Pneumococcal (PCV15/PCV20 + PPSV23 per CDC)

— COVID-19 per CDC schedule

— RSV in eligible adults

— Tdap, zoster

— Sodium restriction (<2 g/day)

— Fluid restriction (1.5–2 L/day) if volume overload-prone

— Avoid pregnancy in Group 1; effective contraception

— Avoid high-altitude travel without supplemental O₂; commercial flights generally safe with portable O₂

— Avoid decongestants with sympathomimetics

— Goals of care, code status, palliative care referral in advanced disease

— Transplant evaluation when class III/IV despite optimal therapy

Step 3 management: At every outpatient visit document WHO functional class, 6MWD, BNP/NT-proBNP, and updated risk stratification — therapy escalation is driven by these metrics, not symptoms alone.

Disease-modifying therapy continuity:

Cardiovascular risk factor optimization:

Anticoagulation:

Diuretics:

Oxygen:

Vaccinations:

Lifestyle counseling:

Advance care planning:

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— Stable low-risk PAH: every 3–6 months at PH center

— Intermediate/high risk: every 1–3 months

— After therapy change: reassess within 3 months

— Post-hospitalization for decompensation: outpatient follow-up within 7–14 days

— WHO functional class

— 6-minute walk distance

— BNP/NT-proBNP

— Vital signs, weight trend, edema

— Medication adherence and side effects

— REMS pregnancy test (ERAs)

— Echo every 6–12 months or with clinical change (RV size/function, TAPSE, RA area, pericardial effusion)

— Repeat RHC when therapy escalation considered, clinical worsening unexplained, or before transplant listing

— Cardiac MRI optional for serial RV assessment

— Annual CBC (anemia, iron deficiency), LFTs (especially on bosentan/macitentan), CMP

— Supervised, low-to-moderate intensity aerobic + light resistance training

— Demonstrated to improve 6MWD, QoL, and WHO class

— Avoid heavy isometric exercise (Valsalva → syncope)

— Initial 8–12 weeks supervised, then home program

— Daily weights — call if >2 lb overnight or >5 lb/week

— Recognize early decompensation: increased dyspnea, leg edema, abdominal distension, syncope/presyncope

— Sick-day plan for nausea/vomiting (prostacyclin pump, hydration, dose adjustment)

— Depression and anxiety prevalence high; screen with PHQ-9, GAD-7

— Connect with PHA (Pulmonary Hypertension Association) support resources

— Caregiver education for pump care

— Shared care between PH center and primary care; clear communication on med changes

— Insurance and specialty pharmacy logistics — case manager involvement reduces interruption-related decompensations

Board pearl: A 6-minute walk distance <165 m or BNP >800 pg/mL signals high risk — escalate to parenteral prostacyclin and consider transplant referral.

Visit cadence:

At each visit, document:

Periodic studies:

Pulmonary rehabilitation:

Self-monitoring:

Psychosocial support:

Care coordination:

Ethical, Legal, and Patient Safety Considerations

— Pregnancy counseling in reproductive-age PAH patients is mandatory at every visit — document discussion of 25–50% maternal mortality, contraception options, and that elective termination is a clinically reasonable option. Failing to counsel may carry liability if a high-risk pregnancy proceeds without warning.

— IV prostacyclin initiation requires extensive consent: central line risks, infection, pump malfunction, and the fact that abrupt interruption can be fatal within minutes. Document teach-back.

— Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) require enrollment in REMS, monthly pregnancy tests, and dual contraception in reproductive-age women. Prescribers must be certified. Pharmacies cannot dispense without documentation.

— Methamphetamine-associated PAH — screen with urine toxicology; counsel cessation. Reporting requirements vary by state; some jurisdictions mandate reporting impaired drivers.

— HIV-related PAH — partner notification per state law; ART is standard of care regardless of CD4.

— Medication reconciliation at every transition — PAH-specific drugs are frequently omitted from hospital formularies and may be missed at admission or discharge. Missing a single prostacyclin dose can be fatal.

— Communicate directly with PH center on admission and discharge; do not adjust PAH medications without their input

— Post-discharge follow-up within 7–14 days; specialty pharmacy must be activated before discharge

— All elective surgery should be reviewed with the PH team

— Anesthesia mortality 4–7% for non-cardiac surgery — patient and family must understand this risk

— Continue PAH medications throughout the perioperative period

— Early palliative care integration for class III/IV patients

— Discuss code status, deactivation of prostacyclin pumps near end of life

— Lung transplant decision-making requires explicit informed consent about waitlist mortality, rejection, immunosuppression complications, and 5-year post-transplant survival (~55%)

— Delayed diagnosis disproportionately affects women, Black patients, and the uninsured. Address access barriers proactively; referral to PH center improves outcomes.

Step 3 management: A PAH patient on IV epoprostenol admitted for an unrelated issue → confirm pump function, ensure backup cassette and supplies, notify the PH center, and never hold the infusion during NPO status. This is a tested safety event.

Informed consent edge cases:

REMS program compliance:

Mandatory reporting and public health:

Transition-of-care risks (high Step 3 yield):

Perioperative safety:

End-of-life and goals of care:

Healthcare disparities:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: "Mean PAP >20, PAWP ≤15, PVR >2 WU" → memorize the pre-capillary triad. Recognizing this on an RHC table is the single most common PH question pattern on Step 3.

BMPR2 mutation — autosomal dominant, incomplete penetrance, 70% of heritable PAH and 20% of "idiopathic" PAH; genetic counseling for family

Scleroderma + dyspnea + low DLCO + normal lung volumes → PAH until proven otherwise; annual echo screening

Fenfluramine, dexfenfluramine, aminorex, methamphetamine, dasatinib → drug-induced PAH

Schistosomiasis — most common cause of PAH worldwide (not in US, but tested)

Loud P₂ + RV heave + clear lungs → think PAH

D-shaped LV on echo (septal flattening) = RV pressure overload

Bubble study positive → screen for ASD/PFO with shunt

Ortner syndrome → hoarseness from enlarged PA compressing recurrent laryngeal nerve

Graham Steell murmur → high-pitched early diastolic murmur of pulmonic regurgitation

CTEPH after PE → 2–4% of survivors; V/Q scan is screening test of choice

PTE is potentially curative for CTEPH — refer all candidates

Riociguat — contraindicated with PDE-5 inhibitors and nitrates

Epoprostenol half-life 3–5 min — abrupt interruption = death

REVEAL/ESC risk score variables: WHO class, 6MWD, BNP, RA pressure, cardiac index, mixed venous O₂, RA area, pericardial effusion

Pregnancy in PAH → 25–50% mortality; avoid combined OCPs (use IUD or progestin)

Eisenmenger syndrome → unrepaired left-to-right shunt → reversed to right-to-left with cyanosis and clubbing; survival better than other PAH

PVOD → flash pulmonary edema after PAH vasodilator initiation; HRCT shows septal lines + centrilobular nodules

Atrial septostomy = palliative bridge to transplant

High-altitude PH → Group 3

Sickle cell PH → TRV >2.5 m/s predicts mortality; Group 5

Sleep apnea–associated PH → CPAP first; PAH-specific drugs not indicated unless severe

Schistosomiasis, HIV, portopulmonary, drugs/toxins, CTD → all WHO Group 1 etiologies

Group 2 PH is the most common in clinical practice; Group 1 is the most tested

Acute vasoreactivity testing only for idiopathic, heritable, and drug-induced PAH — never for Groups 2–5

Board Question Stem Patterns

— 50-year-old woman with sclerodactyly and Raynaud presents with 6 months of progressive dyspnea. CXR clear, PFTs show low DLCO with preserved spirometry. Next step → TTE; if elevated TRV → RHC.

— 32-year-old woman with exertional syncope, loud P₂, RV heave, and JVD. Echo shows D-shaped LV and severe TR. Next step → V/Q scan to exclude CTEPH, then RHC.

— 60-year-old man 6 months after a "treated" PE, now with worsening exertional dyspnea. Echo: PASP 70. Diagnosis → CTEPH. Next step → V/Q scan, then refer for pulmonary thromboendarterectomy. Anticoagulate for life.

— Patient on sildenafil for PAH presents to ED with chest pain; nitroglycerin given → profound hypotension. Mechanism → PDE-5 inhibitor + nitrate. Or: PAH patient started on riociguat while still on sildenafil → hypotension. Stop riociguat.

— 72-year-old obese woman with HTN, DM, AFib, and exertional dyspnea. Echo shows elevated PASP, LA enlargement, and diastolic dysfunction. Diagnosis → Group 2 PH. Do NOT start sildenafil. Treat HFpEF: diuresis, BP control, SGLT2 inhibitor, weight loss.

— 28-year-old with idiopathic PAH asks about pregnancy. Counsel against pregnancy; offer IUD; avoid estrogen-containing contraception.

— PAH patient with sepsis, hypotension, rising lactate. Vasopressor of choice → norepinephrine; add dobutamine or milrinone for RV inotropy; inhaled NO; avoid aggressive fluids.

— PAH patient started on epoprostenol → develops pulmonary edema within hours. Diagnosis → PVOD. Stop vasodilator; transplant referral.

— RHC during NO challenge: mPAP falls from 55 to 35 with preserved CO. Treatment → high-dose CCB (nifedipine, diltiazem, or amlodipine — not verapamil).

— Woman on bosentan presents for routine visit. Required → monthly pregnancy test, LFTs, dual contraception, REMS documentation.

Step 3 management: When a stem describes "PH on echo," your reflex sequence is V/Q scan → PFTs → polysomnography → RHC with appropriate WHO group classification before any therapeutic decision.

Pattern 1 — The dyspneic scleroderma patient:

Pattern 2 — The young woman with syncope:

Pattern 3 — The post-PE patient with persistent dyspnea:

Pattern 4 — The wrong-drug trap:

Pattern 5 — The HFpEF mimic:

Pattern 6 — Pregnancy in PAH:

Pattern 7 — Decompensated RV failure in ICU:

Pattern 8 — PVOD trap:

Pattern 9 — Vasoreactivity responder:

Pattern 10 — REMS compliance:

One-Line Recap

Pulmonary hypertension is mPAP >20 mmHg confirmed by right heart catheterization, classified into five WHO groups whose management diverges entirely — Group 1 PAH gets pulmonary vasodilators at a PH center, Group 2 gets left-heart therapy, Group 3 gets oxygen and lung disease control, Group 4 (CTEPH) gets lifelong anticoagulation plus surgical thromboendarterectomy, and Group 5 gets treatment of the underlying disorder.

Workup reflex: Echo → BNP, CTD serologies, HIV, LFTs → V/Q scan (mandatory to exclude CTEPH) → PFTs + DLCO → polysomnography if indicated → RHC for confirmation and PAWP-based classification. Pre-capillary = mPAP >20, PAWP ≤15, PVR >2; post-capillary = PAWP >15.

Therapy reflex: Vasoreactivity testing only for idiopathic/heritable/drug-induced PAH; positive responders get high-dose CCB. All others get ERA + PDE-5 inhibitor as initial dual therapy, with parenteral prostacyclin (epoprostenol) added for high-risk or class IV disease. Never combine riociguat with a PDE-5 inhibitor or nitrates.

Special situations: Avoid pregnancy in Group 1 (25–50% mortality); use IUD or progestin-only contraception. Refer CTEPH for PTE — potentially curative. PVOD presents as pulmonary edema after vasodilator initiation. Manage acute RV failure with norepinephrine, dobutamine/milrinone, and inhaled NO — not aggressive fluids.

Step 3 thread: Classify before treating, document WHO class and 6MWD at every visit, reconcile PAH medications at every transition of care, and refer to a PH expert center early — the wrong drug given to the wrong WHO group is a fatal and frequently tested error.