Pah management

PH MANAGEMENT
Dr. Abhinav Agarwal

 Median survival:
 Adults- 2.8 years
 Pediatric – 10 months
 Improved after newer therapies.
 80 -90 % at 1 year
 At 5 years: 75% in IPAH, 57% in associated PAH
 Incidence of IPAH = 0.48 per million
 Prevalence = 2.1 per million.

Clinical Presentation:
 Initial symptoms - induced by exertion.
 Shortness of breath
 Fatigue
 Weakness
 Angina
 Syncope.
 Less commonly - dry cough and exercise-induced nausea and
vomiting.
 Symptoms at rest occur only in advanced cases.
 RV failure. - Abdominal distension and ankle oedema

 Mechanical complications of PA
dilatation:
 Compression of the left recurrent
laryngeal nerve
 Large airway compression
 Compression of the left main
coronary artery.
 Haemoptysis related to rupture
of hypertrophied bronchial
arteries
 Rupture or dissection of PA.

Physical Signs:
 Left parasternal lift
 Loud P2
 RV third heart sound
 PSM of tricuspid regurgitation
 Diastolic murmur of pulmonary regurgitation
 Elevated jugular venous pressure
 Hepatomegaly, ascites, peripheral oedema
 Wheeze and crackles are usually absent.
 Digital clubbing - PVOD, cyanotic CHD, interstitial lung
disease or liver disease

 Telangiectasia, digital ulceration and sclerodactyly-
scleroderma
 inspiratory crackles - interstitial lung disease
 spider naevi, testicular atrophy, and palmar erythema –
CLD

Electrocardiogram
 Abnormal ECG –
 severe PH.
 P pulmonale
 Right axis deviation,
 RV hypertrophy
 RV strain
 RBBB
 Supraventricular arrhythmias
 Upright T wave in V1 (7 days to 7 years)
 QRS and QTc prolongation - severe disease
 Ventricular Arrythmia - Rare
 ECG differential diagnosis
 Anterolateral myocardial ischaemia. - rarely cause RAD

CXR:
 Central pulmonary arterial
dilatation, with ‘pruning’
 Right atrium (RA) and RV
enlargement
 Signs suggesting lung disease
(group 3)
 Pulmonary venous congestion
due to LHD (group 2).
 Degree of PH does not
correlate with the extent of
radiographic abnormalities.

Pulmonary Function Test and ABG:
 Reduction of lung volumes related to disease severity.
 Decreased lung diffusion capacity for carbon monoxide
(DLCO). (May be Normal also)
 Differential diagnosis of a low DLCO in PAH
 PVOD
 PAH associated with scleroderma
 Parenchymal lung disease
 Alveolar hyperventilation at rest- PaO2 normal, PaCO2
decreased

ECHO:
 Estimation of systolic PAP
 Peak TR + RAP
 RAP
 IVC diameter <2.1 cm with collapsibilty >50%  0–5 mmHg
 IVC diameter >2.1 cm with collapsibility <50% on sniff or <20% on
quiet inspiration  10–20 mmHg
 Not fitting  5–10 mmHg
 PH cannot be reliably defined by a cut-off value of TRV.
 Not suitable for screening for mild, asymptomatic PH
 Echocardiographic result is required to decide the need
for cardiac catheterization in individual patients.

ECHO:
Probability of PH to be judged as high,
intermediate and low:

 Systolic PA pressure:
 4(TR max)²+mean RA pressure (mRAP)
 SPAP=SBP − 4V (VSD) max² (for left to right shunts)
 SPAP=SBP+4V (VSD) max² (for right to left shunts)
 Diastolic PA pressure:
 DPAP=4V(EDV of PR)² + RA pressure
 Mean PA pressure:
 mPAP=4V(PV of PR)² + RA pressure

Ventilation/perfusion lung scan
 To look for CTEPH.
 Higher sensitivity compared with CT pulmonary
angiogram (CTPA),
 Excludes CTEPH with a sensitivity of 90–100% and a
specificity of 94–100%
 Unmatched perfusion defects may also be seen in
PVOD.
 CT is preferred as readily available.
 MR - assess both ventilation and perfusion in CTEPH

High-resolution computed tomography
 Diagnose PAH - PA or RV enlargement
 Identify a cause of PH
 CTEPH
 lung disease
 PVOD
 PCH
 Provide prognostic information
 CT may raise a suspicion of PH in those examined for unrelated
indications
 Collaterals from bronchial arteries can be identified
 Angiography - evaluation of possible vasculitis or pulmonary
arteriovenous malformations

Cardiac magnetic resonance imaging
 Identification of PAH:
 Presence of late gadolinium enhancement
 PA distensibilty
 Suspected CTEPH, in pregnant women, young patients or
when iodine-based contrast media injection is contraindicated
 CMR prognostic markers:
 Increased RV volume
 Reduced LV volume
 Reduced RV ejection fraction
 Reduced stroke volume.

Blood tests and immunology
 Identify Aetiology & end organ damage.
 Routine biochemistry, haematology
 Liver function tests may be abnormal
 High hepatic venous pressure
 liver disease
 Endothelin receptor antagonist (ERA) therapy.
 Hepatitis serology
 Thyroid disease considered in cases of abrupt deterioration.
 Serological testing - CTD, hepatitis and HIV.
 CTEPH - thrombophilia screening
 HIV testing
 NT-proBNP
 Coagulation studies
 Connective tissue disease workup

Right heart catheterization:
 To confirm the diagnosis of PAH and CTEPH
 To assess the severity of haemodynamic impairment
 To undertake vasoreactivity testing of the pulmonary
circulation
 Left heart catheterization in addition to RHC:
 Clinical risk factors for coronary artery disease or heart failure with
preserved ejection fraction
 Echocardiographic signs of systolic and/or diastolic LV dysfunction.
 Specific recommendations for catheterization of patients with LHD or
lung disease

Vasoreactivity Testing:
 Pulmonary vasoreactivity testing - only for patients with IPAH, HPAH or
drug-induced PAH.
 Drugs used
 Inhaled NO at 10–20 ppm - standard of care
 i.v. epoprostenol
 i.v. adenosine
 inhaled iloprost
 The use of CCBs, O2, PDE-5 inhibitors or other vasodilators is discouraged.
 Positive acute response is defined as:
 20% decline in mPAP and PVRI (Pediatric)
 reduction of mPAP ≥10 mmHg to reach an absolute value of mPAP ≤40 mmHg.
 In patients with LHD, PAWP may be reduced to <15 mmHg with diuretics.
 A fluid bolus of 500 ml may discriminate patients with PAH from those with LV
diastolic dysfunction

 Derived variables calculated from the RHC
measurements:
 Transpulmonary pressure gradient (TPG)
 PVR.
 DPG between the mean PAWP and diastolic PAP
 Coronary angiography
 presence of angina
 coronary artery compression by an enlarged PA
 risk factors for coronary artery disease
 listing for PEA or lung transplantation.

Recommendations for RHC:
 To confirm the diagnosis of pulmonary arterial
hypertension and type of PH
 To assess the treatment effect of drugs and before
therapeutic decisions
 In patients with congenital cardiac shunts to support
decisions on correction
 In patients with left heart disease (group 2) or lung disease
(group 3) if organ transplantation is considered

Prognostic Markers in RHC:
 RA pressure
 Cardiac index (CI)
 Mixed venous oxygen saturation (SvO2)
 PVRI
 Acute Vasodilator Response
 PAPm provides little prognostic information (except for
CCB responders)

Genetic Testing:
 Sporadic or familial PAH or PVOD/PCH
 BMPR2 mutation screening (point mutations and large
rearrangements)
 ACVRL1 and ENG genes screening : When BMPR2 mutation -ve
 familial PAH patients
 in IPAH patients <40 years old
 family history of hereditary haemorrhagic telangiectasia,
 Rare mutations may be considered (KCNK3, CAV1, etc.).
 Presence of a bi-allelic EIF2AK4 mutation is sufficient to confirm a
diagnosis of PVOD/PCH without performing lung biopsy

 Systolic PAP (PAPs) at rest
 Not prognostic and not relevant for therapeutic decision
 Increase in PAPs does not necessarily reflect disease
progression
 Decrease in PAPs does not necessarily signal improvement
 Increase of PAPs > 30 mmHg during exercise (contractile
reserve)
 reflects better RV function
 better long-term outcome

Exercise Capacity:
 The 6-minute walking test (6MWT)
 Submaximal exercise test
 Must always be interpreted in the clinical context
 6MWD Influenced by: sex, age, height, weight, comorbidities, need
for O2, learning curve and motivation.
 No single threshold that is applicable for all patients
 Cardiopulmonary exercise testing (CPET)
 Maximal exercise test
 Typical pattern:
 low end-tidal pCO2
 low peak oxygen uptake (peak VO2)
 high ventilatory efficiency ratio (VE/VCO2)
 low oxygen pulse (VO2/HR)

Biochemical Markers:
 No specific marker for PH
 Markers of vascular dysfunction
 Asymmetric dimethylarginine (ADMA)
 Endothelin-1
 Angiopoeitins
 Von willebrand factor
 Markers of inflammation
 C-reactive protein
 Interleukin 6
 Chemokines
 Markers of low co and/or tissue hypoxia
 Pco2
 Uric acid
 Growth differentiation factor 15 (GDF15)
 Osteopontin

 Markers of secondary organ damage
 Creatinine
 Bilirubin
 Markers of myocardial stress
 Atrial natriuretic peptide
 Troponins
 Brain natriuretic peptide (BNP)/ NT-proBNP
 Correlate with myocardial dysfunction.
 BNP have correlation with pulmonary haemodynamics and is less affected
by kidney function
 NT-proBNP seems to be a stronger predictor of prognosis
 BNP >130pg/ml – increased risk of death and transplant

Risk Assessment:
 Important questions to be addressed at each visit
 (i) is there any evidence of clinical deterioration since the last
assessment?;
 (ii) if so, is clinical deterioration caused by progression of PH
or by a concomitant illness?;
 (iii) is RV function stable and sufficient?
 (iv) Does the patient meet the low-risk criteria?

 Basic Assessment:
 Determination of functional capacity
 Exercise capacity : 6MWT or CPET
 RV Function: BNP/ NT ProBNP/ Echocardiography
 Complications: ECG, ABG, RFT, LFT, PT INR (if on warfarin)
 Once a year or on Clinical Deterioration:
 Troponin
 Iron Status
 Thyroid function
 RHC can be considered

Growth Failure to thrive
mPAP/mSAP <0.75 >0.75
PVRI >20WUm²
Acute Vasoreactivity present absent

 Not all variables may be in the same risk group
 The individual risk is further modified by:
 Co-morbidities
 Age
 Sex
 Background therapy
 PAH subtype
 Treatment goal : achieving a low risk status

Therapy:
 Three main steps:
 General measures
 Supportive Treatment
 Drug Therapy:
 High-dose CCB in vasoreactive patients
 Other drugs for non-vasoreactive patients
 Inadequate response
 Combinations of drugs
 Lung transplantation

General measures:
 Physical activity and supervised rehabilitation
 Activity within symptom limits.
 Trained PAH patients have higher levels of physical activity and better
quality of life.
 Pregnancy:
 62% pregnancies were successful
 17% Maternal mortality
 Termination of the pregnancy should be discussed.

 Contraception:
 Barrier contraception
 Progesterone-only preparations (bosentan reduces efficacy of OCP)
 Intrauterine coil may rarely lead to a vasovagal reaction, which may be
poorly tolerated in severe pah
 Elective surgery,
 Epidural is better tolerated than GA
 Infection prevention
 Pneumonia causes death in 7% patients
 Pneumococcal and influenza vaccine recommended
 RSV prophylaxis

 Psychosocial support
 Genetic counselling
 In-flight O2 administration
 WHO-FC III and IV
 Arterial PO2 < 60 mmHg
 Anaemia and iron status:
 Associated with reduced exercise capacity and with higher mortality

 Supportive therapy
 Oral anticoagulants: IPAH, HPAH and PAH due to anorexigens
 Target INR = 1.5 – 2.0
 Diuretics: signs of RV failure and fluid retention
 O2:
 Long-term O2 therapy is not beneficial
 Nocturnal O2 therapy does not modify the natural history of Eisenmenger
syndrome. (may improve symptoms)
 PO2 < 60 mmHg or < 91% SpO2.
 Digoxin: PAH who develop atrial tachyarrhythmia
Patients with RV Failure

Drug Therapy:
 Calcium channel blockers:
 Bradycardia – Nifedipine, Amlodipine
 Tachycardia - Diltiazem
 Start with an initial lower dose and increase cautiously to the max tolerated dose
 If no response- additional PAH therapy
 Combination required if clinical deterioration on CCB withdrawal
 Vasodilator responsiveness does not predict a favourable long-term response to
CCB therapy in patients with CTD, HIV, porto-pulmonary hypertension (PoPH)
and PVOD
 C/I= low cardiac output, high RAP

 Prostacyclin analogues:
 Beraprost:
 Improvement in exercise capacity persists up to 3–6 months.
 No long-term outcome benefits.
 Epoprostenol: continuous administration by infusion pump.
 Improves symptoms, exercise capacity and haemodynamics
 Only treatment shown to reduce mortality in IPAH
 Initiated at a dose of 2–4 ng/kg/min, optimal dose 20 and 40 ng/kg/min
 Abrupt interruption of the epoprostenol infusion - rebound PH
 Iloprost: i.v., oral or aerosol administration.
 Treprostinil: i.v. and subcutaneous routes

 Prostacyclin receptor agonists: Selexipag
 Selective prostacyclin IP receptor agonist
 Reduces morbidity and mortality endpoint
 Endothelin receptor antagonists:
 Ambrisentan: binds to ER type A.
 Bosentan: Both endothelin receptor type A and B antagonist
 10% patients have reversible liver damage
 Macitentan: Dual ERA
 No liver toxicity
 Showed improvement in exercise capacity, FC, haemodynamics,
echocardiographic and Doppler variables and time to clinical worsening.

 Phosphodiesterase type 5 inhibitors:
 Sildenafil:
 orally TDS
 Max dose: : 10 mg/dose @ wt 8–20 kg, 20 mg/dose >20 kg or 1mg/
kg/dose
 Tadalafil: OD Dose
 Vardenafil: BD Dose
 Down titrate from high dose
 Favourable results on exercise capacity, symptoms, haemodynamics
and time to clinical worsening
 Guanylate cyclase stimulators:
 Riociguat: Favourable results on exercise capacity, haemodynamics, WHO-
FC and time to clinical worsening.

 Experimental compounds and strategies:
 Unsatisfactory results
 Inhaled VIP
 Tyrosine kinase inhibitors
 Serotonin antagonists.
 Earlier stage of development:
 Rho kinase inhibitors - Fasudil
 VEGF receptor inhibitors
 Angiopoietin-1 inhibitors
 Elastase inhibitors
 Tacrolimus
 Gene therapy
 Stem cell therapy
 PA denervation by a radiofrequency ablation catheter.

Combination therapy:
 Combination therapy may be applied sequentially or
initially
 Goal-oriented therapy v/s non-structured approaches
 Goals:
 WHO-FC I or II,
 Near-normalization of resting CI
 Near-normalization of NT-ProBNP plasma levels

Surgical Decompression:
 Ballon Atrial Septostomy
 Ductal stenting
 Potts Shunt

Balloon Atrial Septostomy:
 Decompress the right heart chambers (decrease in RAP)
 Increase LV preload and CO
 Improves systemic O2 transport despite arterial O2 desaturation
 Decreases sympathetic hyperactivity
 Improvement in 6MWD
 Diastolic Pop off
 Avoided in
 Mean RAP >20 mmHg
 Spo2 <85% on room air at rest
 Indicated in
 NYHA IV refractory to medical therapy
 Severe syncopal symptoms
 Awaiting lung transplantation

Pott’s Shunt
 Systolic Pop off
 Decreases RV afterload
 Increases RV Function
 Maintenance of upper body saturation
 Indication:
 RH Failure not responding to other therapies

ICU Management:
 Treatment of triggering factors (anaemia, arrhythmias, infections or
other co-morbidities)
 Optimization of fluid balance (usually with i.v. diuretics)
 Reduction of RV afterload (parenteral prostacyclin analogues)
 Improvement of CO with inotropes (dobutamine)
 Maintenance of systemic blood pressure with vasopressors
 Intubation should be avoided in patients
 Veno-arterial extracorporeal membrane oxygenation (ECMO)

Transplantation:
 Survival :
 52– 75% at 5 years
 45–66% at 10 years
 Median survival = 5.8 years
 Listing:
 Inadequate clinical response on max combination therapy
 Probability of 2 year survival without transplant ≤50%
 Listed at Diagnosis:
 PAH associated with CTD
 PVOD
 PCH

Complications:
 Arrhythmias:
 Ventricular arrhythmias rare (Except LHD)
 SVT annual incidence of 2.8%
 Persistent atrial fibrillation 2-year mortality >80%
 Indication for oral anticoagulation
 Haemoptysis
 Prevalence 1% to 6%
 Bronchial artery embolization - acute emergency procedure
 Mechanical complications:
 PA aneurysms, rupture and dissection
 Compression of left main coronary artery, pulmonary veins, main
bronchi and the recurrent laryngeal nerves

Poor Prognostic Markers:
 Clinical RV failure
 Progression of symptoms
 WHO-FC III/IV
 Elevated BNP levels
 Failure to thrive
 PAP :systemic artery pressure ratio
 RAP >10 mmHg
 PVR index >20 WU/m2

PAH in CHD:
 No prospective data are available on the
usefulness of vasoreactivity testing,
closure test or lung biopsy for operability
assessment.
 Phlebotomy - hct >65%.
 CCBs not used in Eisenmenger
 Bosentan - improves exercise capacity and
quality of life
 ‘Treat-to-close’ concept, is not supported
 PAH completely reversible if repaired <
9month of age
 Residual PAH if operated after 2 years

Cath
PVRI< 6WU m²
PVR/SVR <0.3
Operate
PVRI > 6WUm²
PVR/SVR >0.3
Vasoreactivity
testing
Reactive
Operate with
Post op PAH
management
Non reactive
PH therapy and
repeat cath after
3 months
Reactive
High risk,
consider
fenestration
Non reactive Inoperable

PAH in Portal Hypertension:
 Different From Hepatopulmonary syndrome
 1–5% develop PAH
 Not necessarily with the presence of liver disease.
 Beta-blockers, used to lower the portal pressure
 Not to be used in patients with PAH
 Mortality rate
 100% - PAPm ≥50 mmHg
 50% - PAPm 35 - 50 mmHg
 Liver transplantation - screened for PH
 Pretreating these patients with PAH drugs might improve
the outcome after liver transplantation

PAH with HIV:
 Anticoagulation is not routinely recommended
 Non-responders to acute vasodilator challenge – No CCBs
 Sildenafil, the dose should be reduced if ritonavir and
saquinavir are co-administered
 Exclusion criterion for lung transplantation

PAH in Hemoglobinopathies:
 Sickle cell Disease- PAH 30%
 PAH increases mortality

Pulmonary Veno occlusive Disease and
Pulmonary Capillary Hemangiomatosis:
 PCH + - in 73% of PVOD , PVOD + - in 80% of PCH
 PCH could be a secondary angioproliferative process caused by post-capillary obstruction
 Bi-allelic mutations in EIF2AK4. (Autosomal Recessive) sufficient to confirm
 Lung biopsy - the gold standard
 PVOD/PCH are more severely hypoxaemic than in other forms of PAH
 PAWP is normal, because the pathological changes occur in small venule and capillaries
 Vasoreactivity testing may be complicated by acute pulmonary oedema
 No established therapy- Lung Transplantation, Interferon α- 2a (under Trial)

PH due to Left Heart Disease:
 ‘Passive’ PH - TPG <10 mmHg and PVRI < 5WUm²
 ‘Reactive’ PH - TPG ≥10 mmHg and PVRI > 5WUm²
 Superimposed component leading to vascular remodelling
 Treatment:
 PAH drugs not recommended
 Repair of valvular heart disease
 Aggressive therapy for heart failure
 Not enough evidence to support the use of drugs

PH due to Lung Disease
 Indications for RHC
 (i) Clinical detrioration not related to airway disease
 (ii) PH despite adequate t/t of lung disease
 (iii) Unexplained recurrent pulmonary edema
 (iv) Chronic PH drug therapy
 Cath done only if therapeutic consequences are expected
 Long-term O2 therapy
 Treatment of the underlying lung disease
 Drugs not recommended for patients with PH due to lung
disease
 PAH in addition to lung diseases treated according to the
recommendations for PAH

PH in CTEPH
 Incidence 0.1–9.1% within the first 2 years after a symptomatic PE event
 Routine screening for CTEPH after Pulmonary Embolism is not supported
 Paediatric cases are rare.
 Median time -14 months between symptom onset and diagnosis
 Oedema and haemoptysis more often
 Planar V/Q lung scan or CT pulmonary angiography
 RHC - pulmonary angiography
 Ring-like stenosis
 Webs (‘slits’), pouches
 Wall irregularities
 Complete vascular obstructions
 Bronchial collaterals
 Treatment:
 Pulmonary Endarterectomy
 Non operable : Riociguat.
Balloon Pulmonary Angioplasty

Pah management

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