Pulmonary Hypertension

Best Method for Mx of PHTN isPREVENTION

Conditions associated with PAH Acyanotic CHD

Increased Pulmonary Blood Flow Cyanotic CHD

Increased Pulm Blood Flow

CLASSIFICATION OF CHD

ACYANOTIC Increased PBF

ATRIAL: ASD VENTR: VSD ARTERIAL: PDA COMBINED:

VSD+PDA No Shunts

Pulm or Aortic Stenosis

CYANOTIC Decreased Flow

TOF Pulm Atresia

Increased Flow TAPVD TGA Truncus Tricuspid Atresia

So what is the right time to operate in these conditions

Timing of surgery: Acyanotic

ASD: 2 years or later

VSD Large: 3-6 months Moderate: when there is FTT Small: when there is AI or

InfectiveEndocardiaits

Acyanotic, when to operate PDA

Infancy ALL PDA’S CAN BE CLOSED WITH DEVICE

Neonatal Prematurity

Closure by surgical ligation Full Term

Wait for child to grow if possible

ATRIAL SEPTAL DEFECTPRIMUM SINUS

VENOSUS

ATRIAL SEPTAL DEFECT-II

ATRIAL SEPTAL DEFECT-II

ASD-DEVICE

Acyanotic CHD Increased Pulmonary Blood Flow

PRETRICUSPID SHUNT: RA RV DILATATION ATRIAL SEPTAL DEFECT

POST TRICUSPID SHUNT: LA V DILATATION VENTRICULAR SEPTAL DEFECT

PATENT DUCTUS ARTERIOSUS

What is a Large, Moderate, Small VSD Effects of VSD

PRESSURE EFFECT: Pulmonary Hypertension

VOLUME EFFECT: Cardiac enlargement

Pressure Effect: Types Flow Related PAH: Reversible

Irreversible PAH due to permanent Changes

Flow Related PAH Increased Flow Increased Pressure

When you remove the extra flow ie close the VSD, the Pulmonary Pressure comes back to normal

Flow related PAH (Pre/Post Tricuspid Shunt) Symptoms of increased Flow

Tachypnea, Rec infections, failure to thrive Signs

Tachycardia, Harrison’s sulcus, retractions X-ray

Cardiac enlargement, Increased Pulmonary Blood Flow

Increased Flow PAH All these indicate

Patient is operable with good results without post-op PAH

Till when is this phase: Reversible PAH

VSD-LARGE: UPTO 6 MONTHS

PDA-LARGE: UPTO 6 MONTHS

ASD: LARGE: UPTO LATER 4-8 YRS

So, What is a Large Shunt Post tricuspid Large VSD/PDA

Clinically PAH Present (Pressure Effect)

Clinically Volume Effect Present (Cardiac Enlargement)

Moderate Shunt No Pressure Effect

But Volume Effect Present

Small Shunt No Pressure or Volume Effect

No Symptoms or Signs of increased flow

So if the surgery is done at the right time it is likely the patient will not get pulmonary hypertension

What Happens when Reversible PAH starts becoming

Irreversible

…the child shows some signs and these are signs of Post Op PAH

Signs of Reversible to Irreversible PAH Symptoms:

Start improving Less FTT Less Infectios Less tachypnea

Signs: Murmur shorter, P2 Louder, Cardiac

Enlargement less

When Reversible Changing to Irreversible Patient still operable

But the post op risks are more and episode of life threatening PAH in immediate post op period is high

When Completely Irreversible Patient now has Eisenmanger’s

Decreased Pulm Blood Flow

Cyanosis starts

Now risk of surgery more than living without surgery

Chest Xrays Indicating Increased PBFw PAH ie operability

VSD

ASD

MODERATE VSD

LARGE VSD LARGE SHUNT

AV CANAL

TGA

TRUNCUS

EISENMANGERS

Pulmonary Hypertension

ClassificationGroup 1 PAH Examples: "Pulmonary arterial

hypertension". 1. Idiopathic (IPAH) 2. Familial (FPAH) 3. Associated with (APAH):

Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension HIV infection Drugs and toxins Other (thyroid disorders, glycogen storage disease, Gaucher disease,

hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)

4. Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis (PCH)

5. Persistent pulmonary hypertension of the newborn

ClassificationGroup 2 PH — "Pulmonary venous

hypertension".Examples:

1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease

Group 3 PH — "Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia".

Examples: 1. Chronic obstructive pulmonary disease 2. Interstitial lung disease 3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude 6. Development abnormalities

ClassificationGroup 4 PH — "Pulmonary hypertension caused

by chronic thrombotic or embolic disease". Examples:

1. Thromboembolic obstruction of proximal pulmonary arteries

2. Thromboembolic obstruction of distal pulmonary arteries 3. Non-thrombotic pulmonary embolism (tumor, parasites,

foreign material)Group 5 PH — These patients have PH caused by

inflammation, mechanical obstruction, or extrinsic compression of the pulmonary vasculature (eg, sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels by adenopathy, and fibrosing mediastinitis).

Histologically Speaking The above mechanisms all cause

small muscular arteries and arterioles to undergo intimal hyperplasia and medial hypertrophy 1

Narrowed lumen

Decreased cross-sectional area

Increased resistance1 - Though again with PPH likely primary process, rather than reactive

PULMONARY VASODILATION HYPEROXIA HYPOCARBIA ALKALOSIS

NON REM SLEEP SEDATED PARALYSED

Basic 3 Mechanisms2º pulmonary arterial hypertension:

Reduced cross-sectional area of pulmonary vasculature, secondary to: Occlusion of vessels (e.g. emboli) Primary disease of pulmonary vasculature walls (e.g.

1º pulmonary hypertension, portal hypertension) Primary parenchymal disease (e.g. interstitial lung

disease, emphysema) Vasoconstriction 2/2 hypoxia or acidosis

Increased flow through pulmonary vascular bed secondary to left to right shunts

Increased “back pressure” secondary to pulmonary venous hypertension

3 types of abnormalities Maladaptation

Maldevelopment

Underdevelopment

Maladaptation Prototype: Meconium aspiration pneumonia Pneumonia, RDS

Obstruction of the airways Chemical pneumonitis Release of endothelin,thromboxane

vasoconstrictors

Maldevelopment Prototype: Idiopathic PPHN (“black lung” PPHN) Vessel wall thickening Smooth muscle hyperplasia Cause – intrauterine exposure to NSAID constriction of ductus

arteriosus genetic

Disruption of NO-cGMP pathway Disruption of PGI2-cAMP pathway Guanylate cyclase is less active Increased ROS (reactive oxygen

species) vasoconstrictor Increased thromboxane, endothelin

Maldevelopment

Underdevelopment Prototype: Congenital diaphragmatic

hernia Pulmonary hypoplasia Decreased cross sectional area of

pulmonary vasculature Decreased pulmonary blood flow Abnormal muscular hypertrophy of the

pulm arterioles

MEDIATORS OF PULMONARY HYPERTENSION Prostacycline Thromboxane A2 Endothelin-1 Nitric Oxide (NO) Serotonin Adrenomedullin Vasoactive Intestinal Peptide (VIP) Vascular Endothelial Growth Factor

(VEGF)

ENDOTHELIN-1 Potent vasoconstrictor Stimulates proliferation of smooth

muscle cells in PA Plasma levels increased in PHT Level inversely proportional to

pulmonary blood flow & CO - ? Direct effect

VASODILATORS Oxygen CCBs Endothelin-receptor antagonists BNP Calcitonin gene-related peptide

Bosentas

ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelin-1 overexpressed in PHT

Improve pulmonary haemodynamics, exercise capacity, functional status, clinical outcomes

Bosentas, sitaxentan and ambrisentan

BOSENTAS Sulphonamide-based ETA & ETB receptor

blocker Inducer of

CYP2C9 - Vori/ fluconazole, warfarin, digoxin, simvastatin, tac/ sirolimus, sildenafil, OCP

CYP3A4 – ketaconazole t½ 5.6 +/- 1.6 hours

PHOSPHODIESTERASE INHIBITORS Sildenafil

PDE type5 inhibitor Reduce metabolism of cGMP t½ 3-5 hours CYP3A4 & 2C9 substrate Concentration increased by concurrent

bosentan – I/As nitrates Tadalafil

t½ 17 hours CYP 3A4

PROSTACYCLINE ANALOGUES Vasodilators

Reduce R & L afterload & increase SV & CO

Platelet aggregation inhibitors

Main ADRs H/A and dizziness (~80%) Nausea and jaw pain

PROSTACYCLINE ANALOGUES Iloprost

IV or Inhaled I/As with CCBs, BBs and ACEIs (animal

data) NO PK STUDIES FOLLOWING INHALATION!! t½ ~ 0.7 hours

Treprostinol IV or s/c injection No CYP inhibition - ? induction t½ 2-4 hours

Epoprostenol Continuous IV infusion F 0.2/ t½ 2-6 mins Spontaneous B/D to 6-oxo-prostaglandin

F1α

WHERE TO NOW? PDE5 inhibitors & ERAs first line for

1oPHT

Increasing evidence that combination therapies are more effective (theoretical)

Nitric OxideSelective pulmonary vasodilation,

improves oxygenation↑ cGMPUsed in ARDS, PPHN, cardiogenic

shock, post CPBRisks: methemoglobinemia and

carboxyhemoglobinemia, rebound pulm HTN when stopped

Requires closed inhalational circuit

Phosphodiesterase inhibitors Inhibition of nitric oxide degradation Sildenafil (PDE-5 inhibitor): ↓ PAP/PVR

Min effects on systemic vasculature Synergistic with NO Reduction in RV mass: role in prevention

or reversal of remodeling of RV Milrinone (PDE-3 inhibitor): ↓

PVR/PAP/SVR in setting of CV shock Nebulized minimizes systemic

vasodilation

Prostacyclins Potent pulm and systemic

vasodilators with antiplatelet properties Epoprostenol (IV): ↓ PVR, better CO/ex.

Tolerance s/e: ↓BP, need for central line (risk of

infection) Beraprost (PO): Longer duration Iloprost (nebulized)

Endothelin receptor antagonists Endothelin-1: neurohormone that causes

pulm vasoconstriction, smooth muscle proliferation, fibrosis Stimulates endothelin receptors A & B A: vasconstriction B: vasodilation Nonselective: Bosentan A selective: sitaxsentan, ambrisentan Chronic pulm htn tx given long ½ life and no

IV preparation s/e: hepatic toxicity

BOSENTAS

BOSENTAS

BOSENTAS

BOSENTAS

BOSENTAS

BOSENTAS

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BOSENTAS

DEFINITION Pulmonary hypertension is mean

pulmonary artery pressure greater than 25mmHg at rest or greater than 30mmHg with exercise