Pulmonary Hypertension

-Definition:

.It represents a heterogeneous group of disorders sharing common histological abnormalities and patho-physiology; and is characterized by a progressive increase in pulmonary vascular resistance (PVR = >120 dynes/sec/cm⁵) and mean pulmonary artery pressure (PAP = > 25 mmHg at rest or 30 mmHg with exercise, as measured by right heart catheterization) with normal pulmonary artery wedge pressure (PAWP = <15mmHg) leading to right ventricular after-load and failure.

-Classification:

*Venice Clinical classification–2003:

Class 1: Pulmonary arterial hypertension (PAH):

· Idiopathic (IPAH) à (hpre-capillary pulmonary arterial pressure)

· Familial (FPAH)

· Conditions associated with (all hpre-capillary pul. Arterial pressure):

o Connective tissue disease (Scleroderma (60% with CREST), SLE, Polymyositis, RA or Mixed)

o Congenital systemic to pulmonary shunts (VSD, ASD, PDA)

o Portal hypertension

o HIV infection (may be by Human herpesvirus-8 (HHV-8) or called Kaposi's sarcoma associated gamma herpes virus, suspected when some cases of IPAH associated with multicentric Castleman's disease which is also caused by HHV-8)

o Drugs (e.g. anorexigenic as serotonin transporters) and toxins (e.g. cocaine, toxic oil syndrome and L-tryptophan)

o Others: which include thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, spleenectomy

· Conditions associated with significant venous or capillary involvement (all hpost-capillary pulmonary venous pressure):

o Pulmonary veno-occlusive disease (PVOD)

o Pulmonary capillary hemangiomatosis (PCH)

o Persistent pulmonary hypertension of the newborn (PPHN)

Class 2: Pulmonary hypertension associated with left heart diseases: (hpre-capillary pulmonary arterial pressure)

· Lt atrial or ventricular HD, including lt vent. diastolic dysfunction

· Lt valvular HD & Constrictive pericarditis/ Myocarditis (hLt. atrial pressure)

Class 3: Pulmonary hypertension associated with lung respiratory diseases and/or hypoxia: (hpre-capillary pulmonary arterial pressure)

· Chronic obstructive pulmonary disease

· Interstitial lung disease

· Sleep disordered breathing

· Alveolar hypoventilation disorders

· Chronic exposure to high altitude

· Developmental abnormalities

Class 4: Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH): (hpre-capillary pulmonary arterial pressure)

· Thrombo-embolic obstruction of proximal pulmonary arteries

· Thrombo-embolic obstruction of distal pulmonary arteries

· Non-thrombotic pulmonary embolism (tumor, parasites, F.B)

Class 5: Miscellaneous

· Sarcoidosis

· Histiocytosis X

· Lymphangiomatosis

· Compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

*N.B. PPHN: Physiologically, hypoxic pulmonary VC à ↑PVR in the fetus à diverting the circulation away from the lungs.

At birth, the pulmonary circulation dilates upon exposure to atmospheric O₂ and from then on receives 100% of the COP à Disruption of this mechanism results in PPHN, a serious condition affecting 1-2 infants per 1000 live births. Mortality from PPHN is approximately 10-20%.

After birth, hypoxic pulmonary VC becomes an important negative-feedback mechanism diverting blood away from hypoxic areas of the lung and ensuring ventilation-perfusion matching. However, low O₂ concentrations throughout the lung, as observed in patients with COPD or following chronic exposure to high altitude, commonly result in the development of PAH.

*Wood's classification (pathogenetic mechanisms):

· Passive: (pulmonary venous hypertension, back pressure)

o MS

o Lt atrial myxoma

o Fibrosing mediastinitis

o Pulmonary venous occlusive disease

· Hyper kinetic: (Pulmonary blood flow)

o Lt to Rt shunt

o Pulmonary A-V fistulas

· Obstructive: (impedance to flow through large pulmonary arteries)

o Thrombosis of minute vessels

o PE and Pulmonary artery stenosis

· Obliterative: (inflammatory or proliferative pul. muscular disease)

o ILD

o PPH (primary pulmonary hypertension or now called IPAH)

o Schistosomiasis-collagen vascular disease

· Vasoconstrictive: (Hypoxia and Acidosis)

o COPD

o Sleep apnea syndrome

· Polygenic: (two or more of the above causes) as COPD-ILD

*WHO and NYHA (Functional classification):

Class 1:

· No limitation of physical activity (asymptomatic)

· Ordinary physical activity doesn't cause dyspnea, fatigue, chest pain or near syncope

Class II

· Slight limitation of physical activity ($ on moderate exertion)

· They are comfortable at rest

· Ordinary activity causes dyspnea, fatigue, chest pain or near syncope

Class III

· Marked limitation of physical activity (on mild exertion)

· They are comfortable at rest

· < ordinary activity à dyspnea, fatigue, chest pain or near syncope

Class IV

· Inability to carry out any physical activity without symptoms

· Dyspnea and/or fatigue at rest (Symptoms at rest)

· Discomfort increased by any physical activity

-Treatment:

• Primary therapy: to the underlying cause of PH (not in gp 1 PH).

• General therapy:

o Physical activity

o Control anemia (as it increases hypoxia)

o Control infections (as it aggravates condition)

o Strict FU in pregnancy (as it # COP, hyperdynamic circulation)

o Prevent OCP

o Psychological assistance

• General approach:

1. Patients with PH should undergo an invasive hemodynamic assessment and an acute vasoreactivity test (VRT) prior to the initiation of advanced therapy:

• Patients with +ve VRT can be given a trial of oral CCB therapy.
• Patients with -ve VRT require advanced therapy with a prostanoid, endothelin receptor antagonist, or PDE₅ inhibitor.

2. Combination advanced therapy may be appropriate in truly refractory cases, although data are limited.

3. Lastly, some patients will be refractory to all medical interventions. à Lung transplantation or creation of a right to left shunt by atrial septostomy and thromboendarterectomy may be considered.

*Vasoreactivity test:

a. The test involves administration of a short-acting VD à measuring the hemodynamic response with a right heart catheter.

b. Agents commonly used for vasoreactivity testing include: epoprostenol (infused at a starting rate of 1-2 ng/kg/min and increased by 2 ng/kg/min every 5-10 minutes until a clinically significant fall in BP, increase in HR, or adverse symptoms (e.g., nausea, vomiting, headache) develop), adenosine (IV in doses of 50 mcg/kg/min and increased every 2 mins until uncomfortable symptoms develop or a maximal dose of 200 to 350 mcg/kg/min is reached), and inhaled nitric oxide (10-20 ppm is selective for the pulmonary vasculature à better tolerated than the IV agents).

c. An acute vasoreactivity test is considered +ve if à mean PAP decreased at least 10 mmHg and to a value < 40 mmHg, with an increased or unchanged COP, and a minimally reduced or unchanged systemic BP.

d. Patients with portopulmonary hypertension are rarely vasoreactive and are at increased risk for adverse sequelae from pure VD therapy à vasoreactivity testing and CCB therapy is not indicated in this gp.

· Advanced therapy: administration of agents with complex mechanisms of action which promote vasodilatation and impact vascular growth and remodeling (antiproliferative); these include:

• Prostanoids (e.g. epoprostenol, treprostinil, and iloprost)
• Endothelin receptor antagonists (e.g. bosentan)
• Phosphodiesterase-5 (PDE₅) inhibitors (e.g. sildenafil)
• Calcium channel blockers (CCBs, primarily nifedipine) (VD only)

DRUG	ROUTE	DOSE RANGE	HALF-LIFE
Epoprostenol	IV infusion	1 to 20 ng/kg/min	3-5 min
Treprostinil	SC/IV	0.625 to 1.25 ng/kg/min	4-5 hr
Iloprost	Inhaled	2.5 to 5 mcg, 6-9 times/day	1-2 hr
Bosentan	Oral	62.5 to 125 mg, 2 times/day	5 hr
Sildenafil	Oral	20 mg, 3 times/day	4 hr
Adenosine	IV	50 to 200 μg/kg/min	5-10 sec
Nitric oxide	Inhaled	5 to 80 ppm	15-30 sec
Nifedipine	Oral	30 to 240 mg/day	2-5 hr
Diltiazem	Oral	120 to 900 mg/day	2-4.5 hr

• Other medical: in all patients with PH, regardless of the etiology:

1. Diuretics:

Diminish hepatic congestion and peripheral edema à given with caution to avoid: $COP (due to $ right ± left ventricular preload), arrhythmias induced by hypokalemia, and metabolic alkalosis (which can depress ventilation) à if refractory can use ultrafiltration and dialysis sometimes.

2. Continuous Oxygen therapy: (1-4L/min)

• Remains the cornerstone of therapy in patients with class 3 PH.
• May benefit other gps of pts with PH (as congenital HD) + resting, exercise-induced, or nocturnal hypoxia.
• Improves mean PAP >5mmHg after 24 hrs.

3. Anticoagulation:

• Patients with PH are at # risk for intrapulmonary thrombosis and thromboembolism, due to:

§ Sluggish pulmonary blood flow.

§ Dilated right heart chambers.

§ Venous stasis.

§ Sedentary lifestyle.

• Even a small thrombus can produce hemodynamic deterioration in a patient with a compromised pulmonary vascular bed that is unable to dilate or recruit unused vasculature.
• Used also in class 4 PH, IPAH and FPAH.
• Warfarin is the anticoagulant of choice, with a therapeutic goal of an International Normalized Ratio (INR) of approximately two.

4. Digoxin: its beneficial effects and drawbacks:

• In patients with class 3 PH due to COPD (they are more sensitive than other patients to digitalis toxicity and require close monitoring) and biventricular failure.
• Improves left ventricular EF.
• In patients with supraventricular tachycardias associated with right ventricular dysfunction à control the heart rate (CCB is preferred for multifocal atrial tachycardia unless there is concurrent LVF).

· Surgery:

1. Lung transplantation

2. Right to left shunt by atrial septostomy

3Pulmonary Thromboendarterectomy (PTEA)

4. Balloon Pulmonary Angioplasty (BPA)

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