.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.
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
· Histiocytosis X
· 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 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 PPH (primary pulmonary hypertension or now called IPAH)
o Schistosomiasis-collagen vascular disease
· Vasoconstrictive: (Hypoxia and Acidosis)
o Sleep apnea syndrome
· Polygenic: (two or more of the above causes) as COPD-ILD
*WHO and NYHA (Functional classification):
· No limitation of physical activity (asymptomatic)
· Ordinary physical activity doesn't cause dyspnea, fatigue, chest pain or near syncope
· Slight limitation of physical activity ($ on moderate exertion)
· They are comfortable at rest
· Ordinary activity causes dyspnea, fatigue, chest pain or near syncope
· Marked limitation of physical activity (on mild exertion)
· They are comfortable at rest
· < ordinary activity à dyspnea, fatigue, chest pain or near syncope
· Inability to carry out any physical activity without symptoms
· Dyspnea and/or fatigue at rest (Symptoms at rest)
· Discomfort increased by any physical activity
• 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.
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)
1 to 20 ng/kg/min
0.625 to 1.25 ng/kg/min
2.5 to 5 mcg, 6-9 times/day
62.5 to 125 mg, 2 times/day
20 mg, 3 times/day
50 to 200 μg/kg/min
5 to 80 ppm
30 to 240 mg/day
120 to 900 mg/day
• Other medical: in all patients with PH, regardless of the etiology:
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.
- 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).
1. Lung transplantation
2. Right to left shunt by atrial septostomy
3Pulmonary Thromboendarterectomy (PTEA)
4. Balloon Pulmonary Angioplasty (BPA)
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