Classification
Definition/title
Pre- or postcapillary
Class 1
Pulmonary arterial hypertension (PAH)
Precapillary PH
Class 2
PH due to left heart disease
Postcapillary PH
Class 3
PH due to chronic obstructive lung disease (pulmonary disease)
Precapillary PH
Class 4
PH due to chronic thromboembolic (CTEPH)
Precapillary PH
Class 5
PH because of unclear multifactorial mechanisms
Precapillary PH
In addition, based on another classification, PH may be classified as precapillary PH and postcapillary PH; groups 1, 3, 4, and 5 are considered as precapillary PH and group 2 as postcapillary PH (Ivy et al. 2013; Pristera et al. 2016).
In adult patients, the most common frequencies of PH according to Anderson et al. are accordingly (Anderson and Nawarskas 2010):
Idiopathic/familial PAH is the predominant etiology of PH (40–48 %).
Connective tissue disorders (15–30 %).
Congenital heart abnormalities (11 %).
Portal hypertension (7–10 %).
Anorexigens (3–10 %).
HIV infection (1–6 %).
However, in pediatric population, though there are many similarities with adult PH, the frequency rates of PH etiologies differ from adults; pediatric PH is most commonly due to congenital heart disease (PH-CHD), idiopathic PH (also known as primary PH), and hereditary PH; neglected or poorly managed congenital heart diseases, especially when prolonged, are among the most common etiologies for pediatric PH (Donti et al. 2007; Kim et al. 2016).
Clinical Features
The main clinical signs and symptoms in PH-CHD include (Friesen and Williams 2008; McDonough et al. 2011; Monfredi et al. 2016):
Shortness of breath (dyspnea)
Early fatigability and exercise intolerance
Chest pain
Syncope or presyncope on exertion
Right ventricular heave
Ejection click of pulmonary valve
Split second heart sound with loud P2
Systolic murmur in tricuspid valve due to tricuspid regurgitation
Diastolic murmur due to pulmonary insufficiency
Bulged jugular vein
Paraclinical Studies
Right heart catheterization and pulmonary angiography are the gold standard for hemodynamic assessment, definitive diagnosis, and assessment of vascular architecture in PH; however, a number of modern sensitive and specific noninvasive imaging modalities have been developed, and more are in progress with especial aim to replace these imaging tools instead of angiography for diagnosis, follow-up, and management of PH (Lang et al. 2010; Kreitner 2014; Gerges et al. 2015; Pristera et al. 2016).
Chest X-Ray
Cardiomegaly mainly in the right-sided chambers
Elevated cardiac apex due to RV enlargement and RV hypertrophy
Enlargement of the pulmonary artery trunk especially in the outflow tract
Decreased retrosternal border in lateral X-ray due to RV enlargement
Shrinkage of distal branches of pulmonary arterial system leading to oligemic lung fields
Electrocardiography
Right axis deviation
Right ventricular hypertrophy presenting as R-to-S wave ratio > one in V1
Right atrial enlargement presenting as amplitude of P wave especially in lead II
Right bundle branch block (Fig. 29.1)
Fig. 29.1
Right ventricular hypertrophy. Typical ECG features are tall R wave in V1, deep S wave in V6, and right axis deviation (Courtesy of Dr Majid Haghjoo and Dr Mohammadrafie Khorgami)
Imaging Studies
Right heart catheterization and pulmonary angiography are the gold standard for hemodynamic assessment, definitive diagnosis, and assessment of vascular architecture in PH; however, a number of modern sensitive and specific noninvasive imaging modalities have been developed, and more are in progress in the next years with especial aim to replace the new imaging tools instead of angiography for diagnosis, follow-up, and management of PH (Lang et al. 2010; Kreitner 2014; Gerges et al. 2015; Pristera et al. 2016).
Echocardiography
Signs of RV hypertrophy and some degrees of RV failure are seen; pulmonary insufficiency in diastole and tricuspid regurgitation in systole are seen in some of the patients.
Cardiac MR (CMR) and Multi-slice CT Scan
Both of them are very important noninvasive imaging modalities and help us perform sophisticated and comprehensive assessments; according to “Expert consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension” declared on May 2016 by “European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK,” both CMR and CT have definitive role in pediatric PH; they let us gain noninvasive invaluable data regarding the right heart and the myocardium as well as the pulmonary vascular system hemodynamics; some believe that parenchymal and vascular assessment of the lungs may be more definitively assessed using CT (Gerges et al. 2015; Santos et al. 2015; Latus et al. 2016).
Radioisotope Ventilation/Perfusion Scan
Demonstrates the vascular architecture of the lung demonstrating defects and gives structural information about the pathologies that could lead to PH or they can be due to PH (Latus et al. 2016).
Management
There are a number of major scopes in management of children congenital heart disease associated with PH (Kozlik-Feldmann et al. 2016):
Definitive criteria should be used for operability and/or starting advanced therapies.
Preoperative and postoperative management are really a great challenge.
Management of Eisenmenger’s syndrome needs sophisticated vigilance and advanced care.
Pharmacological Treatment
The pharmacology of PH for anesthesiologist involves two subclasses: pulmonary vascular system drugs and anesthetic drugs.
A full description of pharmacological agents used for the treatment of pulmonary hypertension could be found in Chap. 4 – Cardiovascular Pharmacology in Pediatric Patients with Congenital Heart Disease.
When using pharmacologic agents to treat PH, we should always consider that there are two distinct stages in treatment of PH:
Reversible stage: in this stage, the changes in pulmonary vascular bed could be partially or near totally reversed using pharmacologic agents.
Irreversible stage: if the disease progresses, the changes in pulmonary vascular system are fixed due to permanent vascular bed remodeling, and so, the pharmacologic agents are not usually effective.
Except for pharmacologic therapy, other treatment alternatives include “heart and lung transplantation” or “lung transplant with repair of the underlying cardiac defect”; however, they are not used in the majority of the patients (Suesaowalak et al. 2010).
The only FDA-approved pharmaceutical specifically for the treatment of pulmonary hypertension in children is inhaled nitric oxide (iNO) which is administered through the lungs. The other FDA-approved drugs for the treatment of pulmonary hypertension are used in adults and are often based on the pathways related to the endothelial cells, including prostacyclin analogues (epoprostenol, iloprost, treprostinil), phosphodiesterase 5 inhibitors (sildenafil and tadalafil), phosphodiesterase 3 inhibitors (mainly milrinone), endothelin receptor antagonist (bosentan, ambrisentan, and macitentan), and soluble guanylate cyclase stimulator (riociguat) (Benedict et al. 2007; Poor and Ventetuolo 2012; Ventetuolo and Klinger 2014; Abman et al. 2015; Jentzer and Mathier 2015; Liu and Jing 2015; Kim et al. 2016).
Currently available medications for pediatric PH follow one of the following pathways (Table 29.2):
Table 29.2
Pharmacological agents used in the management of pulmonary hypertension
Drug | Recommended dose | Adverse effects | Clinical considerations |
|---|---|---|---|
Inhaled nitric oxide (iNO): mechanism of action is increasing cGMP, leading to smooth muscle relaxation and, subsequently, pulmonary vasodilation | |||
iNO | 2–5 ppm to a maximum of 40 ppm | Lung injury Increased methemoglobin levels Rebound severe pulmonary hypertension due to abrupt iNO withdrawal | The only FDA-approved agent for pediatric pulmonary hypertension Should not be over administered to prevent side effects Its cost may suggest to consider the drug as the last choice |
Prostacyclin/prostacyclin analogues: their mechanism of action is pulmonary and systemic vasodilation through increasing cAMP; also, antiplatelet aggregation | |||
Epoprostenol | Initial infusion rate: 1–3 ng/Kg/min Maintenance infusion rate: 50–80 ng/Kg/min | Flushing, headache, nausea, diarrhea, jaw discomfort, rash, hypotension, and thrombocytopenia | Potential risk of hypotension and bleeding in children receiving drugs, such as anticoagulants, platelet inhibitors, or other vasodilators |
Iloprost | Initial dose: 2.5 μg per inhalation; six times/day Maintenance dose: 5 μg per inhalation nine times/day | Cough, wheeze, headache, flushing, jaw pain, diarrhea, rash, and hypotension (at higher doses) | Potential risk of exacerbation of reactive airway disease |
Treprostinil (IV/subcutaneous) | Initial infusion rate: 1.25–2 ng/Kg/min Maintenance infusion rate: 50–80 ng/Kg/min | Flushing, headache, nausea, diarrhea, musculoskeletal discomfort, rash, hypotension, thrombocytopenia, and pain at subcutaneous infusion site | Similar to epoprostenol |
Treprostinil (inhaled) | Initial dose: three breaths (18 μg)/four times/day Maintenance dose: nine breaths (54 μg) four times/day | Cough, headache, nausea, dizziness, flushing, and throat irritation | Reactive airway symptoms and hypotension may occur at high doses |
Treprostinil (oral) | Initial dose: 0.25 mg PO BID Maintenance dose: determined by tolerability | Headache, nausea, diarrhea, jaw pain, extremity pain, hypokalemia, abdominal discomfort, and flushing | If “twice daily” dosing is not tolerated, consider “three times daily” dosing |
PDE–5 inhibitors: inhibit phosphodiesterase-5, leading to pulmonary vasodilation and inhibition of vascular remodeling | |||
Sildenafil | Oral dose: 0.25–0.5 mg/Kg/q4–8 h Intravenous dose: loading dose 0.4 mg/Kg over 3 h Maintenance: continuous infusion of 1.5 mg/Kg/day | Headache, flushing, rhinitis, dizziness, hypotension, peripheral edema, dyspepsia, diarrhea, myalgia, and back pain | Coadministration of nitrates is contraindicated; sensorineural hearing loss and ischemic optic neuropathy have been reported |
Tadalafil | Oral dose: 1 mg/Kg per day (single daily dose): preliminary studies | Similar to sildenafil No significant effect on vision | Similar to sildenafil |
Antagonists of endothelin receptor: counteract with the effects of both endothelin receptors (ETA and ETB), vasodilation of the pulmonary vascular system, and vascular remodeling inhibition | |||
Ambrisentan | Body weight <20 kg: 2.5–5 mg PO/four times daily Body weight >20 kg: 5–10 mg PO/four times daily | Peripheral edema, nasal congestion, headache, flushing, anemia, nausea, and decreased sperm count | Baseline liver enzymes and hemoglobin are needed Monitor based on clinical parameters |
Bosentan | 2 mg/Kg per dose PO, two times daily If body weight is 10–20 kg: 31.25 mg PO, two times daily If body weight is 20–40 kg: 62.5 mg PO, two times daily If body weight is >40 kg: 125 mg PO, two times daily | Pediatric abdominal pain, vomiting, extremity pain, fatigue, flushing, headache, lower limb edema, nasal congestion, hypotension, palpitations, dyspepsia, anemia, and decreased sperm count Potential risk of dose dependent increases in amino-transaminase levels | Liver enzymes and hemoglobin levels should be monitored; in patients with moderate or severe degrees of hepatic impairment , should be used cautiously Also, concomitant use of CYP3A4 inducers and inhibitors should be considered as important caution |
Macitentan | 10 mg PO, four times daily | Nasal congestion, headache, flushing, anemia, and decreased sperm count | The incidence of serum aminotransferase elevation is low Obtain baseline liver enzymes and hemoglobin and monitor as clinically indicated Teratogenicity REMS* |
sGC stimulator: its action mechanism is stimulation of soluble guanylate cyclase leading to pulmonary vasodilation associated with inhibition of vascular remodeling | |||
Riociguat | Initial dose: 0.5–1 mg PO Maintenance dose: 2.5 mg PO, three times daily | Headache, dizziness, dyspepsia, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation | Coadministration of nitrates and/or PDE-5 inhibitors is contraindicated In growing rats, effects on bone formation were observed Teratogenicity is a potential risk
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