Pulmonary hypertension

Definitions:

Knowing that MPAP = Qp x PVR + LAP,

where MPAP = mean pulmonary arterial pressure

Qp = pulmonary flow; PVR = pulmonary resistance; LAP = pressure in the LA

There are 3 main categories of pulmonary arterial hypertension:

a hyperkinetic form (increased pulmonary flow): in case ofsignificant left-to-right shunt (e.g. non-restrictive VSD)
a pre-capillary form (increased pulmonary resistance): abnormal small airways (e.g. lung hypoplasia), chronic hypoxemia, abnormality of the pulmonary vascular network (hypertrophy of the media and intimal proliferation following for example the late management of a hyperkinetic form)
a post-capillary form (increased venous pressure): increased pressure in the pulmonary veins following dysfunction of the left heart (mitral stenosis, small left ventricle) or stenosis of the pulmonary veins

A patient may therefore present successively different forms of pulmonary hypertension:

for example,

a large VSD initially produces a hyperkinetic form but, if not corrected, structural changes in the pulmonary arterioles will gradually lead to a pre-capillary form and, eventually, an Eisenmenger syndrome.
pulmonary bronchodysplasia is often associated with a pre-capillary form (abnormality of the pulmonary arteries and alveoli) but can be secondarily complicated by a post-capillary form in case of acquired stenosis of the pulmonary veins (see this term)

1) in the presence of a biventricular heart,

pulmonary arterial hypertension is present in the nchild more than 3 months age when the MPAP is greater than 20 mmHg at rest and the indexed pulmonary vascular resistance is greater than 3 Wood units (W.U.)/m2. Pulmonary arterial hypertension can be observed without an increase in pulmonary vascular resistance (cfr precapillary). The echographic criteria at are a pulmonary systolic pressure greater than 50 % of the systemic blood pressure or a velocity greater than 2.5 m / sec of the regurgitation flow at the tricuspid valve. Pulmonary arterial hypertension is considered to be:

- low, if the systolic pulmonary arterial pressure (SPAP) is less than 70 % of the systemic systolic blood pressure (SBP)

- moderate, if the SPAP is between 70 and 100 % of the SBP;

- severe, if the SPAP is higher than the SBP.

Precapillary arterial hypertension is considered to respond to vasodilator therapy if during cardiac catheterization, following the administration of NO or high FiO2, one observes:

- a decrease ≥ to 10 mmHg of MPAP and down to < 40 mmHg when the baseline PAP is greater than 40 mmHg;

- a ≥ 20 % decrease from the starting value when the basal MPAPm is < 40 mmHg

2) in the presence of a univentricular heart, pulmonary vascular hypertension is present when the indexed vascular resistance is greater than 3 W.U./m2 or the transpulmonary gradient (MPAP – LAP) is greater than 6 mmHg

The causes of pulmonary arterial hypertension are multiple and often associated with structural changes in pulmonary vessels, chronic vasoconstriction or thrombosis in situ. They are described in detail in the 2 folowwing tables.

Table 1: Classification of the causes of pulmonary arterial hypertension in children

Ref: de Cerro MJ, Abman S, Diaz G et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: report from the PVRI Taskforce, Panama 2011. Pulm Circul 2011; 1: 286-98.

Category	Description
Prenatal problem or development	1. associated with a maternal or placental abnormality:pre-eclampsia, chorioamnionitis, NSAIDs intake 2. associated with a disorder of the development of the fetal pulmonary vascularization 2.1: associated with pulmonary hypoplasia * familial pulmonary hypoplasia * idiopathic pulmonary hypoplasia * diaphragmatic hernia * hepatopulmonary fusion * Scimitar syndrome * associated with pulmonary compression in utero: oligohydramnios, giant omphalocele, gastroschisis, cystic adenomatous malformation, tumor mass 2.2: associated with an interruption in lung development * acinar dysplasia * congenital alveolar dysplasia * alveolo-capillary dysplasia * lymphangectasia * abnormalities of the pulmonary artery * pulmonary venous abnormalities 3. associated with a fetal heart defect 3.1 premature closure of the ductus arteriosus or foramen ovale: idiopathic or drug-induced 3.2 cardiac malformation involving the fetal pulmonry vessels: transposition of large vessels with intact intraventricular septum, hypoplasia of the left ventricle with intact atrial septum, total obstruction of pulmonary venous return, atresia of the common pulmonary vein
Perinatal vascular maladaptation (pulmonary arterial hypertension of the neonate)	1. idiopathic 2. associated with or caused by: * sepsis * meconium inhalation * congenital heart disease * diaphragmatic hernia * trisomy 21 * drugs and toxics: e.g. diazoxide
Pediatric heart disease	1. systemic-to-pulmonary shunt * with elevated pulmonary resistance without right-to-left shunt: operable or inoperable * classic Eisenmenger syndrome associated with a simple (ASD, VSD, PDA) or complex (truncus arteriosus, single ventricle, transposition of large vessels with VSD) lesion * small lesion associated with disproportionate pulmonary arterial hypertension due to associated pulmonary hypoplasia or idiopathic or familial pulmonary arterial hypertension 2. Postoperative * shunt closure with - pulmonary resistance > 3 W.U. persistently - recurrence of pulmonary resistance > 3 W.U. * correction of transposition of great vessels with intact septum by arterial or atrial switch * repair of obstruction of the LV * repair of Tetralogy of Fallot * repair of pulmonary atresia with VSD * after surgical aortopulmonary shunt 3. after palliative surgery for single ventricle * after first palliative surgery: Blalock shunt, modified Norwood, hybrid procedure * after Glenn's shunt * after Fontan 4. associated with a congenital abnormality of the pulmonary veins or arteries * congenital anomalies of the pulmonary arteries - pulmonary artery originating from the aorta - absence or ductal origin of the PA * congenital anomalies of the pulmonary veins - Scimitar syndrome - pulmonary vein stenosis - Cant� syndrome 5. Pulmonary venous hypertension * pulmonary venous hypertension following congenital valvular malformation, triatrial heart, cardiomyopathy, fibroelastosis * pulmonary venous hypertension following an acquired disease: valvular (RAA), cardiomyopathy, constrictive pericarditis
Bronchopulmonary dysplasia	1. with pulmonary hypoplasia 2. with pulmonary venous stenosis 3. with LV dysfunction 4. with systemic-pulmonary shunts * aortopulmonary collaterals * ASD * ductus arteriosus * VSD 5. with hypoxemia and/or significant hypercarbia
Isolated pulmonary arterial hypertension	1. idiopathic 2. familial: BMPR2, TBX4, ACVRL1, KCNK3, EIF2AK4 Alk1, ENG (endoglin), CAV1, SMAD9 genes 3. induced by drugs or toxicants * certain association: toxic oil * probable combination: amphetamines * possible combination: cocaine, methylphenidate, diazoxide, cyclosporine, phenylpropranolamine 4. pulmonary veno-occlusive disease * idiopathic * familial
Hypertensive pulmonary disease present in congenital syndromes	1. syndromes with cardiac malformation 2. syndromes without cardiac malformation in the 2 categories: VACTERL, CHARGE, Poland, Adams-Oliver, Scimitar, trisomy 21, Di George, Noonan, von Recklinghausen, Dursun, Cant�, von Hippel Lindau (VHL), cobalamin C deficiency (MMACHC gene), multisystemic smooth muscle dysfunction (ACTA2 gene)
Pediatric lung diseases	1. cystic fibrosis 2. interstitial lung disease: surfactant deficiency 3. sleep-related breathing disorders 4. deformation of the chest and spine 5. restrictive syndrome 6. obstructive syndrome
Pediatric thrombo- embolic disease	1. chronic thromboembolism following central venous catheterization 2. chronic thromboembolism on pacemaker electrodes 3. ventriculo-atrial shunt for hydrocephalus 4. sickle cell disease 5. primary cardiac fibroelastosis 6�. anticardiolipins or antiphospholipid syndrome 7. methylmalonic acidemia and homocystinuria(cobalamin C deficiency, MMACHC gene) 8. associated with cancer: osteosarcoma, nephroblastoma 9. post-splenectomy
Hypobaric hypoxic exposure	1. high altitude acute pulmonary edema (mountain sickness) 2. subacute infant mountain pain 3. Monge disease 4. in association with neonatal pulmonary arterial hypertension, congenital heart disease or idiopathic pulmonary arterial hypertension
Association with other systemic disorders	1. portal hypertension * extrahepatic portosystemic shunt: Abernethy, Alagille (JAG1), portal atresia or thrombosis, left atrial isomerism, trisomy 21 * hepatic cirrhosis, 2. haematological disorders; * hemolytic anemia: sickle cell disease, �- thalassemia * post-splenectomy 3. cancers * pulmonary arterial hypertension associated with cancer * pulmonary veno-occlusive disease after bone marrow transplantation and chemotherapy 4. metabolic/endocrine disease Gaucher, mucopolysacharidosis, hypo- or hyperthyroidism, non-ketotic hyperglycinemia, some glycogenosis, mitochondrial disease 5. autoimmune pathology POEMS, isolated or diffuse scleroderma, dermatomyositis, lupus; anticardiolipins or antiphospholipid syndrome, juvenile polyarthritis, pulmonary veno-occlusive disease associated with lupus 6. infectious disease Schistosomiasis, HIV, pulmonary tuberculosis 7. chronic renal failure * pulmonary arterial hypertension predialysis or associated with hemodialysis or peritoneal dialysis * pulmonary veno-occlusive disease after kidney transplantation

Table 2: Simplified classification of causes of pulmonary arterial hypertension in children

1. Pulmonary arterial hypertension (PAH)

1.1 idiopathic

1.2 congenital

1.3 associated with toxics or drugs

1.4 associated with a

1.4.1 inflammation of the connective tissues

1.4.2 HIV infection

1.4.3 portal hypertension

1.4.4 congenital heart disease

1.4.5 schistosomiasis

1.5 PAH with prolonged response to calcium channel blockers

1.6 PAH with obvious signs of venular/capillary involvement (pulmonary veno-occlusive disease / pulmonary capillary hemangiomatosis)

1.7 persistent neonatal PAH

2. PAH due to a left heart disease

2.1 PAH due to left heart failure with preserved ejection fraction

2.2 PAH due to left heart failure with reduced ejection fraction

2.3 PAH due to valvular heart disease

2.4 PAH due to acquired or congenital heart disease

3. PAH due to respiratory diseases and/or diseases associated with chronic hypoxia

3.1. obstructive respiratory pathology

3.2. restrictive respiratory pathology

3.3. mixed obstructive and restrictive respiratory pathology

3.4. hypoxemia without respiratory disease

3.5. abnormal lung development

4. PAH due to pulmonary arterial obstruction

4.1 chronic thromboembolic PAH

4.2 other pulmonary arterial obstructions

5. multifactorial PAH or due to uncertain mechanisms

5.1. hematological diseases

5.2. systemic and metabolic diseases

5.3. other

5.4. complex congenital heart diseases

Clinical signs:

auscultation: intense B2 (not very specific), a pulmonary murmur is a late sign
dyspnea at exercise and then at rest
in case of RV insufficiency or failure: cyanosis, hepatomegaly

Diagnosis:

echography: flattened or concave interventricular septum on the right side, hypertrophic RV, assessment of the pressures in case of tricuspid or pulmonary insufficiency, measurement of pulmonary flow (acceleration time)
cardiac catheterization

In addition to oxygenation, the treatment of precapillary arterial hypertension is based on the administration of selective pulmonary vasodilators such as:

NO (5-10 ppm) in inhalation, particularly in the neonatal and post-operative periods;
prostacyclin IV (Flolan�, (2-20 �g/kg/min), subcutaneous (Remodulin�) or by inhalation (iloprost every 2-3 h);
sildenafil (Viagra�, Revatio�), a phosphodiesterase type 5 inhibitor, p os: the starting dose is 0.1 mg/kg up to 0.6 mg/kg or even 1.5 mg/kg every 6 hours
bosentan (Tracleer�), an endothelin 1A and 1B receptor antagonist, per os, at a dose of 2 to 4 mg/kg twice daily.

In case of suprasystemic PAH, palliative interventions to avoid death from acute right ventricular failure in case of PAH attacks are the realization of inter-atrial communication by balloon septostomy or, better, the realization of a Potts shunt between the left pulmonary artery and the descending aorta.

Anesthetic implications:

Preoperative echocardiography to determine what type of pulmonary arterial hypertension the patient suffers from.

In case of hyperkinetic PAH: decrease the left-to-right shunt: PEEP, avoid high FiO2 etc. Avoid pulmonary vasodilators that increase the shunt.

In precapillary PAH, there is a significant risk of hemodynamic complications, including right cardiac failure, pulmonary hypertension attack, and cardiac arrest. A recent series has shown that chronic administration of pulmonary vasodilator does not decrease the anesthetic risk associated with PAH and that the main preoperative risk factors are a systemic and especially suprasystemic SPAP as well as patients of less than 2 years of age.

In addition to continuing the chronic pulmonary vasodilator therapy, the basic principle of anesthesia of a child suffering from PAH is to avoid:

any increase in pulmonary vascular resistance, which can lead to an attack of pulmonary arterial hypertension and / or right and then biventricular heart failure (by moving the intraventricular septum to the LV leading to a decrease in cardiac output and coronary ischemia); factors increasing lung resistance are hypoxemia, alveolar hypoxia, hypercarbia, metabolic acidosis and pain: thus, intubation and endotracheal aspiration are stimuli that can cause an attack of pulmonary arterial hypertension;
hypovolemia
systemic hypotension or decreased systemic resistance, as this decreases coronary blood flow (hypertrophic LV) and can lead to ischemic heart failure

The choice of anesthetic agents will be based on these objectives knowing that:

halogenated agents have a vasodilator effect on the pulmonary vascularization (and inhibit hypoxic vasoconstriction) but also decrease systemic resistance;
propofol decreases systemic resistance and contractility;
opioids have little effect on systemic and pulmonary resistance; however, it is necessary to avoid chest rigidity and bradycardia;
ketamine does not increase pulmonary resistance, even during spontaneous breathing, if the permeability of the airways is ensured; combined with a low dose of sevoflurane or a high FiO2, ketamine does not increase pulmonary resistance and maintains stable SPAP and systemic resistances: it is therefore a good choice in this context.
experimental data and one clinical case in adults have shown that it is dangerous (risk of collapse) to use thoracic epidural anesthesia in patients with PAH (acute in the experimental model) because the sympathetic block decreases the positive inotrope response of the RV to increased lung pressure. Even if, experimentally, a lumbar epidural block causes only small hemodynamic changes, it is necessary to be careful because systemic hypotension can occur.

Balanced anesthesia using low doses of different agents is therefore often the best choice.

Treatment of a PAH attack:

Action	Pathophysiological basis
give 100 % O2	increasing pAO2 decreases pulmonary resistance
moderate hyperventilation	hypercarbia increases pulmonary resistance (beware of the systemic effects of hypocarbia)
correct metabolic acidosis	pulmonary resistance is directly correlated with pH
administer a pulmonary vasodilator	NO, milrinone, prostacyclines (beware of systemic effects)
maintain cardiac output	preload, inotropes (dobutamine, adrenaline rather than norepinephrine)
treat pain	opiates to decrease the sympathetic response

In case of post-capillary PAH: depending on the type of dysfunction of the left heart. Avoid pulmonary vasodilators because they increase the pulmonary blood flow and so the pulmonary venous pressures.

References:

- Carmosino MJ, Friesen RH, Doran A, Ivy DD.
Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization.
Anesth Analg 2007; 104:521-7.

- Williams GD, Maan H, Ramamoorthy C, Kamra K, Bratton SL, Bair E, Kuan C, Hammer GB, Feinstein JA.
Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine.
Pediatr Anesth 2010; 20:28-37.

- Petros AJ, Pierce CM.
The management of pulmonary hypertension.
Pediatr Anesth 2006; 16:816-21.

- de Cerro MJ, Abman S, Diaz G et al.
A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease�: report from the PVRI Taskforce, Panama 2011.
Pulm Circul 2011; 1: 286-98

- Williams GD, Friesen RH.
Administration of ketamine to children with pulmonary hypertension is safe�: pro-con debate.
Pediatr Anesth 2012; 22: 104-52

- Friesen RH, Williams GD.
Anesthetic management of children with pulmonary arterial hypertension.
Pediatr Anesth 2008; 18:208-16.

- Taylor K, Moulton D, Laussen P.
The impact of targeted therapies for pulmonary hypertension on pediatric intraoperative morbidity and mortality.
Anesth Analg 2015�; 120�: 420-6.

- Missant C, Rex S, Claus P, Derde S, Wouters PF.
Thoracic epidural anaesthesia disrupts the protective mechanism of homeometric autoregulation during right ventricular pressure overload by cardiac sympathetic blockade�: a randomised controlled animal study.
Eur J Anaesthesiol 2011; 28: 535-43

- Subash G, Mohammed S.
Perioperative cardiac arrest after thoracic epidural analgesia in a patient with increased pulmonary artery pressure.
Br J Anaesth 2011, 107�: 108-9

- Eggers A, Latham GJ, Geiduschek J, Yung D, Chen JM, Joffe DC.
Anesthesia for Potts shunt in a child with severe refractory idiopathic pulmonary arterial hypertension.
A &A Case Reports 2016; 6: 56-60.

- Haarman MG, Kertsjens-Frederikse WS, VissiaKazemier TR, Breerman KTN, Timens W et al.
The genetic epidemiology of pediatric pulmonary arterial hypertension.
J Pediatr 2020; 225: 65-73.

- Valent A, Nefzi I, Lopez V, Mirabile C, Orliaguet G.
Anesthetic management for percutaneous reverse Potts shunt creation in children with refractory idiopathic pulmonary arterial hypertension: a case series.
Pediatr Anesth 2021; 312:644-9.

- Rosenzweig EB, Abman SH, Adatia I, et al.
Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management.
Eur Respir J 2019;53(1).

Updated: April 2022