Pulmonary Hypertension

1. What every clinician should know

Pulmonary hypertension (PH) is a serious medical condition that may coexist with pregnancy and cause significant morbidity and mortality. Classically, pregnancy termination has been recommended for women with this disease; however, good outcomes are possible with adequate treatment. Of paramount importance is to correctly identify the subtype of pulmonary hypertension in order to establish the correct treatment.

PH is defined as a mean pulmonary pressure above 25 mm Hg. This value must be confirmed by right heart catheterization.

PH may be divided into the following categories:

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  • Pulmonary Arterial Hypertension: This group includes patients with disease localized prior to the lungs, that is in the pulmonary arterial circulation. These include idiopathic and familiar forms of pulmonary hypertension. Also included are cases secondary to HIV infection, porto-pulmonary hypertension, drug induced (cocaine, fenfluramine), congenital cardiac shunts (like unrepaired ventricular or atrial septum defects), collagen disease (mainly systemic sclerosis), sickle cell anemia, and schistosomiasis.
  • Pulmonary Venous Hypertension: This group includes patients whose pulmonary hypertension originates from anomalies distal to the lungs, mainly heart anomalies, such as mitral or aortic stenosis, and left systolic or diastolic dysfunction. Heart dysfunction leads to retrograde congestion elevating pulmonary pressure. Chronically, the pulmonary vasculature may undergo remodeling, adding a component of pulmonary arterial dysfunction.
  • Pulmonary Hypertension secondary to thromboembolic disease: Chronic thromboembolism to the pulmonary vessels leads to mechanical obstruction with consequent elevation of pulmonary pressure.
  • Pulmonary Hypertension secondary to lung disease (hypoxemia): Includes patients with lung disease like chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and obstructive sleep apnea. Chronic hypoxia leads to pulmonary hypoxic vasoconstriction (pulmonary arterioles will constrict in areas where there is not enough alveolar oxygen to avoid perfusion of nonoxygenated areas in an attempt to maintain ventilation/perfusion matching) with consequent elevation of pulmonary pressure.
  • Pulmonary Hypertension from miscellaneous causes: Includes conditions such as histiocytosis X.

2. Diagnosis and differential diagnosis

Clinical manifestations of PH include dyspnea, exercise intolerance, light-headedness, elevated jugular pressure (distended jugular veins on physical examination), hepatomegaly, peripheral edema, tricuspid regurgitation murmur, and a loud S2 heart sound on auscultation.

Electrocardiographic findings include an axis deviated to the right, P-pulmonale (a prominent P wave), right bundle blocks, ST and T wave changes in right sided precordials (V1,V2), sinus tachycardia, right ventricular hypertrophy, and a S1Q3T3 (S wave in D1, Q wave in D3, and an inverted T wave in D3).

Echocardiographic findings include right ventricular dilation or hypertrophy, tricuspid regurgitation, and elevated estimated pulmonary pressure. The interventricular septum may be displaced to the left, compromising filling of the left ventricle (“D” shaped left ventricle in the low short axis view). Pulmonary pressure estimated by transthoracic echocardiography is not always reliable and large differences between noninvasive and invasive pressures are not uncommon. Inaccurate echocardiographic estimations may be due to technical issues such as poor acoustic windows and poor Doppler beam alignment with the tricuspid jet. Importantly, changes in blood viscosity (anemia) and other conditions with an elevated cardiac output (pregnancy, hyperthyroidism, cirrhosis) may lead to elevated pulmonary arterial systolic pressure without the presence of true pulmonary hypertension. Due to all these limitations, all cases of suspected pulmonary hypertension must be confirmed by a right heart catheterization. As stated before, the diagnosis is confirmed by a mean pulmonary pressure above 25 mm Hg.

Patients with pulmonary arterial hypertension will have an elevated mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) with a normal pulmonary capillary wedge pressure.

Patients with pulmonary venous hypertension will typically have an elevated mean pulmonary artery pressure and an elevated pulmonary capillary wedge pressure (reflecting the high filling pressure from left heart dysfunction). Chronically, these patients may develop superimposed pulmonary vascular disease secondary to chronic high pressure with vascular injury. In the latter case, the PVR may also be elevated.

The transpulmonary gradient may be used to differentiate these 2 groups. The transpulmonary gradient (TPG) is the mean pulmonary artery pressure minus the pulmonary artery occlusion pressure (PAOP) [ (TPG= MPAP-PAOP)]. The normal value for the TPG is <12 mm Hg. If the gradient is normal, then most of the pulmonary hypertension comes from left-sided heart failure. If the gradient is elevated, it means that the elevation of the MPAP is out of proportion with the elevated PAOP, indicating an additional component of pulmonary vascular disease.

The differential diagnosis includes an endless list of cardiopulmonary conditions; however, a transthoracic echocardiography must be part of the workup of patients with symptoms such as the ones described above. The imaging will easily identify patients likely to have PH. Consequently, the most important step in the differential is to correctly identify the subtype of PH affecting the patient. For example, before a diagnosis of idiopathic PH is made, the clinician must be certain that left ventricular diastolic dysfunction is not the cause of the “apparently idiopathic” elevation of pulmonary pressure as the treatment of both entities is entirely different.

3. Management

Patients with a diagnosis of PH must be referred to a center that can provide care for them. A multidisciplinary approach, including maternal fetal medicine, obstetrical anesthesiology, intensive care, and a pulmonary specialists is required.

Different etiologies will require specific therapies. For example, patients with sleep obstructive apnea will benefit from continuous noninvasive positive pressure ventilation (CPAP). Patients with chronic thromboembolic events may require anticoagulation and/or surgical thrombectomy. Patients with intracardiac shunts may require surgical closure of the defect.

In patients with venous pulmonary hypertension, treatment must be directed toward the specific cause (mitral or aortic valve repair if needed, use of beta blockers or calcium channel blockers, and treatment of systemic hypertension in cases of left ventricular diastolic dysfunction, optimization of left ventricular function, and fluid restriction in patients with left ventricular systolic dysfunction). The use of pulmonary vasodilators in patients with venous pulmonary hypertension may be detrimental and must be approached carefully. If a pulmonary vasodilator (e.g., prostacyclin) is given to a patient with venous pulmonary hypertension from mitral stenosis, dilation of the arterial pulmonary vasculature will increase preload to the left side of the heart and may lead to pulmonary edema. Recent evidence suggests that sildenafil may be used in these patients when the pulmonary artery diastolic pressure minus the pulmonary artery occlusion pressure (PAD-PAOP) is more than 5 mm Hg.

Pulmonary arterial hypertension is commonly managed with fluid and sodium restriction combined with the use of diuretics. Limiting fluid accumulation is very important during pregnancy to counterbalance the physiologic volume expansion that occurs with human gestation.

Excessive fluid in patients with PH may be detrimental in two ways. Since the pulmonary vascular resistances are elevated, the right ventricle has a limited capacity to empty. Excessive fluid will then accumulate in the right ventricle leading to distention of it. Distention of the free wall will compress the coronaries, resulting in ischemia and eventually a myocardial infarction of the right heart.

Second, excessive fluid within the right ventricular cavity will also displace the interventricular septum to the left causing constriction of the left ventricle (diastolic dysfunction as the left ventricle will not be able to fill), leading to a sudden decrease in cardiac output. The latter will worsen hypoxia, which in turn is a powerful stimulator of pulmonary vasoconstriction, and worsen pulmonary hypertension. The latter sequence of events is typical in the early post-partum period as a consequence of the physiologic “autotransfusion” that happens once delivery is completed.

Certain medications are also available to diminish pulmonary vasoconstriction in patients with pulmonary arterial hypertension. These pulmonary vasodilators include phosphodiesterase 5 inhibitors (sildenafil), prostacyclin analogues (epoprostenol, treprostinil, iloprost), and endothelin receptor antagonists (bosentan, ambrisentan). Endothelin receptor antagonists may be teratogenic and are not first line during pregnancy.

Sildenafil may be used during pregnancy at a starting dose of 20 mg tid. Epoprostenol infusions through a central line are commonly the first-line therapy for patients with moderate-severe disease. Infusions are started at 2 ng/kg/min and then titrated to the desired effect. Side effects include headache, nausea, vomiting, hypotension, jaw pain, myalgias, thrombocytopenia, and arthralgias.

Calcium channel blockers may be used mainly in the subset of patients with idiopathic pulmonary arterial hypertension who have a positive vasodilator test. When these patients undergo the diagnostic right heart catheterization, a vasodilator test is performed by adding adenosine, nitric oxide, or prostacyclin. The patient is considered a responder if the main pulmonary arterial pressure decreases to less than 40 mm Hg, with a decline of at least 10 mm Hg with a normal or increased cardiac output. Only these patients should be candidates to calcium channel blockers. If these agents are given to patients with a negative test, then the calcium channel blocker may not dilate the pulmonary vasculature but will dilate the systemic vasculature leading to systemic hypotension.

The use of therapeutic anticoagulation in patients with pulmonary hypertension is controversial. The one group for which there is more evidence (albeit not that strong) for use of therapeutic anticoagulation is those with idiopathic arterial pulmonary hypertension. For all other categories, we recommend prophylactic doses for deep venous thrombosis prevention during pregnancy.

Delivery mode may be either vaginally or by cesarean section. The main advantage of a cesarean section is the timely delivery when most specialists are available in the hospital. There is no evidence that outcomes are clearly affected by mode of delivery. Provided an effective epidural is administered and an assisted second stage of labor given, vaginal delivery is safe.

Pain should be avoided as an increase in catecholamines will increase the pulmonary vascular resistances leading to worsening pulmonary hypertension. The epidural anesthesia should be provided gradually with an arterial catheter in place for continuous arterial blood pressure monitoring in order to avoid sudden decreases in systemic blood pressure. Commonly a central venous catheter is required; however, a pulmonary artery catheter is not mandatory and in many published series it was commonly not used. If a sudden increase in the central venous pressure is noted immediately after delivery (indicating massive autotransfusion and potential right ventricular dilation), then diuretics should be administered.

4. Complications

The most important complication that may arise during pregnancy in these patients is right ventricular failure. The increase in volemia, particularly around 28 to 32 weeks and later in the peripartum period (with autotransfusion after delivery), may lead to acute right ventricular dilation (cor pulmonale), with potentially lethal complications such as right ventricular infarction and hemodynamic instability due to left ventricular acute diastolic dysfunction (displacement of the interventricular septum leads to obliteration of the left ventricle with decreased cardiac output). Shock secondary to right ventricular failure should not be treated with fluids. Treatment is directed to achieve the following goals:

  • Sustain right ventricular function: Inotropes such as dobutamine at doses of 1 to 5 mcg/kg/min or milrinone at doses of 0.25 to 0.75 mcg/kg/min will increase right ventricular contractility. Sildenafil is also an inotrope for the right ventricle as it potentiates inhibition of the enzyme phosphodiesterase type 3. Sildenafil may be added at a dose of 20 mg tid. Atrial tachyarrhythmias should be treated as needed since they may compromise the filling time of the right ventricle (if atrial fibrillation with rapid ventricular response, consider synchronized cardioversion).
  • Maintain right ventricular coronary perfusion pressure: With right ventricular dilation, the coronaries within the myocardium get compressed, requiring more perfusion pressure to maintain oxygenation. The use of vasoconstrictors (e.g., norepinephrine) will elevate mean arterial pressure and consequently perfusion pressure. Commonly, aim to a mean arterial pressure of around 65 mm Hg with the use of vasoconstrictors. Excessive doses may be harmful as they will increase the pulmonary vascular resistances.
  • Decrease pulmonary vascular resistances: The use of pulmonary vasodilators is fundamental. Oxygen should be administered (pulmonary vasodilator) and it is of paramount importance to avoid hypoxemia, hypercarbia, or acidosis as all three are potent pulmonary vasoconstrictors. Pulmonary vasodilation may be achieved with dobutamine, milrinone, sildenafil, inhaled nitric oxide, and inhaled prostacyclin. Intravenous or subcutaneous prostacyclin may also be used.

5. Prognosis and outcome

Classically, women with pulmonary hypertension are advised to either avoid or terminate pregnancy due to an unacceptable elevated mortality rate (50% or higher). Most of these mortalities have been described during the peripartum period as described above. Recent publications have described a much lower maternal mortality rate (15% to 30%) when a multidisciplinary team with experience in the management of pulmonary hypertension is involved in the patient’s care.

6. What is the evidence for specific management and treatment recommendations

Shah, SJ. “Pulmonary hypertension”. JAMA. vol. 308. 2012. pp. 1366-75. (Good updated review article with basic concepts of pulmonary hypertension.)

Duarte, AG, Thomas, S, Safdar, Z. “Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience”. CHEST. vol. 143. 2013. pp. 1330-6.

Detsky, ME, Balter, MS, Sridhar, SK. “Under pressure”. New Engl J Med. vol. 362. 2010. pp. 449-54. (Good explanation on the pathophysiology of venous pulmonary hypertension.)

Galie, N, Ghofrani, HA, Torbicki, A. “Sildenafil citrate therapy for pulmonary arterial hypertension”. New Engl J Med. vol. 353. 2005. pp. 2148-57. (Good review on pharmacology of agents used for the treatment of pulmonary hypertension.)