Inflammatory Basis of Pulmonary Arterial Hypertension

Implications for Perioperative and Critical Care Medicine

Neil M. Goldenberg, M.D., Ph.D.; Marlene Rabinovitch, M.D.; Benjamin E. Steinberg, M.D., Ph.D.


Anesthesiology. 2019;131(4):898-907. 

In This Article

Perioperative Management of Patients With Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension represent some of the greatest management challenges for anesthesiologists and critical care physicians alike.[9] Their perioperative risk has primarily been evaluated through retrospective studies,[10–14] partly limited by differences in methodology and consideration of combined World Health Organization pulmonary hypertension groups. Yet, together they uniformly speak to the considerable risk of morbidity and mortality in patients with pulmonary arterial hypertension across the perioperative period,[10–15] above that seen in other types of pulmonary hypertension.[16] Rates of serious perioperative complications, including respiratory failure, heart failure, cardiovascular instability, and myocardial infarction, approach 40%,[10] and noncardiac surgical mortality occurs in 3.5% to 8% of patients.[10,11,15] Death occurs most commonly within the first 48 h of surgery and typically results from right heart failure.[12,16] The risk of death remains elevated after both minor and major surgeries, with a further increase in the context of emergency procedures.[13,15] No differential risk of complication or death has been demonstrated between anesthetic techniques.[16] Not surprisingly, patients with pulmonary arterial hypertension experience longer intensive care unit and hospital lengths of stay with higher 30-day readmission rates.[11]

Given the high risk of morbidity and mortality in the perioperative period for patients with pulmonary arterial hypertension, delaying elective procedures to undertake a thorough preoperative evaluation by a multidisciplinary team with specific consultation with a pulmonary hypertension specialist is warranted.[9] Pulmonary arterial hypertension is itself an independent predictor of perioperative complications.[17] Patient-risk factors of morbidity and mortality include a right atrial pressure greater than 7 mmHg and a 6-min walk test shorter than 399 m.[15] The preoperative period is thus an opportunity to optimize medical therapy and exercise capacity. Pulmonary vasodilators are generally routinely continued perioperatively.[18,19]

At present, the U.S. Food and Drug Administration has approved 14 pulmonary arterial hypertension–specific therapies that target four major molecular pathways all related to pulmonary vascular tone (Figure 1). Notably, none directly addresses pulmonary vascular remodeling or targets the right ventricle. Approaches to pulmonary arterial hypertension treatment and the pulmonary arterial hypertension–specific therapies have been thoroughly reviewed[2] and are summarized in figure 1. The management of severe pulmonary hypertension in the operative setting has similarly been comprehensively reviewed.[9]

Figure 1.

(A) Current pulmonary arterial hypertension (PAH)–specific therapies target four molecular pathways, all of which are directed at vasodilating the pulmonary vasculature. (1) Calcium channel blockers: The calcium channel blockers amlodipine, nifedipine, and diltiazem all block calcium entry into vascular smooth muscle cells (SMC), thereby preventing SMC contraction and pulmonary vasoconstriction. Unfortunately, this class of medications is only effective in less than 10% of PAH patients, and long-term responses are often limited. (2) Endothelin pathway: Endothelin acts through its endothelin A and B receptors (ETA and ETB, respectively) to cause vasoconstriction as well as SMC proliferation. Bosentan and macitentan are both dual endothelin receptor antagonists (ERA), whereas ambrisentan is a selective endothelin receptor A antagonist. (3) Nitric oxide pathway: Nitric oxide (NO) is a vasodilator that signals through soluble guanylate cyclase (sGC), which generates cyclic guanosine monophosphate (cGMP) and causes pulmonary artery SMC relaxation. The cGMP is subsequently degraded by phosphodiesterases (PDE). Accordingly, the (3) direct sGC stimulator riociguat and the (4) PDE5 inhibitors sildenafil and tadalafil drive the NO pathway to enhance vasodilation. The use of inhaled nitric oxide is currently reserved for the intraoperative and intensive care unit acute management of pulmonary hypertension treatment. (5) Prostacyclin pathway: Prostacyclin and prostanoids bind the IP receptor to stimulate cyclic adenosine monophosphate, which in turn causes pulmonary vasodilation. Various preparations of prostanoids are available and can be administered via different routes, including continuous infusion intravenously or subcutaneously, by inhalation, and orally. The prostanoids include epoprosternol, treprostinil, iloprost, and beraprost. Selexipag, in contrast, is the first nonprostanoid IP receptor activator. (B) Currently approved PAH-specific medications with their respective pathway target and mechanism of action. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CCB, calcium channel blocker; GTP, guanosine monophosphate; IP, Prostacyclin receptor; PGI, Prostaglandin I.

In this review, we deal separately with the chronic management of pulmonary arterial hypertension (the main focus herein) and the rescue of acute, decompensated right-sided heart failure or an acute PVR crisis. In the acute setting, the importance of pulmonary vasodilators and inotropic support cannot be overemphasized: reduction in PVR and support of the right ventricle represent the anesthesiologist's most pressing priorities. Pulmonary vasodilator drugs target one of four major pathways using several routes of administration. The cellular pathways in question involve L-type calcium channels, endothelin-1, nitric oxide, and prostacyclin.[9,20] Calcium channel blockers, specifically indicated for the subset of patients demonstrating positive vasoactive testing in the cardiac catheterization laboratory, can be used at high doses and should be terminated or supplemented by other drugs if no effect is noted.[6] Of note, significant systemic hypotension may arise as a result of calcium channel blockade in this population. Careful multidisciplinary consultation is advised for potential bridging to other drugs in the perioperative setting.

Endothelin receptor antagonists (bosentan, macitentan, ambrisentan) are among the best-studied drugs for the chronic management of pulmonary arterial hypertension. The landmark Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome trial demonstrated the efficacy of macitentan in pulmonary arterial hypertension patients for decreasing risk of a primary outcome of clinical worsening, lung transplantation, atrial septostomy, initiation of prostanoids, or death.[21] Importantly, patients taking macitentan may develop both elevated liver enzymes and anemia, so testing liver function and hemoglobin concentration before major surgery would be prudent.[21] Although macitentan has a clinical effect shortly after initiation of therapy, patients should ideally be at a steady-state with respect to their disease before nonemergent surgery.

Nitric oxide is a potent pulmonary vasodilator, endogenously produced in the lung endothelium, acting through the production of cyclic guanosine monophosphate by the enzyme soluble guanylyl cyclase.[22] Patients with pulmonary arterial hypertension often produce less NO, as part of an overall endothelial dysfunction and imbalance of vasoconstrictor versus vasodilator substances.[23] Pharmacologically, NO can be targeted in three ways: by delivering inhaled NO acutely,[24] using oral phosphodiesterase-5 inhibitors (sildenafil, tadalafil) to decrease cyclic guanosine monophosphate breakdown,[25] or more recently, using an activator of soluble guanylyl cyclase (riociguat).[26] For acute use, inhaled NO can be attached to an anesthesia circuit for rapid addition, and has a long history of successful use in the acute intraoperative setting.[9] The ongoing INOvation-1 trial is a placebo-controlled, randomized, controlled trial designed to evaluate the long-term safety and efficacy of inhaled NO in pulmonary arterial hypertension ( NCT02725372). The chronic vasodilatory effects of sildenafil and other drugs discussed herein should give pause to anesthesiologists, as they can cause hypotension, have antiplatelet effects, and may also inhibit hypoxic pulmonary vasoconstriction during thoracic surgery and one-lung ventilation.[9,27] Stable patients are unlikely to be successfully transitioned away from these drugs before elective surgery, so continuing them through the perioperative period, with knowledge of their potential adverse effects under anesthesia, is of paramount importance.

Finally, another mainstay drug class in the therapy of pulmonary arterial hypertension are the prostanoids. These drugs can be inhaled for acute use, delivered by continuous intravenous infusion, or given orally in a new formulation.[6] The inhaled formulations demonstrate a high degree of specificity for the pulmonary vasculature, and can synergize with inhaled or intravenous milrinone as well.[28] These drugs are direct vasodilators of the pulmonary circulation, while also providing some antiplatelet and anti-inflammatory benefit.[23] In the commonest form for chronic use, intravenous epoprostenol is delivered centrally via continuous infusion. In the operating room, such a system requires the utmost vigilance, as access to the line, as well as its patency, must be maintained or a critical PVR crisis may arise upon discontinuation.[6] Furthermore, meticulous sterile technique must be maintained, because line infection and loss of central access is a devastating complication for this group.[29]

In summary, great care and planning must go into the surgical care of pulmonary arterial hypertension patients. Multidisciplinary involvement is critical, and major surgery should be carried out in centers with appropriate postoperative intensive care available. The specific interactions of pulmonary arterial hypertension therapies with anesthesia and surgical insults (including systemic hypotension, antiplatelet effects, interaction with other vasodilators, the need for special access and delivery equipment, and other considerations) necessitate holistic planning on the part of the perioperative team for the safe management of a high-risk population.[29]