Since PH has a high mortality rate perioperatively (11-13) as shown in table 3, appropriate pharmacological control of PAP will be critical for the successful management of these patients perioperatively. Ideally all symptomatic patients should be treated preoperatively. There are multiple pharmacological agents for the control of increased PAP. The pharmacological treatment is believed to be the cornerstone of managing patients with pH perioperatively. Pharmacological management of perioperative PH is discussed as following.
Oxygen supplement is one of the most critical elements in the management of perioperative PH. Though there is no controlled clinical study to analyze the effect of oxygen on the outcome of patients with PH, hypoxemia will be very devastating to these patients, because hypoxemia per se may induce hypoxemic pulmonary vasoconstriction (14, 15).
Inhaled Nitric Oxide
Inhaled nitric oxide (iNO) is one of the most potent medications in lowering PAP commonly used perioperatively. The usual dose is 20-80 ppm (parts per million). The iNO delivery system includes a control panel, a circuit, a nitric oxide tank and related special tubing (Figure 2). iNO can diffuse from the alveoli to the pulmonary capillaries and assert its biological function via stimulating guanylate cyclase and increasing intracellular cyclic guanosine monophosphate (cGMP) level which leads to pulmonary vasodilation. In general, iNO does not produce systemic vasodilatation or hypotension, because nitric oxide is immediately deactivated when bound to hemoglobin, so it can only act locally. It also has the benefit of improving ventilation-perfusion matching by increasing perfusion to areas of the lungs which are well ventilated. iNO has also been shown to improve PH during cardiopulmonary bypass settings (16-18). iNO may increase the risk of perioperative renal dysfunction, especially in prolonged use and in patients with acute respiratory distress syndrome (ARDS) (19).
Milrinone is a phosphodiesterase-3 inhibitor. It prevents the breakdown of cyclic adenosine monophosphate (cAMP). Milrinone can potentially reduce both PVR and systemic vascular resistance (SVR) in addition to inducing increases in myocardial contractility (20). If the clinical picture is of PAH with coexisting systemic hypotension, intravenous vasodilators may cause worsening of systemic hypotension, and subsequently leading to ventricular hypoperfusion, ischemia and potential heart failure. For patient with this situation, selective pulmonary vasculature dilators such as iNO or prostacyclin will benefit patient tremendously more. The usual loading dose of milrinone is 50 mcg/kg, and the maintaining dose is at 0.25-0.75 mcg/kg/minute.
Calcium Channel Blockers
Several calcium channel antagonists have been shown to inhibit the contraction of pulmonary artery smooth muscle cells, thus lowering PAP, reducing the right ventricular hypertrophy, and improving long-term hemodynamics in patients with PH (21). Only in a small subset of patients has been shown to have an acute hemodynamic response to calcium channel blockers. An investigation yielded an interesting finding that survival was greatly improved in patients who showed a long-term response to calcium channel blockers; patients who failed on long-term calcium channel blocker therapy, the 5-year survival rate was only 48% (22). Currently, calcium channel blockers are only used for patients with a positive response during acute vasoreactivity testing and patients who have shown hemodynamic improvement (22, 23). Calcium channel blockers are the only systemic antihypertensive drugs shown to benefit patients with PH. By blocking calcium entry into the smooth muscle cells of the pulmonary arterial vasculature, calcium channel blockers can induce pulmonary arterial vasodilation (or at least prevent vasoconstriction) (22). There is another study showed that in patients who demonstrated a response to calcium channel blockers during acute testing, use of calcium channel blockers could lead to a significant reduction in mPAP and PVR after 24 hours of treatment. Continued use over one year was associated with improvements in symptoms (24).
Prostaglandin Related Drugs
Prostacyclin is an endogenous eicosanoid produced by endothelial cells. It enhances vasodilation through actions on vascular smooth-muscle cells. Iloprost is a synthetic analogue of prostacyclin PGI2. It can be nebulized into inspiratory limb of the ventilatory circuit. An example of a prostacyclin nebulizing delivery system that can be integrated into the anesthesia circuit is shown in figure 3. Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of PH is unknown. There are two diastereoisomers of iloprost which differ in their potency in dilating blood vessels, with the 4S isomer being substantially more potent than the 4R isomer. Prostacyclin, available in inhaled and intravenous forms, stimulates adenylate cyclase and increases cAMP and release of endothelial NO leading to decreases in PAP, right atrial pressure (RAP), and increase in cardiac output (25, 26). Epoprostenol was the first prostacyclin therapy approved for the management of PAH. Randomized, controlled, clinical trials in PAH demonstrated improvements in exercise tolerance, as measured by the 6 minute walking distance test (6MWD), hemodynamics, quality of life, and survival over a 12-week period. Long-term observational series have also suggested improved survival on intravenous epoprostenol synthase expression is decreased in lungs from patients with severe PH (25). Combination therapy, with both iNO and prostacyclin, has also been shown to enhance the therapeutic effects compared to monotherapy (18, 27). Due to the extremely short half-life of these medications, one should ensure that the medication is delivered continuously without interruption to minimize the risk of rebound PH. Weaning from these medications should be performed gradually with frequent assessment of PAP and the right ventricle (RV) function. A disadvantage of iNO compared to inhaled prostacyclin is its very high cost. A recent analysis revealed that iNO is approximately 20 times more expensive than inhaled prostacyclin ($3000/day vs. $150/day) (27).
Continuous Intravenous Infusion of Prostacyclin
Prostacyclin comes in different formulations, inhaled, intravenous and subcutaneous. Continuous intravenous administration of prostacyclin 50 ng/kg/minute after reconstituting prostacyclin in sterile glycine diluent to 30,000 ng/ml (1.5 mg of prostacyclin in 50 ml of diluent) can help patients with PH (28). For an 80 kg patient, 50 ng/kg/minute will be 8 ml per hour. The usual intravenous dose is 4-10 ng/kg/minute. In the US, ventavis is supplied in 1 ml single-dose glass ampules containing either 10 mcg/ml or 20 mcg/ml. The 20 mcg/ml concentration is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times which could result in inadequate dosing. Transitioning patients to the 20 mcg/ml concentration using the I-neb adaptive aerosol delivery (AAD) System will decrease treatment times to help maintain patient compliance. The approved dosing regimen for iloprost is 6 to 9 times daily (no more than every 2 hours) during waking hours, according to individual need and tolerability. Iloprost is inhaled specifically using the I-Neb AAD or Prodose AAD delivery systems.
Thromboxane Synthase Inhibitor
Dipyridamole can be used intraoperatively in managing patient with PH. The usual dose of dipyridamole is 0.2-0.6 mg/kg intravenously over 15 minutes, repeat after 12 hours. Lepore et al. (29) reported combining intravenous dipyridamole with iNO in 9 patients with congestive heart failure (CHF) and severe PH who were breathing 100% oxygen during right heart catheterization. The authors compared administered iNO (80 ppm) alone and in combination with intravenous dipyridamole (0.2 mg/kg bolus, with an infusion of 0.0375 mg/kg/minute), and they found that intravenous dipyridamole augments and prolongs the pulmonary vasodilator effects of iNO in CHF patients with severe PH.
Diuretics helps patient with edema due to various causes. Its use in the treatment of PH patients with peripheral edema is also widely accepted. Majority of the patients can have some improvement and reduction of shortness of breath. Spironolactone 12.5 mg in combination with angiotensin inhibitor could reduce two-year mortality from 46% to 35% (30). Amiloride has been shown to reduce PH from hypoxia in animal models. There is no clinical human study on the effect of amiloride on primary pulmonary hypertension. The mechanism of amiloride is associated with the prohibition of sodium-proton pump's replacement. The right ventricular failure might require large amounts of diuretics. Some patients will need 600 mg of furosemide and 10 mg of bumetanide on daily basis (30).
Sildenafil can produce significant pulmonary vasodilatory effect in anesthetized cardiac surgical patients with PH. The selective effects of sildenafil on pulmonary vasculature and other potentially beneficial effects such as myocardial protection make sildenafil very useful in the perioperative period in cardiac surgical patients with PH (23). Sildenafil citrate (INN sildenafil) is a selective PDE type-5 inhibitor, which is being increasingly recognized as a treatment modality for PH.
Endothelins induce blood vessel constrictions and raise blood pressure. Endothelin receptor antagonists selectively block endothelin-A receptors or work by dual blockage of endothelin-A and -B receptors. These endothelin receptor antagonists can decrease blood pressure and lower PAP (31).
Bosentan is a nonselective endothelin-A and -B receptor antagonist, which has been shown to have symptomatic improvement in all Class II, III and IV patients with PAH in randomized, multicenter, placebo-controlled clinical trials (1, 32). Bosentan is currently widely used in patients with PAH. When patient is treated with bosentan, close follow-up of both efficacy and safety is encouraged, and Food and Drug Administration (FDA) requires liver function monitoring on monthly basis. In addition to hepatic complications, other side effects from bosentan treatment could include headache, anemia, and edema.
Ambrisentan is a selective endothelin-A receptor antagonist which has also been studied in multicenter, randomized, placebo-controlled trials. Treated PAH patients also demonstrated an improvement in 6MWD and time to clinical worsening (33). The FDA no longer requires monthly liver function test monitoring for patients taking ambrisentan.
Macitentan is another nonselective endothelin-A and -B receptor antagonist. Macitentan has a unique feature which is its increased tissue penetration and more sustained receptor blockade when compared with bosentan (34). Phase III long-term morbidity and mortality trial showed a 30% and 45% risk reductions in the primary endpoint with the 3- and 10-mg doses, respectively. Macitentan was FDA-approved to delay disease progression (including death), initiation of prostanoid therapy, or clinical worsening in PAH. Unlike bosentan, monthly liver function test monitoring is not required by FDA. There is a report stating that severely worsening dyspnea was found after initiation of macitentan therapy for a patient with PAH (35).
Beta-Adrenergic Receptor Blocker
Beta-blockers have been shown to decrease mortality in left-sided heart failure. Patients with PH may have other cardiac comorbidities where β-blocker therapy could be indicated. The results of a cohort study of 564 PAH patients from 1982 to 2013 showed no difference in absolute mortality between those with and without β-blockers (P=0.71). Thus β-blocker use is believed not associated with increased all-cause mortality after adjusting for propensity score (adjusted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5) and in the matched cohort (hazard ratio, 1.2; 95% confidence interval, 0.8-2.0). Therefore the authors considered that β-blocker therapy can be used in patients with PH and it is not associated with significant increase in long-term mortality (36).
Complex medical conditions will need comprehensive management. Combination therapy is the most commonly applied strategy in clinical management of patients with PH (29). Combining inhaled iloprost and oral sildenafil was reported to achieve better clinical outcomes by Wilkens et al. Oral sildenafil induces a long-lasting reduction in mean PAP and PVR, and iloprost inhalation brings additional improvement in reduction of PAP and PVR (36). A meta-analysis conducted by Bai et al. of all randomized controlled combination therapy trials that evaluated efficacy and safety in PAH patients showed that combination therapy in 858 patients reduced clinical worsening (relative risk [RR] 0.48, P=0.023), increased the 6MWD significantly by 22.22 meters, and reduced mPAP, RAP and PVR, when compared with the control group. The incidence of serious adverse events was similar in the 2 groups (RR 1.17, P=0.77). Unfortunately based on this meta-analysis, combination therapy did not seem to influence long-term mortality of patients with PH. Therefore, the authors concluded that treatment of PH with combination therapy improves multiple clinical and hemodynamic outcomes, but not mortality (37).
Table 4 lists the medical management options, including common doses and common side effects, for intraoperative management of PH. Lastly, patients who are refractory to the above therapies, right ventricular assist device implantation should be considered.