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Selective Pulmonary Vasodilators for Pulmonary HypertensionAndrew Maslow, MD
The low pressure compliant pulmonary vascular system offers little resistance to right ventricular ejection and provides a large surface area for gas exchange. This is largely due to the effects of nitric oxide (NO) and prostacyclin (PGI2) released from the pulmonary vascular endothelium and alveolar macrophages.1-5 Activation of guanylate and adenylate cyclase by NO and PGI2 respectively, increases intracellular cyclic-guanosine monophosphate (cGMP) and adenosine monophasphate (cAMP). These secondary messengers activate protein kinases, which reduces calcium influx, dephosphorylates myosin light chains, and promotes vascular relaxation.1-7 Both NO and PGI2 depress platelet and inflammatory cell function activation and aggregation, and proliferation, all of which are responses to stress, hypoxemia, and disease. Normal cellular suppression reduces chemical mediators from the pulmonary endothelium cells (endothelin-1; subtype ETA), platelets (thromboxane, serotonin), and inflammatory cells (cytokines, interleukins 1 and 6, and tumor necrosis factor) which counter the effects of NO and PGI2 and cause pulmonary vascular constriction and remodeling resulting in pulmonary hypertension. Pulmonary hypertension (PHTN) is defined as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg at rest or > 30 mmHg with exercise. Alternatively, PHTN can be defined by a pulmonary vascular resistance (PVR) > 2 -3 Wood units or > 200 - 300 dynes s-1 cm-5. The microcellular development of PHTN is complex, involving platelet activation and aggregation, pulmonary vascular smooth muscle and endothelial cell proliferation, endothelial cell dysfunction, and activation and influx of inflammatory mediators. These cause acute and chronic changes of the pulmonary vascular architecture resulting in vasoconstriction, pulmonary 'vascular remodeling' and subsequent PHTN. Causes of perioperative of PHTN include hypoxemia, acidosis, inflammation, hypothermia, changes in sympathetic stimulation, and pulmonary endothelial dysfunction. These lead to cellular activation and aggregation, release of vasoconstrictors, and a reduction of NO and PGI2.1-4 Hypoxic pulmonary vasoconstriction (HPV) reduces blood flow to poorly oxygenated alveoli, and shifts blood toward oxygenated alveoli. Although this improved matching of ventilation and perfusion is initially protective, persistent HPV results in PHTN and vascular remodeling. Pulmonary endothelial dysfunction is a contributor to PHTN seen after cardiopulmonary bypass.1-4 Regardless of its cause or onset, PHTN results in varying degrees of pulmonary dysfunction, and/or right heart dysfunction. Transient changes are usually managed by supporting the respiratory and cardiovascular systems, however if severe and/or allowed to continue, cardiopulmonary failure develops, increasing mortality. There is increasing emphasis on the need to diagnoses PHTN, assess the severity and reversibility, and administer therapy to improve function and prevent exacerbations. This is best illustrated in the cardiac transplant patient with preoperative PHTN. Preoperative assessment predicts the reversibility of PHTN to prevent RV failure due to the acute increase of RV afterload to the donor heart. Management of PHTN includes treatment of its cause, correction of metabolic abnormalities (hypothermia, acidosis), reduction of the sympathetic response, anticoagulation, and, for acute cases, support of the cardiopulmonary systems. The latter often involves a combination of oxygen therapy, mechanical ventilation when necessary, and manipulation of cardiac (especially the right heart) loading conditions. While a balance is sought between too much and too little preload, a reduction in RV afterload (pulmonary vasodilation) and maintenance of right coronary perfusion are desirable. Available pulmonary vasodilators can be categorized by selectivity, by pharmacologic class, and by route of administration. Medications either directly or indirectly (NO donors; nitroglycerin (NTG); sodium nitroprusside (SNP)) stimulate adenyl or guanylyl cyclase, or inhibit hydrolysis of cAMP or cGMP (phosphodiesterase inhibitors (PDEi). Sympathetic agonists (epinephrine) and prostaglandins (PGE1, PGI2) activate adenyl cyclase, and/or inhibit platelet function and cellular activation (PGI2). Nitric oxide is the only therapy approved by the FDA for inhalation (INO) administration, and only for treatment of near-term newborns with acute lung injury and persistent pulmonary hypertension. Since its identification as endothelium-derived relaxing factor (EDRF) in 1987 and the delineation of its role in biology by 1998, nitric oxide has been extensively studied allowing establishment of guidelines.1-7 Although FDA approval is limited for newborns with PHTN, INO has been administered safely to both pediatric and adult patients with PHTN. Inhaled NO (1-40 parts per million (ppm)) causes selective pulmonary vasodilation, inhibition of the function, adhesion and activation of inflammatory cells and platelets, inhibition of cell proliferation, and reduction in intrapulmonary shunt.1-3 Reductions in mPAP and PVR are proportional to the severity of PHTN and associated with improvement in right heart function, and increases in cardiac output.5-8 Dilation of pulmonary vessels associated with alveoli delivering the NO results in improved matching of ventilation and perfusion and reduction in intrapulmonary shunt.5-8 Although clinical benefits have been demonstrated across a wide range of patients, a 20-30% hypo-response rate has been described, and the benefit for patients with chronic obstructive lung disease is not clear, perhaps due to abnormal airways.1-7 The absence of systemic vasodilation after inhalation of NO is the result of rapid binding to hemoglobin to form methemoglobin. Serum methemoglobin levels in cardiac surgical patients have been reported on average 1.9%.5-8 High doses (> 500 ppm) result in platelet dysfunction, pulmonary alveolar edema and hemorrhage, alveolar hyperplasia, hypoxemia, depletion of pulmonary surfactant, pulmonary accumulation of inflammatory cells, and death due to acute respiratory failure.5-8 Rapid discontinuation of INO may lead to rebound PHTN and severe respiratory failure. NO can be cytotoxic and cause DNA damage. Practical problems with the delivery of INO exist. The necessary specific equipment costs 3,000 dollars for the first day and 125 dollar/hour thereafter.8 An analysis of 17 adult cardiac surgical patients with PHTN recorded an average cost of 6,417 dollars for a mean administration of 30.2 hours per patient.8 Since a specific delivery system is required INO is not readily available like other vasoactive medications at our disposal.
Alternative pulmonary vasodilators include intravenous NTG, SNP, prostaglandins (PGE1, PGI2) and PDEi, which are known to dilate both the pulmonary and systemic circulations.1-4,9-11 Schmid et al compared inhaled NO (40 ppm) to intravenous PGE1 (0.1 ug/kg/min) and intravenous NTG (3-5 ug/kg) in 14 cardiac surgical patients with postoperative PHTN. All three medications reduced mPAP and PVR, while only INO and PGE1 increased cardiac index.11 While PGE1 and NTG reduced mean systemic arterial pressure, INO produced selective dilation of the pulmonary circulation.11 Other data report the need for high dose norepinephrine (> 1-2 ug/kg/min) in more than 50% of patients receiving intravenous prostaglandin.1,9,10 In contrast to INO, intravenous NTG and PGE1 increase intrapulmonary shunt.1-9,11,12
Data have demonstrated selective pulmonary vasodilator effect of inhaled NTG, SNP, PGI2, PGE1, and PDEi (milrinone PDEi III; Zaprinast PDEi V).1-7 Benefits include reductions in mPAP, PVR, increases in cardiac output, and reductions in intrapulmonary right to left shunting without reductions in systemic arterial pressure.1-3,12-17 Compared to INO, these medications are as efficacious and easier to prepare and administer using simple nebulizers.
Of these alternatives, inhaled prostacyclin (Epoprostenol, Prostacylcin, Flolan) or its derivative (Iloprost) have been studied more extensively. Data reports selective reductions in PVR, and mPAP within minutes of its administration, which may last up to one hour or longer.1-7 Inhaled PGI2 has compared favorably to INO regarding improved right heart function, reductions in mPAP, PVR, and decreased intrapulmonary shunt.1-3,12,13,15,16 Reduction of mPAP and PVR range from 15-40% of baseline along with up to 10% increases in cardiac index.1-3,12-16 Dosing varies from single inhaled doses of 15-20 ug to continuous doses of 2-70 ng/kg/min using simple nebulizers.1,12-16 Intravenous, and not inhaled, administrations is associated with reductions in systemic blood pressure, flushing, headache, jaw pain, and diarrhea.13-15 Preparation of inhaled prostacyclin, supplied as a powder, requires mixing with saline and/or glycine, the latter of which has been associated with excess moisture in the gas sampling tubing and, in one case, obstruction of the expiratory valve of the breathing circuit.15
Compared to INO, inhaled PGI2 is significantly less expensive and easier to deliver.8,15 For 126 patients who received inhaled prostacyclin for a mean of 45.6 hours, the cost was 35,878 dollars (150 dollars/day). If INO were administered instead of PGI2 the total study cost would have been 717,564 dollars (125 dollars/hour), a difference of 681,686 dollars.8,15
Alternatively, inhaled milrinone and nitroglycerin have also resulted in similar selective reductions of mPAP, PVR and intrapulmonary shunt.16,17 Combining inhaled milrinone and PGI2 resulted in an additional 5-8% improvement in cardiac indices than either medication alone, without reduction in systemic blood pressure.16 Both nitroglycerin and milrinone are mixed in saline and may be simpler, safer, and cheaper alternatives.
Prophylactic administration of continuous nebulized prostacyclin during 90 minutes of CPB was compared to an untreated CPB group (CPB without PGI2.18 Significant benefits of the study group included lower post CPB mPAP, preservation of pulmonary endothelial function and reactivity, and improved oxygenation.
The indications for inhaled pulmonary vasodilators are not known since they are considered experimental (i.e. not FDA approved). However, on-going experience and continued data collection will further delineate the role of inhaled selective pulmonary vasodilators, alone or in combination, for the treatment of PHTN, especially when complicated by hypoxemia, and/or right heart failure. Alone or in combination with other therapies, inhaled selective pulmonary vasodilators offer unique benefits for patients with PHTN and secondary dysfunctions. Although effects may be transient, they may last long enough to treat acute increases in mPAP, or exacerbations of chronic PHTN during the perioperative period. Continued research will likely result in greater acceptance and approval for the use of these inhaled alternatives to NO. Newer therapies will be more specific for abnormalities in ion channels, endothelin receptors, the inflammatory system, and causes of cellular proliferation.1-4
The alternatives to INO discussed above meet the needs of the perioperative intensivist in that they can be prepared and administered with relative ease at a significant cost reduction, and would be at our disposal '24/7'.
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