Aerosolized Prostacyclin vs Inhaled Nitric Oxide
Pulmonary hypertension (PH) is a serious disease that arises from several different etiologies: pulmonary vascular, lung, or cardiac diseases. In addition to chronic disorders, acute events, such as acute respiratory distress syndrome (ARDS), pulmonary embolism, acute left ventricular dysfunction, or cardiothoracic surgery, can also cause PH (Zamanian et al. Crit Care Med. 2007; 35[9]:2037). PH occurs primarily through the down-regulation of endogenous vasodilators (nitric oxide and prostacyclin) and the up-regulation of the endogenous vasoconstrictor endothelin-1 (Weitzenblum and Chaouat. Pulmonary Circulation: Diseases and Their Treatment. 2nd Edition. New York, NY: Oxford University Press; 2004:376; Ishikawa et al. J Thorac Cardiovasc Surg. 1995; 110[1]:271). The consequence of this imbalance is increased pulmonary vascular resistance (PVR), eventually leading to right ventricular hypertrophy and ischemia. Systemic vasodilators, while effective in decreasing pulmonary artery pressure (PAP) and PVR, may induce systemic hypotension and worsen right ventricular function. Local administration of vasodilators through inhalation can reduce PAP and PVR with minimal effects on systemic arterial pressure. In addition, inhaled vasodilators may improve arterial oxygenation by redistributing pulmonary blood flow to ventilated areas of the lung and reduce intrapulmonary shunt (Lowson. Anesthesiology. 2002;[6]:1504; Kemming et al. Eur Surg Res. 2002; 34[1-2]:196).
Inhaled nitric oxide (iNO) was the first inhaled vasodilator investigated and has gained widespread off-label clinical use for PH due to various causes (Lowson. Anesthesiology. 2002;96[6]:1504; Kemming G. Eur Surg Res. 2002;34[1-2]:196). Nitric oxide (NO) is a gaseous molecule that is synthesized endogenously from the amino acid L-arginine via nitric oxide synthase. The primary effects of NO include vasodilation of pulmonary vessels secondary to activation of soluble guanylate cyclase, inhibition of platelet aggregation and leukocyte adhesion, and modulation of bronchomotor tone (Riddell and Owens. Vitam Horm. 1999;57:25; Hickey and Kubes. Exp Physiol. 1997;82[2]:339; Giaid and Saleh. N Engl J Med. 1995;[4]:214). NO has a half-life of about 3 to 50 s, and standard doses used in clinical practice range from 5 to 40 ppm (Ignarro. Circ Res. 1989;65[1]:1; Dellinger et al. Crit Care Med. 1998;26[1]:15). NO is inactivated via hemoglobin. Methemoglobinemia can be a byproduct, but this is uncommon with doses < 40 ppm ( Jindal and Dellinger. J Lab Clin Med. 2000;136[1]:21). Although several trials have evaluated iNO for acute lung injury (ALI), none have demonstrated significant mortality benefit (Taylor et al. JAMA. 2004;291[13]:1603; Jindal and Dellinger. J Lab Clin Med. 2000;136:21). In addition, its use is limited by cost and need for special delivery equipment. As such, there is a growing interest for potential alternatives, such as aerosolized prostacyclin (prostaglandin I2, epoprostenol).
Epoprostenol (PGI2), a prostacyclin derivative, is formed by arachidonic acid metabolism. It stimulates adenylate cyclase receptors to activate cyclic adenosine monophosphate and protein kinase A, resulting in smooth muscle relaxation and pulmonary vasodilation. PGI2 has a short half-life of 3 to 6 min, with the most common adverse effect from systemic administration being hypotension (see Flolan® package insert). Epoprostenol can also be aerosolized via jet or ultrasonic nebulization, which offers the advantage of lower systemic side effects while effectively achieving pulmonary vasodilation (Siobal. Respir Care. 2004;49[6]:640). Additionally, epoprostenol has no known toxic metabolites, and its inhalation could be considerably safer and cheaper than iNO (De Wet et al. J Thorac Cardiovasc Surg. 2004;127:1058).
iNO vs PGI2: Pulmonary Hypertension
Inhaled PGI2 was compared with iNO for the management of primary (n=7) and secondary (n=5) PH. All patients received PGI2 at increasing doses of 15 to 50 ng/kg/min for a period of 20 min with a 10-min washout between doses, while eight patients received iNO at doses of 10 to 100 ppm, as well as IV prostacyclin at doses of 1 to 5 ng/kg/. Hemodynamic measurements were taken before, during, and after each treatment. Nebulized PGI2 produced greater decrease in PAP (54 ± 5 to 44 ± 5 mm Hg, P =.0005) compared with iNO (54 ± 5 to 48 ± 5 mm Hg, P =.02), as well as PVR (38% vs 12 %, respectively, P =.0001). No dose-dependent effect of inhaled PGI2 was identified, which suggests that lower doses could be used to attain significant response. There was no change in systemic arterial pressure with either agent (Mikhail. Eur Heart J. 1997;18[9]:1499). Short-term effects of aerosolized PGI2 (52-112 mcg/kg/min), iNO (10-28 ppm), and iloprost were compared in six patients with PH. PGI2 was nebulized for 15 min and resulted in greater reduction in pulmonary hemodynamics: PAP (18%), PVR (41%) (P <.05). There was a significant improvement in CO and Svo2 and a nonsignificant change in systemic arterial pressure (Olschewski. Ann Intern Med. 1996;124[9]:820). Another study evaluated short-term response after 10 min of aerosolized PGI2 (20-30 mcg via nebulization) compared with iNO (40 ppm) in 10 patients with PH awaiting heart transplantation. Both PGI2 and iNO had a similar effect on mean PAP (7% reduction) and PVR (49% vs 43% reduction, respectively), while PGI2 had a significantly greater effect on CO (11% increase vs 0%) (Haraldsson. Chest. 1998;114[3]:780).
iNO vs PGI2: Following Cardiothoracic or Transplant Surgery
Inhaled PGI2 (3 mcg/min) and iNO (20 ppm) were examined in 58 intubated patients with mitral valve stenosis and elevated PVR after mitral valve surgery. Drugs were given for 30 min followed by a 15-min washout. PGI2 and iNO significantly reduced PVR (50% vs 45%, respectively), mean PAP (20% vs 19%, respectively), and transpulmonary gradient (TPG) (64% vs 62%, respectively) (Fattouch et al. J Card Surg. 2005;20[2]:171). These same authors also reported significant reductions in mean PAP and PVR with inhaled PGI2 and iNO compared with systemic therapy, as well as significant improvements in cardiac indices, weaning from cardiopulmonary bypass, and shorter intubation times and ICU stay (Fattouch et al. J Cardiovasc Med. 2006;7[2]:119).
Inhaled PGI2 has also been evaluated following lung and heart transplantation in 25 patients who were randomized to inhaled PGI2 (20,000 ng/mL) or iNO (20 ppm) as initial therapy, followed by a crossover to the other agent after 6 h. Both PGI2 and iNO similarly improved hemodynamics (cardiac index [CI], central venous pressure [CVP], Svo2) and PAP initially and at the 6-h crossover trial (change in mean PAP: 13 ± 1 mm Hg, 95% CI 9-16 and 12 ± 1 mm Hg, 95% CI 9-15, respectively. P =.32). Neither agent affected the oxygenation index or systemic blood pressure (Khan. J Thorac Cardiovasc Surg. 2009;138[6]:1417).
iNO vs PGI2: ARDS
Five patients with hypoxemia secondary to ARDS were examined after receiving 30 min of either iNO (10 ppm) or aerosolized PGI2 (50 ng/kg/min) in a crossover study. The increase in Pao2 post PGI2 therapy (29%) compared with iNO (12%) was not statistically significant (P =.06). Hemodynamic parameters (mean arterial pressure, CI, CVP, pulmonary capillary wedge pressure) and shunt fraction did not change significantly (van Heerden et al. Anaesth Intens Care. 1996;24[5]:564). Inhalation of NO and PGI2 was compared in a dose-response study in eight patients with ARDS (1, 4, 8 ppm and 1, 10, 25 ng/kg/min for 15 min each, respectively). PGI2 resulted in significant, dose-dependent reduction in mean PAP, while iNO did so only at 4 and 8 ppm. PGI2 reduced PVR by 20% at 10 ng/kg/min only, while iNO had no significant effect on PVR. Increases in Pao2 were significant with PGI2 doses of 10 (+18%) and 25 (+ 24%) ng/kg/min and all doses of iNO, with 8 ppm resulting in the greatest increase (+ 45%). Only iNO produced a significant decrease in intrapulmonary shunt (Zwissler. Am J Respir Crit Care Med. 1996;154[6]:1671- 1677; Lowson. Anesthesiology. 2002;96[6]:1504). Both agents were investigated in a dose titration study for 48 h to find maximum improvement of arterial oxygenation and the lowest effective dose in 16 patients with ARDS. Mean doses of iNO and PGI2 that resulted in similar and significant increase in Pao2/Fio2 and significant decrease in intrapulmonary shunt were 17.8 ± 2.7 ppm and 7.5 ± 2.5 ng/kg/min, respectively. Inhaled PGI2 produced a significantly greater decrease in mean PAP and PVR than iNO, with little impact on systemic arterial pressure (Walmrath et al. Am J Respir Crit Care Med. 1996;153[3]: 991-6). The use of iNO and inhaled prostacyclin in ARDS and ALI has been recently reviewed (Puri and Dellinger. Crit Care Clin. 2011; 27[3]:561-87; Siobal and Hess. Respir Care. 2010;55[2]:144).
Conclusion
Based on the available evidence, it appears that inhaled PGI2 is as effective as iNO for short-term management of PH and impaired oxygenation with potentially fewer side effects, lower costs, and greater ease of administration. However, further randomized, controlled studies are needed to prove the efficacy of inhaled PGI2 and determine its place in therapy for patients with PH.
Marina Rabinovich, PharmD;
Derek Burden, PharmD;
Vivian Liao, PharmD; and
Prasad Abraham, PharmD
Grady Health System
Atlanta, GA
Comment From the Guest Editor
Pulmonary hypertension is a life-threatening condition that, left untreated, portends a poor prognosis. Although the pathophysiology of PH is not fully understood, it is known that the condition involves an imbalance between endogenous vasodilators and vasoconstrictors. Several novel therapeutic strategies to combat PH are currently under investigation. Inhaled PGI2 demonstrates potential as an effective, yet safe, option for treating patients with PH. We look forward to further investigation and development of aerosolized prostacyclins for the treatment of PH.
DR. MARSHALEEN HENRIQUESFORSYTHE,
Director, Pulmonary
Hypertension Clinic, Morehouse
School of Medicine, Atlanta, GA
