- Email: [email protected]
Con: Inhaled Prostaglandin as a Pulmonary Vasodilator instead of Nitric Oxide
Con: Inhaled Prostaglandin as a Pulmonary Vasodilator instead of Nitric Oxide Marc L. Dickstein, MD
I
NHALED NITRIC OXIDE (iNO) achieved favored status as a pulmonary vasodilator principally because of its remarkable pulmonary selectivity. Previously available methods for reducing pulmonary vascular resistance (PVR) were all accompanied by the risk of systemic hypotension. However, because iNO is immediately bound by hemoglobin, its vasodilatory effects are limited to the pulmonary vasculature at any dose. Although the only Food and Drug Administration (FDA)approved indication for the use of iNO is in the setting of respiratory failure of the newborn, iNO has been used off-label in a wide range of patients and clinical settings and with several very different objectives.1 For example, iNO is used to test vascular reactivity in pulmonary hypertensives,2,3 to reduce the incidence or severity of lung reperfusion injury after lung transplantation,4 to improve oxygenation in the setting of acute lung injury,5 and to either prevent or treat right heart failure.6-8 In fact, iNO was considered a true breakthrough in the treatment of perioperative right heart failure because maintenance of coronary perfusion pressure is so critical when reducing right ventricular afterload in this setting.9 In addition, because iNO preferentially dilates well-ventilated regions of the lung and thereby improves ventilation/perfusion matching and arterial oxygenation, iNO is used to correct life-threatening hypoxemia; this is despite the disappointing finding that iNO did not improve survival in patients with the acute respiratory distress syndrome.10,11 However, the improvement in oxygenation in hypoxic neonates and the resultant reduction in the need for extracorporeal membrane oxygenation12 was the breakthrough that won FDA approval for iNO therapy. After obtaining FDA approval in 1999, the cost of administration of iNO was set at what most clinicians (and hospital administrators) considered exorbitant ($3,000/day with a $12,000 cap). Understandably, this generated great interest in finding a less expensive alternative.13 Consequently, a wide variety of intravenous vasodilators were tested via the inhaled route with the expectation that maximizing drug levels at the target organ would minimize their systemic effects. In addition to prostacyclin (prostaglandin I2 [PGI2], which is discussed in detail later), clinical studies report selective pulmonary vasodilation by inhaled milrinone,14 NO adducts,15 nitroglycerin,16 sodium nitroprusside,17 prostaglandin E1,18 and a more stable analog of PGI2, iloprost.19 Based on a number of encouraging reports, numerous centers (and the accompanying “pro” paper) are now advocating that iPGI2 should be used instead of iNO. They argue that the actions of iPGI2 are equivalent to iNO, and iPGI2 is safer, easier, and less costly to administer than iNO. The purpose of this “con” section of the debate is to present evidence to the contrary. This article argues that (1) the appropriate studies have not yet been done to affirm equivalency of these 2 drugs; (2) assertions of the lack of systemic effects of iPGI2 represent overzealous interpretations of limited or poorly controlled studies; (3) the safety profile of iNO is quite good, whereas iPGI2 has a number of concerning safety issues; (4) the administration system for iPGI2 has a number of important limitations; and (5) the fact that a day’s supply of iPGI2 costs less than a day’s
supply of iNO does not necessarily translate into less overall cost. Irrespective of their actions, iNO and iPGI2 have a number of important pharmacologic differences. Firstly, the mechanism by which vasodilation occurs involves separate signaling pathways; NO works via the cyclic guanosine monophosphate signaling cascade, whereas PGI2 works via the cyclic adenosine monophosphate cascade. Secondly, the delivery to the site of absorption (the alveoli) is different; iPGI2 is administered as a nebulized liquid, much of which layers out in the ventilator tubing and large airways, whereas NO is a gas that is evenly mixed with nitrogen and oxygen. Thirdly, PGI2 and its metabolites reach the systemic circulation,20 whereas iNO is immediately bound and inactivated instantly by hemoglobin. Finally, the administration of PGI2 requires a continuous aspiration of a highly basic diluent (glycine), whereas nitric oxide is mixed in nitrogen gas. What is the evidence that iPGI2 and iNO are clinically equivalent? Most of the studies that compare iPGI2 and iNO report similar hemodynamic effects after very brief drug exposure.21-25 To date, there are no randomized trials in patients that compare iNO and iPGI2 to test whether there is any difference in outcome. The finding that there is a similar reduction in PVR after brief exposure does not necessarily mean that the 2 drugs have similar clinical efficacy. Furthermore, the pulmonary selectivity that was documented after brief exposure to iPGI2 may be lost during more prolonged therapy. Unlike iNO, PGI2 is known to cause hypotension when large doses are inhaled,26 its half-life is sufficiently long to allow for systemic effects, and systemic arterial levels of an active metabolite have been measured during inhalation of even small doses of PGI2; presumably, it is the lower dosing regimen and short duration of therapy that limit the systemic levels short of a clinical response. Therefore, it is not even clear if iPGI2 maintains its pulmonary selectivity during prolonged administration. The only study that describes the prolonged administration of PGI2 in a large series of patients was recently published by De Wet and colleagues.27 One hundred twenty-six postcardiothoracic surgical patients received iPGI2 for an average of 2 days. The authors found a reduction in mean pulmonary arterial pressure and stable mean arterial blood pressure during the first 4 to 6 hours of iPGI2 therapy. However, important methodologic issues preclude concluding that iPGI2 lacked systemic effects. For example, the authors state that “systemic arterial pressure was closely monitored, and the PGI2 dose was adjusted accordingly if a clinical change in blood pressure was
From the Division of Cardiothoracic Anesthesia, Columbia University College of Physicians and Surgeons, New York, NY. Address reprint requests to Marc L. Dickstein, MD, Division of Cardiothoracic Anesthesia, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail: [email protected] © 2005 Elsevier Inc. All rights reserved. 1053-0770/05/1903-0025$30.00/0 doi:10.1053/j.jvca.2005.03.037 Key words: prostaglandin, vasodilation, nitric oxide
Journal of Cardiothoracic and Vascular Anesthesia, Vol 19, No 3 (June), 2005: pp 403-405
403
404
MARC L. DICKSTEIN
observed.” Furthermore, the vasopressor doses continued to be titrated to blood pressure during the course of the study, so it should not be surprising that arterial blood pressure measurements did not change. Third, in the absence of a control group, it is difficult to separate the changes attributable to iPGI2 versus time, as improvements in mean pulmonary arterial pressure28 and shunt fraction29 are a matter of course in the first few hours after cardiac surgery. The relevant hemodynamic data were measured in a minority of the subjects; systemic vascular resistance was only measured in 24 of the 126 subjects and PVR in 6 of the 126 subjects. Therefore, the conclusion that the actions of iPGI2 are sustained and not associated with systemic vasodilation cannot be drawn from these data. What are the safety issues that would influence the choice of iNO versus iPGI2? The main safety concern about iNO is the risk of significant methemoglobinemia, whereas the main safety concern about iPGI2 is related to the sticky and highly alkaline drug vehicle. When iNO was first introduced into clinical use, the typical doses were considerably higher than what is used today and development of significant levels of methemoglobin was not uncommon. Subsequently, it was recognized that most of the hemodynamic benefits of iNO are realized with doses of 20 ppm or less,30 and most of the improvement in oxygenation is accomplished with doses of 5 ppm or less. At these levels, the incidence of significant methemoglobinemia (⬎5%) is rare.31,32 iNO has been studied in a large number of trials and is FDA approved as inhalation therapy in neonates. Although no survival benefit was found in acute respiratory distress syndrome trials, these studies did serve to establish the safety of this technique in large populations. In contrast, the safety of PGI2 administered via the inhaled route has not been established. The glycine diluent has a pH of 10.5 and was shown in 1 study to be associated with a mild tracheitis after short-term use.33 Additionally, there is 1 case report of a young woman who developed a severe interstitial pneumonia that was thought to be caused by iPGI2.34 Furthermore, the diluent is quite sticky and poses a risk to the integrity of valves in the ventilator circuit. In the study by De Wet et al, the investigators deemed it necessary to “empirically change filters on the ventilator every 2 hours to prevent ventilator valve malfunction.” Despite this precaution, the authors report one serious adverse event caused by a stuck ventilator valve resulting in auto positive end-expiratory pressure and hypotension. Clearly, the track record for safety for prolonged administration of iPGI2 is not yet established. It is often asserted that an advantage of PGI2 over iNO is its ease of administration. However, given that PGI2 is inactivated by room temperature, light, and physiologic pH, and must be dissolved in a sticky diluent and administered continuously via nebulization, the stated ease of administration of iPGI2 is not
readily apparent. It is recommended that after it is mixed, it should not be at room temperature for more than 8 hours. Furthermore, the tubing should be wrapped to prevent degradation of this photosensitive molecule. Air filters and sidestream analyzer lines are easily clogged by the glycine diluent, and ventilator valves are at risk to malfunction. Moreover, transport of a patient requires meticulous attention to prevent aspiration of the contents of the nebulizer. Lastly, it is difficult to know how much drug the patient is receiving given the many factors that impact on the efficiency of drug delivery by nebulization.35,36 The method of administration of iNO administration, in contrast, is accomplished by an FDA-approved delivery system that displays exhaled NO concentrations and NO2 concentrations in a manner that is quite easy to monitor and control. Although the drug cost associated with prolonged administration of iNO is clearly greater than iPGI2, the cost of therapy may not always favor iPGI2. For example, the cost of the drug itself in a 10-minute diagnostic trial of iNO is $21, whereas the same trial of iPGI2 would cost $150. More importantly, a robust cost comparison of prolonged therapy would take into consideration any impact on overall costs. For example, if one therapy reduced intensive care unit stay by 1 day or the need for a right ventricular assist device or extracorporeal membrane oxygenation support, the difference in drug cost would be incidental. The appropriate study design that could address these issues would, at the least, require randomization of therapy. These studies and cost analyses have not yet been done. To conclude, there is little evidence to support replacing iNO with iPGI2 as the selective pulmonary vasodilator of choice in any of the common usage scenarios. In the hypoxic neonate, there is no justification for substituting an FDA-approved drug with known benefits with the off-label and off-route use of a drug whose safety profile and efficacy are not established, solely for the purpose of cost saving. In diagnostic testing, iNO is less expensive than iPGI2 and thus no reason to replace iNO with iPGI2. In acute respiratory distress syndrome, it is progression of the underlying disease rather than the degree of pulmonary shunt that leads to such a poor outcome; it is not justified to use either of these agents at this point. And lastly, because perioperative right heart failure is associated with significant comorbidity, hospital length of stay, and mortality, and because iNO has been shown to be efficacious in this setting, more compelling evidence would be needed that, in fact, the overall efficacy of iPGI2 is the same in this condition. It is likely that iPGI2 will assume an important role in the armamentarium of drugs to treat perioperative pulmonary hypertension and right heart failure, whether alone or in conjunction with other therapies. Further studies are needed to better define that role.
REFERENCES 1. Ichinose F, Roberts JD Jr, Zapol WM: Inhaled nitric oxide: A selective pulmonary vasodilator: Current uses and therapeutic potential. Circulation 109:3106-3111, 2004 2. Balzer DT, Kort HW, Day RW, et al: Inhaled nitric oxide as a preoperative test (INOP Test I): The INOP Test Study Group. Circulation 106:I76-I81, 2002 (suppl 1)
3. Sitbon O, Humbert M, Jagot JL, et al: Inhaled nitric oxide as a screening agent for safely identifying responders to oral calciumchannel blockers in primary pulmonary hypertension. Eur Respir J 12:265-270, 1998 4. Cornfield DN, Milla CE, Haddad IY, et al: Safety of inhaled nitric oxide after lung transplantation. J Heart Lung Transplant 22:903-907, 2003
PRO AND CON
5. Rossaint R, Falke KJ, Lopez F, et al: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399-405, 1993 6. Argenziano M, Choudhri AF, Moazami N, et al: Randomized, double-blind trial of inhaled nitric oxide in LVAD recipients with pulmonary hypertension. Ann Thorac Surg 65:340-345, 1988 7. Oz MC, Ardehali A: Collective review: Perioperative uses of inhaled nitric oxide in adults. Heart Surg Forum 7:E584-E589, 2004 8. Ardehali A, Hughes K, Sadeghi A, et al: Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation 72:638-641, 2001 9. Vlahakes GJ, Turley K, Hoffman JI: The pathophysiology of failure in acute right ventricular hypertension: Hemodynamic and biochemical correlations. Circulation 63:87-95, 1981 10. Taylor RW, Zimmerman JL, Dellinger RP, et al: Inhaled nitric oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: A randomized controlled trial. JAMA 291:16031609, 2004 11. Dellinger RP, Zimmerman JL, Taylor RW, et al, for the Inhaled Nitric Oxide in ARDS Study Group: Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Crit Care Med 26:15-23, 1998 12. Hoffman GM, Ross GA, Day SE, et al: Inhaled nitric oxide reduces the utilization of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Crit Care Med 25:352-359, 1997 13. Lowson SM: Alternatives to nitric oxide. Br Med Bull 70:119131, 2004 14. Haraldsson A, Kieler-Jensen N, Ricksten SE: The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg 93:1439-1445, 2001 15. Lam CF, van Heerden PV, Ilett KF, et al: Two aerosolized nitric oxide adducts as selective pulmonary vasodilators for acute pulmonary hypertension. Chest 123:869-874, 2003 16. Yurtseven N, Karaca P, Kaplan M, et al: Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Anesthesiology 99:855-858, 2003 17. Mestan KK, Carlson AD, White M, et al: Cardiopulmonary effects of nebulized sodium nitroprusside in term infants with hypoxic respiratory failure. J Pediatr 143:640-643, 2003 18. Sood BG, Delaney-Black V, Aranda JV, et al: Aerosolized PGE1: A selective pulmonary vasodilator in neonatal hypoxemic respiratory failure. Results of a phase I/II open label clinical trial. Pediatr Res 56:579-585, 2004 19. Siobal M: Aerosolized prostacyclins. Respir Care 49:640-652, 2004 20. van Heerden PV, Barden A, Michalopoulos N, et al: Doseresponse to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest 117:819-827, 2000
405
21. Eichelbronner O, Reinelt H, Wiedeck H, et al: Aerosolized prostacyclin and inhaled nitric oxide in septic shock—Different effects on splanchnic oxygenation. Intensive Care Med 22:880-887, 1996 22. Fattouch K, Sbraga F, Bianco G, et al: Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement. J Card Surg 20:171-176, 2005 23. Haraldsson A, Kieler-Jensen N, Nathorst-Westfelt U, et al: Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. Chest 114:780-786, 1998 24. Walmrath D, Schneider T, Schermuly R, et al: Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 153:991996, 1996 25. Mikhail G, Gibbs J, Richardson M, et al: An evaluation of nebulized prostacyclin in patients with primary and secondary pulmonary hypertension. Eur Heart J 18:1499-1504, 1997 26. Kadowitz PJ, Chapnick BM, Feigen LP, et al: Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI2. J Appl Physiol 45:408-413, 1978 27. De Wet CJ, Affleck DG, Jacobsohn E, et al: Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg 127:1058-1067, 2004 28. Bhatia SJ, Kirshenbaum JM, Shemin RJ, et al: Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation. Circulation 76:819-826, 1987 29. Hachenberg T, Tenling A, Nystrom SO, et al: Ventilationperfusion inequality in patients undergoing cardiac surgery. Anesthesiology 80:509-519, 1994 30. Solina AR, Ginsberg SH, Papp D, et al: Dose response to nitric oxide in adult cardiac surgery patients. J Clin Anesth 13:281-286, 2001 31. Guthrie SO, Walsh WF, Auten K, et al: Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure. J Perinatol 24:290-294, 2004 32. Clark RH, Kueser TJ, Walker MW, et al: Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 342:469-474, 2000 33. van Heerden PV, Caterina P, Filion P, et al: Pulmonary toxicity of inhaled aerosolized prostacyclin therapy—An observational study. Anaesth Intensive Care 28:161-166, 2000 34. Morimatsu H, Goto K, Matsusaki T, et al: Rapid development of severe interstitial pneumonia caused by epoprostenol in a patient with primary pulmonary hypertension. Anesth Analg 99:1205-1207, 2004 35. Rau JL: The inhalation of drugs: Advantages and problems. Respir Care 50:367-382, 2005 36. Miller DD, Amin MM, Palmer LB, et al: Aerosol delivery and modern mechanical ventilation: In vitro/in vivo evaluation. Am J Respir Crit Care Med 168:1205-1209, 2003
I
NHALED NITRIC OXIDE (iNO) achieved favored status as a pulmonary vasodilator principally because of its remarkable pulmonary selectivity. Previously available methods for reducing pulmonary vascular resistance (PVR) were all accompanied by the risk of systemic hypotension. However, because iNO is immediately bound by hemoglobin, its vasodilatory effects are limited to the pulmonary vasculature at any dose. Although the only Food and Drug Administration (FDA)approved indication for the use of iNO is in the setting of respiratory failure of the newborn, iNO has been used off-label in a wide range of patients and clinical settings and with several very different objectives.1 For example, iNO is used to test vascular reactivity in pulmonary hypertensives,2,3 to reduce the incidence or severity of lung reperfusion injury after lung transplantation,4 to improve oxygenation in the setting of acute lung injury,5 and to either prevent or treat right heart failure.6-8 In fact, iNO was considered a true breakthrough in the treatment of perioperative right heart failure because maintenance of coronary perfusion pressure is so critical when reducing right ventricular afterload in this setting.9 In addition, because iNO preferentially dilates well-ventilated regions of the lung and thereby improves ventilation/perfusion matching and arterial oxygenation, iNO is used to correct life-threatening hypoxemia; this is despite the disappointing finding that iNO did not improve survival in patients with the acute respiratory distress syndrome.10,11 However, the improvement in oxygenation in hypoxic neonates and the resultant reduction in the need for extracorporeal membrane oxygenation12 was the breakthrough that won FDA approval for iNO therapy. After obtaining FDA approval in 1999, the cost of administration of iNO was set at what most clinicians (and hospital administrators) considered exorbitant ($3,000/day with a $12,000 cap). Understandably, this generated great interest in finding a less expensive alternative.13 Consequently, a wide variety of intravenous vasodilators were tested via the inhaled route with the expectation that maximizing drug levels at the target organ would minimize their systemic effects. In addition to prostacyclin (prostaglandin I2 [PGI2], which is discussed in detail later), clinical studies report selective pulmonary vasodilation by inhaled milrinone,14 NO adducts,15 nitroglycerin,16 sodium nitroprusside,17 prostaglandin E1,18 and a more stable analog of PGI2, iloprost.19 Based on a number of encouraging reports, numerous centers (and the accompanying “pro” paper) are now advocating that iPGI2 should be used instead of iNO. They argue that the actions of iPGI2 are equivalent to iNO, and iPGI2 is safer, easier, and less costly to administer than iNO. The purpose of this “con” section of the debate is to present evidence to the contrary. This article argues that (1) the appropriate studies have not yet been done to affirm equivalency of these 2 drugs; (2) assertions of the lack of systemic effects of iPGI2 represent overzealous interpretations of limited or poorly controlled studies; (3) the safety profile of iNO is quite good, whereas iPGI2 has a number of concerning safety issues; (4) the administration system for iPGI2 has a number of important limitations; and (5) the fact that a day’s supply of iPGI2 costs less than a day’s
supply of iNO does not necessarily translate into less overall cost. Irrespective of their actions, iNO and iPGI2 have a number of important pharmacologic differences. Firstly, the mechanism by which vasodilation occurs involves separate signaling pathways; NO works via the cyclic guanosine monophosphate signaling cascade, whereas PGI2 works via the cyclic adenosine monophosphate cascade. Secondly, the delivery to the site of absorption (the alveoli) is different; iPGI2 is administered as a nebulized liquid, much of which layers out in the ventilator tubing and large airways, whereas NO is a gas that is evenly mixed with nitrogen and oxygen. Thirdly, PGI2 and its metabolites reach the systemic circulation,20 whereas iNO is immediately bound and inactivated instantly by hemoglobin. Finally, the administration of PGI2 requires a continuous aspiration of a highly basic diluent (glycine), whereas nitric oxide is mixed in nitrogen gas. What is the evidence that iPGI2 and iNO are clinically equivalent? Most of the studies that compare iPGI2 and iNO report similar hemodynamic effects after very brief drug exposure.21-25 To date, there are no randomized trials in patients that compare iNO and iPGI2 to test whether there is any difference in outcome. The finding that there is a similar reduction in PVR after brief exposure does not necessarily mean that the 2 drugs have similar clinical efficacy. Furthermore, the pulmonary selectivity that was documented after brief exposure to iPGI2 may be lost during more prolonged therapy. Unlike iNO, PGI2 is known to cause hypotension when large doses are inhaled,26 its half-life is sufficiently long to allow for systemic effects, and systemic arterial levels of an active metabolite have been measured during inhalation of even small doses of PGI2; presumably, it is the lower dosing regimen and short duration of therapy that limit the systemic levels short of a clinical response. Therefore, it is not even clear if iPGI2 maintains its pulmonary selectivity during prolonged administration. The only study that describes the prolonged administration of PGI2 in a large series of patients was recently published by De Wet and colleagues.27 One hundred twenty-six postcardiothoracic surgical patients received iPGI2 for an average of 2 days. The authors found a reduction in mean pulmonary arterial pressure and stable mean arterial blood pressure during the first 4 to 6 hours of iPGI2 therapy. However, important methodologic issues preclude concluding that iPGI2 lacked systemic effects. For example, the authors state that “systemic arterial pressure was closely monitored, and the PGI2 dose was adjusted accordingly if a clinical change in blood pressure was
From the Division of Cardiothoracic Anesthesia, Columbia University College of Physicians and Surgeons, New York, NY. Address reprint requests to Marc L. Dickstein, MD, Division of Cardiothoracic Anesthesia, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail: [email protected] © 2005 Elsevier Inc. All rights reserved. 1053-0770/05/1903-0025$30.00/0 doi:10.1053/j.jvca.2005.03.037 Key words: prostaglandin, vasodilation, nitric oxide
Journal of Cardiothoracic and Vascular Anesthesia, Vol 19, No 3 (June), 2005: pp 403-405
403
404
MARC L. DICKSTEIN
observed.” Furthermore, the vasopressor doses continued to be titrated to blood pressure during the course of the study, so it should not be surprising that arterial blood pressure measurements did not change. Third, in the absence of a control group, it is difficult to separate the changes attributable to iPGI2 versus time, as improvements in mean pulmonary arterial pressure28 and shunt fraction29 are a matter of course in the first few hours after cardiac surgery. The relevant hemodynamic data were measured in a minority of the subjects; systemic vascular resistance was only measured in 24 of the 126 subjects and PVR in 6 of the 126 subjects. Therefore, the conclusion that the actions of iPGI2 are sustained and not associated with systemic vasodilation cannot be drawn from these data. What are the safety issues that would influence the choice of iNO versus iPGI2? The main safety concern about iNO is the risk of significant methemoglobinemia, whereas the main safety concern about iPGI2 is related to the sticky and highly alkaline drug vehicle. When iNO was first introduced into clinical use, the typical doses were considerably higher than what is used today and development of significant levels of methemoglobin was not uncommon. Subsequently, it was recognized that most of the hemodynamic benefits of iNO are realized with doses of 20 ppm or less,30 and most of the improvement in oxygenation is accomplished with doses of 5 ppm or less. At these levels, the incidence of significant methemoglobinemia (⬎5%) is rare.31,32 iNO has been studied in a large number of trials and is FDA approved as inhalation therapy in neonates. Although no survival benefit was found in acute respiratory distress syndrome trials, these studies did serve to establish the safety of this technique in large populations. In contrast, the safety of PGI2 administered via the inhaled route has not been established. The glycine diluent has a pH of 10.5 and was shown in 1 study to be associated with a mild tracheitis after short-term use.33 Additionally, there is 1 case report of a young woman who developed a severe interstitial pneumonia that was thought to be caused by iPGI2.34 Furthermore, the diluent is quite sticky and poses a risk to the integrity of valves in the ventilator circuit. In the study by De Wet et al, the investigators deemed it necessary to “empirically change filters on the ventilator every 2 hours to prevent ventilator valve malfunction.” Despite this precaution, the authors report one serious adverse event caused by a stuck ventilator valve resulting in auto positive end-expiratory pressure and hypotension. Clearly, the track record for safety for prolonged administration of iPGI2 is not yet established. It is often asserted that an advantage of PGI2 over iNO is its ease of administration. However, given that PGI2 is inactivated by room temperature, light, and physiologic pH, and must be dissolved in a sticky diluent and administered continuously via nebulization, the stated ease of administration of iPGI2 is not
readily apparent. It is recommended that after it is mixed, it should not be at room temperature for more than 8 hours. Furthermore, the tubing should be wrapped to prevent degradation of this photosensitive molecule. Air filters and sidestream analyzer lines are easily clogged by the glycine diluent, and ventilator valves are at risk to malfunction. Moreover, transport of a patient requires meticulous attention to prevent aspiration of the contents of the nebulizer. Lastly, it is difficult to know how much drug the patient is receiving given the many factors that impact on the efficiency of drug delivery by nebulization.35,36 The method of administration of iNO administration, in contrast, is accomplished by an FDA-approved delivery system that displays exhaled NO concentrations and NO2 concentrations in a manner that is quite easy to monitor and control. Although the drug cost associated with prolonged administration of iNO is clearly greater than iPGI2, the cost of therapy may not always favor iPGI2. For example, the cost of the drug itself in a 10-minute diagnostic trial of iNO is $21, whereas the same trial of iPGI2 would cost $150. More importantly, a robust cost comparison of prolonged therapy would take into consideration any impact on overall costs. For example, if one therapy reduced intensive care unit stay by 1 day or the need for a right ventricular assist device or extracorporeal membrane oxygenation support, the difference in drug cost would be incidental. The appropriate study design that could address these issues would, at the least, require randomization of therapy. These studies and cost analyses have not yet been done. To conclude, there is little evidence to support replacing iNO with iPGI2 as the selective pulmonary vasodilator of choice in any of the common usage scenarios. In the hypoxic neonate, there is no justification for substituting an FDA-approved drug with known benefits with the off-label and off-route use of a drug whose safety profile and efficacy are not established, solely for the purpose of cost saving. In diagnostic testing, iNO is less expensive than iPGI2 and thus no reason to replace iNO with iPGI2. In acute respiratory distress syndrome, it is progression of the underlying disease rather than the degree of pulmonary shunt that leads to such a poor outcome; it is not justified to use either of these agents at this point. And lastly, because perioperative right heart failure is associated with significant comorbidity, hospital length of stay, and mortality, and because iNO has been shown to be efficacious in this setting, more compelling evidence would be needed that, in fact, the overall efficacy of iPGI2 is the same in this condition. It is likely that iPGI2 will assume an important role in the armamentarium of drugs to treat perioperative pulmonary hypertension and right heart failure, whether alone or in conjunction with other therapies. Further studies are needed to better define that role.
REFERENCES 1. Ichinose F, Roberts JD Jr, Zapol WM: Inhaled nitric oxide: A selective pulmonary vasodilator: Current uses and therapeutic potential. Circulation 109:3106-3111, 2004 2. Balzer DT, Kort HW, Day RW, et al: Inhaled nitric oxide as a preoperative test (INOP Test I): The INOP Test Study Group. Circulation 106:I76-I81, 2002 (suppl 1)
3. Sitbon O, Humbert M, Jagot JL, et al: Inhaled nitric oxide as a screening agent for safely identifying responders to oral calciumchannel blockers in primary pulmonary hypertension. Eur Respir J 12:265-270, 1998 4. Cornfield DN, Milla CE, Haddad IY, et al: Safety of inhaled nitric oxide after lung transplantation. J Heart Lung Transplant 22:903-907, 2003
PRO AND CON
5. Rossaint R, Falke KJ, Lopez F, et al: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399-405, 1993 6. Argenziano M, Choudhri AF, Moazami N, et al: Randomized, double-blind trial of inhaled nitric oxide in LVAD recipients with pulmonary hypertension. Ann Thorac Surg 65:340-345, 1988 7. Oz MC, Ardehali A: Collective review: Perioperative uses of inhaled nitric oxide in adults. Heart Surg Forum 7:E584-E589, 2004 8. Ardehali A, Hughes K, Sadeghi A, et al: Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation 72:638-641, 2001 9. Vlahakes GJ, Turley K, Hoffman JI: The pathophysiology of failure in acute right ventricular hypertension: Hemodynamic and biochemical correlations. Circulation 63:87-95, 1981 10. Taylor RW, Zimmerman JL, Dellinger RP, et al: Inhaled nitric oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: A randomized controlled trial. JAMA 291:16031609, 2004 11. Dellinger RP, Zimmerman JL, Taylor RW, et al, for the Inhaled Nitric Oxide in ARDS Study Group: Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Crit Care Med 26:15-23, 1998 12. Hoffman GM, Ross GA, Day SE, et al: Inhaled nitric oxide reduces the utilization of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Crit Care Med 25:352-359, 1997 13. Lowson SM: Alternatives to nitric oxide. Br Med Bull 70:119131, 2004 14. Haraldsson A, Kieler-Jensen N, Ricksten SE: The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg 93:1439-1445, 2001 15. Lam CF, van Heerden PV, Ilett KF, et al: Two aerosolized nitric oxide adducts as selective pulmonary vasodilators for acute pulmonary hypertension. Chest 123:869-874, 2003 16. Yurtseven N, Karaca P, Kaplan M, et al: Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Anesthesiology 99:855-858, 2003 17. Mestan KK, Carlson AD, White M, et al: Cardiopulmonary effects of nebulized sodium nitroprusside in term infants with hypoxic respiratory failure. J Pediatr 143:640-643, 2003 18. Sood BG, Delaney-Black V, Aranda JV, et al: Aerosolized PGE1: A selective pulmonary vasodilator in neonatal hypoxemic respiratory failure. Results of a phase I/II open label clinical trial. Pediatr Res 56:579-585, 2004 19. Siobal M: Aerosolized prostacyclins. Respir Care 49:640-652, 2004 20. van Heerden PV, Barden A, Michalopoulos N, et al: Doseresponse to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest 117:819-827, 2000
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