| Abstract|| |
Patients with pulmonary hypertension (PH) are at high risk for complications in the perioperative setting and often receive vasodilators to control elevated pulmonary artery pressure (PAP). Administration of vasodilators via inhalation is an effective strategy for reducing PAP while avoiding systemic side effects, chiefly hypotension. The prototypical inhaled pulmonary-specific vasodilator, nitric oxide (NO), has a proven track record but is expensive and cumbersome to implement. Alternatives to NO, including prostanoids (such as epoprostenol, iloprost, and treprostinil), NO-donating drugs (sodium nitroprusside, nitroglycerin, and nitrite), and phosphodiesterase inhibitors (milrinone, sildenafil) may be given via inhalation for the purpose of treating elevated PAP. This review will focus on the perioperative therapy of PH using inhaled vasodilators.
Keywords: Nitric oxide-donating drugs; Phosphodiesterase inhibitors; Prostanoids; Prototypical inhaled pulmonary-specific vasodilator
|How to cite this article:|
Thunberg C A, Morozowich S T, Ramakrishna H. Inhaled therapy for the management of perioperative pulmonary hypertension. Ann Card Anaesth 2015;18:394-402
|How to cite this URL:|
Thunberg C A, Morozowich S T, Ramakrishna H. Inhaled therapy for the management of perioperative pulmonary hypertension. Ann Card Anaesth [serial online] 2015 [cited 2019 Jun 15];18:394-402. Available from: http://www.annals.in/text.asp?2015/18/3/394/159811
| Introduction|| |
The pathology of pulmonary hypertension (PH) involves vascular remodeling due to endothelial cell dysfunction and smooth muscle cell proliferation  that restricts the cross-sectional area of the pulmonary vascular bed, resulting in elevated pulmonary artery pressure (PAP), increased pulmonary vascular resistance (PVR), and hypoxia. Although the right ventricle (RV) has a remarkable ability to compensate for markedly elevated PAP and PVR, RV failure is the ultimate consequence of severe PH. ,,
The arsenal of drugs for the treatment of PH in the perioperative and intensive care settings has traditionally depended on intravenous vasodilators that lack specificity for the pulmonary circulation and may cause systemic vasodilation, which is undesirable. While inhaled nitric oxide (iNO) is the "gold standard" for pulmonary-specific PH treatment in many localities, there has been interest among clinicians in developing less expensive alternatives. Prostacyclin, milrinone, and nitroglycerin (NTG) are examples of intravenous vasodilators that become pulmonary-specific when given via inhalation. This review will discuss the pharmacologic targets and perioperative use of inhaled vasodilators, with an emphasis on intravenous vasodilators given via the inhaled route.
| Targets of drug therapy relevant to pulmonary hypertension|| |
Although numerous cellular mediators associated with PH and RV failure have been targeted for drug development, perioperative drug therapy primarily relies on three pathways of vasodilation: Nitric oxide (NO) donors, adenylate cyclase (AC) stimulators, and phosphodiesterase (PDE) inhibitors.
Nitric oxide donors
NO, first described as the endothelium-derived relaxing factor, is produced by three variants of NO synthase. The endothelial variant (endothelial nitric oxide synthase [eNOS]) is important in the regulation of systemic and pulmonary vascular tone. In the body, eNOS uses the amino acid L-arginine as a substrate to produce NO, which freely diffuses from the endothelial cell into the blood stream and nearby smooth muscle cells. In the blood, NO oxidizes the iron of hemoglobin and is quickly inactivated. In smooth muscle cells, NO interacts with the heme moiety of soluble guanylate cyclase (sGC) to stimulate the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP, in turn, interacts with protein kinases to produce relaxation of myofilaments. The gold standard therapy for PH is iNO, which readily crosses from the alveolus to smooth muscle cell to directly stimulate sGC. Sodium nitroprusside (SNP) and NTG stimulate sGC after undergoing chemical reactions that release NO.
Adenylate cyclase stimulators
AC is a key enzyme in signal transduction pathways throughout the body. In vascular smooth muscle, AC is under regulatory control by stimulatory and inhibitory transmembrane G protein-coupled receptors (Gs and Gi, respectively). Prostacyclin, an endogenous prostaglandin, binds to prostanoid receptor type IP and activates Gs, which in turn simulates AC to convert adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP interacts with protein kinases to promote smooth muscle relaxation. Therapeutic stimulation of AC can be achieved with administration of prostacyclin and its synthetic analogs (epoprostenol, treprostinil, and beraprost).
PDEs are a family of enzymes that regulate vascular tone by hydrolyzing cGMP and cAMP to guanosine monophosphate (GMP) and adenosine monophosphate (AMP), respectively. By reducing the amount of cGMP and cAMP, PDEs tend to increase vascular tone. Phosphodiesterase type 3 (PDE3) hydrolyzes primarily cAMP and is inhibited by milrinone, while PDE5 primarily hydrolyzes cGMP and is inhibited by sildenafil. Both PDE3 and PDE5 are present in vascular smooth muscle and are targets for PH therapy.
| Inhaled Nitric Oxide Donors|| |
Inhaled Nitric Oxide
iNO easily crosses the alveolar-capillary barrier and stimulates sGC in the vascular smooth muscle near the alveoli. Due to rapid inactivation by circulating hemoglobin, iNO has no effect on vascular beds beyond the lungs.  iNO produces pulmonary vasodilation at concentrations from 5 to 40 parts per million (ppm), resulting in a reduction in PVR, PAP, and RV afterload, while avoiding systemic hypotension. Those changes, along with maintenance of coronary perfusion pressure, tend to improve RV performance. iNO can improve oxygenation by increasing blood flow to pulmonary units that are well-ventilated (ventilation-perfusion matching).
iNO is used for management of PH and/or hypoxemia in many perioperative situations where lowering PAP and improving RV function is paramount. In mitral valve surgery in adults with severe PH, iNO significantly reduces PVR, increases cardiac index (CI), reduces the use of systemic vasoactive medications, and reduces Intensive Care Unit stay.  Heart transplant recipients who receive iNO demonstrate improved RV function and a trend toward lower 30-day mortality.  RV failure is a well-known complication that occurs at variable rates following left ventricular assist device (LVAD) implantation  and is associated with higher morbidity and mortality. ,,, iNO reduces PAP and improves LVAD flow in LVAD recipients.  In critically ill patients with circulatory shock due to RV failure, iNO significantly improves CO and mixed venous oxygen saturation (SVO2). 
Use of iNO is limited by the potential for toxicity and high cost. NO forms methemoglobin and nitrate upon exposure to oxyhemoglobin in the pulmonary circulation.  In humans without methemoglobin reductase deficiency, doses <40 ppm do not cause methemoglobinemia,  and animal data suggests that long-term administration at comparable doses are nontoxic.  In addition to methemoglobinemia, lung injury may occur if excessive amounts of NO are oxidized to nitrogen dioxide (NO2), a pulmonary irritant that can cause bronchospasm and pulmonary edema. Modern iNO delivery systems include monitoring for NO and NO2 levels.  Yahagi et al.  followed 65 pediatric recipients of iNO for a mean of 3.1 years and found no occurrence of chronic inflammation or malignancy of the respiratory tract. The daily cost for of iNO using the Food and Drug Administration (FDA)-approved apparatus was $3000 in 1999. ,
SNP is an iron-containing inorganic compound that releases NO and cyanide (CN) after undergoing a redox reaction with hemoglobin in red blood cells. Intravenously administered SNP causes systemic and pulmonary vasodilation. Use of intravenous SNP to lower PAP typically requires a vasoconstrictor to compensate for reduced mean arterial pressure (MAP).
When administered through a nebulizer connected to the inspiratory limb of the breathing circuit, SNP has been shown to be a selective pulmonary vasodilator. , In a porcine model of PH,  nebulized SNP (total dose of 25 mg) caused a rapid reduction in PAP that was equivalent to iNO at 20 ppm, without decreasing MAP. In a sheep model of PH,  low-dose inhaled SNP (concentration ≤0.02 M) decreased PAP by 42% and systemic vascular resistance (SVR) by 5%. However, high-dose inhaled SNP (concentration >0.02 M) caused pulmonary and systemic vasodilation.  Thus, it appears there is a dose ceiling beyond which inhaled SNP becomes a nonselective vasodilator.
Experience with inhaled SNP in human subjects is extremely limited. Several investigators , have found that inhaled SNP significantly increased oxygenation in mechanically ventilated newborns with hypoxia. In the study by Mestan et al.,  newborns with hypoxic respiratory failure receiving nebulized SNP (in doses of 5 mg and 25 mg) had dose-dependent increases in oxygenation that were comparable to iNO. MAP and heart rate (HR) did not change significantly during SNP treatment, and no attempt to record PAP was made.
Toxicity from SNP, which manifests as CN toxicity, thiocyanate toxicity, or methemoglobinemia, is a concern when the drug is administered at high doses for prolonged periods. Multiday intravenous infusions of SNP at doses of 0.5 mcg/kg/min are generally safe, while infusions exceeding 2 mcg/kg/min increase the risk of CN toxicity.  It is difficult to extrapolate these numbers to inhalational SNP therapy as a significant portion of the nebulized drug may not reach the alveolus, where absorption occurs.  In the study of newborns with hypoxia,  the dose of nebulized SNP exceeded 6 mg/kg over 20 min yet was not associated with overt CN toxicity. Patients receiving multiple doses or continuous treatments of nebulized SNP should be monitored for CN toxicity.
In addition to the concern for CN toxicity, there are several caveats to using inhaled SNP clinically. Because the effect of a single dose of nebulized SNP is short,  sustained pulmonary vasodilation requires giving multiple doses or continuous nebulization. As a practical matter, it is probably best to use inhaled SNP as a bridge to starting a conventional pulmonary vasodilator with established safety profile and delivery method.
NTG is a well-known venous-and arterial vasodilator that stimulates sGC through a NO-donating mechanism catalyzed by aldehyde dehydrogenase-2. 
As is the case with inhaled SNP, preliminary experience with inhaled NTG in animal models of PH , was followed by human investigations. , Mandal et al.  compared nebulized and intravenous NTG, both at a dose of 2.5 mcg/kg/min for 10 min, in 40 adults after mitral and aortic valve surgery, and found that inhaled and intravenous NTG produced equivalent reductions in mean PAP (mPAP) (approximately 20% decrease) and pulmonary vascular resistance index (PVRI) (approximately 25% decrease), but only intravenous NTG caused significant changes in central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), MAP, and systemic vascular resistance index. The duration of hemodynamic effect from inhaled NTG lasted about 20 min. 
Yurtseven et al.  recorded hemodynamic and gas exchange data in 20 intubated, mechanically ventilated adults recovering from mitral valve replacement surgery. During the nebulized NTG treatments (2.5 mcg/kg/min over 5 h), there were significant decreases in mPAP and PVR and increases in oxygenation parameters, without significant change CVP, PCWP, MAP, or CI. mPAP and PVR returned to baseline values within 1 h after ending the NTG treatment.
Nebulized NTG (20 mcg/kg) was compared to nebulized iloprost (2.5 mcg/kg) in a study of 100 patients with elevated PAP after mitral valve surgery.  Both drugs produced significant decreases in mPAP and PVR, but the effect was larger with iloprost. In addition, the inhaled iloprost increased cardiac output (CO) and stroke volume, which did not occur with nebulized NTG.
Singh et al.  performed a three-way comparison of nebulized NTG (50 mcg/kg), nebulized milrinone (50 mcg/kg), and 100% inspired oxygen in 40 children with left-to-right intracardiac shunt and elevated mPAP (>30 mmHg) undergoing right heart catheterization. Both nebulized NTG and nebulized milrinone lowered mPAP (−15%) and PVRI (−70%) while keeping other hemodynamic variables stable. Interestingly, the efficacy of nebulized NTG (given with a gas mixture that was 50% oxygen) was not superior to inhalation of 100% oxygen, while inhaled milrinone was slightly better than 100% oxygen. 
In total, while there is more clinical experience with inhaled NTG than with inhaled SNP, both drugs have similar limitations. Given the short duration of action of inhaled NTG, sustained pulmonary vasodilation would require multiple administrations or continuous nebulization. Methemoglobinemia is a theoretical concern with prolonged exposure to NTG. Inhaled NTG might be useful as temporizing agent until a conventional drug can be started.
The inorganic anions nitrate (NO3− ) and nitrite (NO2− ) are end-products of endogenous NO metabolism. Although previously thought to be inert, nitrate and nitrite undergo "recycling" to form NO through a route that is distinct from the classic arginine-NO synthase-NO pathway, occurs predominantly in hypoxic states, and is catalyzed by deoxyhemoglobin, deoxymyoglobin, and xanthine oxidoreductase. ,, Therapeutic use of nitrite anion for PH has been investigated in dietary,  intravenous, , and inhaled ,, preparations. Although inhaled nitrite anion for the management of PH in humans has not yet been reported, studies involving induced PH in animal models suggest that inhaled nitrite anion is a selective pulmonary vasodilator. 
Distinct from the inorganic anion nitrite, the alkyl nitrites are gaseous organic compounds that release NO through an aldehyde dehydrogenase-dependent pathway. Historically, inhalation of amyl nitrite was employed during bedside examination to augment the murmur of mitral stenosis and diminish the murmur of mitral regurgitation.  In a swine model of severe PH induced by a thromboxane analog,  inhalation of amyl nitrate produced substantial decreases in mPAP (−50%) and PVR (−92%) while improving CO and MAP. A small study of newborns with PH  showed that pulmonary gas exchange (oxygenation and ventilation) and blood pressure improved during 4 h of ethyl nitrite inhalation.
| Inhaled prostanoids|| |
Prostacyclin, a naturally occurring prostaglandin derived from arachidonic acid, increases intracellular cAMP, leading to vascular smooth muscle relaxation. It also has antiplatelet effects and suppresses proliferation of smooth muscle cells.  There are three prostacyclin analogs approved by the FDA for treatment of PAH: Epoprostenol, iloprost, and treprostinil.  In addition, beraprost had been approved in Japan. Epoprostenol, the first prostanoid developed, is unstable and has a half-life of 3-6 min, whereas the newer analogs have increasingly longer half-lives (iloprost 20-30 min, treprostinil 4 h).  Although prostacyclin has in vitro antiplatelet effects, it has been shown that inhaled prostanoids can be used safely without increased bleeding risk. 
Although high-quality controlled trials of inhaled prostanoids are lacking, many clinicians have utilized inhaled prostanoids as an iNO alternative. Compared to iNO, the inhaled prostanoids produce similar reductions in PAP, are relatively free of toxicity, require no special monitoring, and may be less expensive to administer. , Inhaled prostanoids have been used in patients with acute lung injury and acute respiratory distress syndrome to improve gas exchange and increase blood flow to well-ventilated lung regions. 
A prospective, randomized, crossover study comparing iNO (20 ppm) and inhaled epoprostenol in heart and lung transplant recipients (n = 25) showed that both drugs similarly reduced PAP and CVP and improved CI and SVO2 without lowering MAP or other complications.  Due to the short half-life of epoprostenol, a syringe pump was utilized to deliver the drug to a jet nebulizer, which in turn was attached to the inspiratory limb of the breathing circuit. Approximately 8 mL of epoprostenol (diluted in a glycine buffer to 20,000 ng/mL) was administered per hour. The authors noted several caveats of epoprostenol administration, including: (1) Uncertainty regarding the amount of epoprostenol reaching the alveoli, (2) the potential for accidental bolus if the nebulization chamber is tipped over, and (3) the potential for ventilator valves to become stuck due to the glycine buffering agent. 
A systematic review of inhaled iloprost in pediatric patients  showed that inhaled iloprost was well-tolerated and apparently safe, although indications, delivery methods, and doses varied greatly. The authors concluded that inhaled iloprost may have a role in countries where iNO is not available or as a "rescue" option, and that well-designed prospective clinical trials are needed.  A recent retrospective study of pediatric patients undergoing congenital heart surgery who were receiving stable doses of iNO were successfully transitioned to inhaled iloprost without adverse hemodynamic effects, thrombocytopenia, or bleeding complications.  Unlike epoprostenol, iloprost does not require continuous nebulization because its half-life is longer, but the frequency of administration must be 6-9 times during waking hours.
Treprostinil and beraprost, the most recently developed prostanoids, have limited history of use in the perioperative setting. Inhaled treprostinil, which is typically administered via ultrasonic nebulizer 4 times daily during waking hours, would be a convenient inhaled therapy for PH. Beraprost, which is available in Japan, has an oral formulation only.
| Inhaled Phosphodiesterase Inhibitors|| |
Intravenous milrinone is a selective PDE3 inhibitor that is commonly given during cardiac surgery to treat left and RV failure, often with a concomitant decrease in systemic blood pressure.  Over the past 15 years, much attention has been directed to inhaled milrinone as a selective pulmonary vasodilator ,,, and to prevent lung injury during warm ischemia , and cardiopulmonary bypass. 
In 2001, Haraldsson et al.  reported the hemodynamic effects of inhaled milrinone in nine patients with PH (mPAP >25 mmHg and PVR >200 dynes/s/cm 5 ) after cardiac surgery. When given by jet nebulizer via the inspiratory limb of a breathing circuit, nebulized milrinone at a concentration of 1 mg/mL was shown to decrease mPAP (−9%), PVR (−20%), transpulmonary gradient (TPG; −15%), and PVR/SVR ratio (−17%) without any effect on HR, MAP, CVP, PAOP, or CO. In a different group of postcardiac surgery patients (n = 11), the same investigators compared nebulized epoprostenol to the combination of nebulized epoprostenol and milrinone. Nebulized epoprostenol, given alone at a concentration of 10 mcg/mL, decreased mPAP by 6%, PVR by 20%, TPG by 21%, and PVR/SVR ratio by 21%. When nebulized milrinone was added, there was an additional 8% decrease in PVR over epoprostenol alone.
Sablotzki et al.  found that nebulized milrinone (2 mg over 10 min) significantly reduced mPAP (−13%), PVR (−25%), and TPG (−29%) in a small study (n = 18) of heart transplant candidates with PH undergoing right heart catheterization. Maximum hemodynamic effect was seen at 10 min after inhalation, and the hemodynamic parameters returned to baseline within 30 min.
In a retrospective review of 70 patients having cardiac surgery, Lamarch et al.  analyzed the effect of nebulized milrinone given either at initiation or termination of CPB. In both groups, there was a similar decrease in mPAP before and after CPB. However, the group receiving nebulized milrinone before CPB had no change in the MAP: mPAP ratio, while the group receiving the drug at the end of CPB had a decrease in the MAP: mPAP ratio, indicating development of PH. In a univariate analysis of predictors for difficult separation from CPB, nebulized milrinone before CPB was a protective factor (odds ratio [OR] = 0.2, confidence interval [CI]: 0.05-0.8; P = 0.02), but the multivariate analysis showed that only CPB duration was a risk factor (OR = 1.02, CI: 1.007-1.03; P = 0.002) for difficult separation from CPB.
As discussed earlier, Singh et al.  performed a three-way comparison of nebulized milrinone, nebulized NTG, and inspiration of 100% oxygen in 35 children with acyanotic congenital heart disease with left-to-right shunt. The group receiving nebulized milrinone had a 15% decrease in mPAP and PVRI decreased from approximately 9 WU/m 2 to 2.9 WU/m 2 . The investigators concluded that the three treatments had comparable effects on PAP.
Sildenafil, a selective PDE5i that slows the degradation of cGMP to GMP, is used to treat erectile dysfunction by enhancing vasodilation in the corpora cavernosa. Oral sildenafil is a selective, well-tolerated PAP-lowering agent for patients with PAH. ,,, Oral sildenafil has been used to manage PH in cardiac surgical patients, in particular as an adjunct to reduce rebound PH during weaning of other pulmonary vasodilators. ,,,,, Intravenous sildenafil is comparable to intravenous milrinone in terms of hemodynamic and right heart inotropic effects. ,
Inhaled sildenafil should theoretically be a potent, selective pulmonary vasodilator. Unfortunately, to date there is little published experience with inhaled sildenafil. A lamb model of PH found that 10 mg and 30 mg aerosols of sildenafil decreased PAP by 21% and 26%, respectively, and that 10 mg of aerosolized sildenafil combined with low-dose iNO (2 and 5 ppm) resulted in even greater PAP-lowering effect (−35% and − 43%, respectively).  Inhaled sildenafil was found to prevent postcardiopulmonary bypass PH, improve oxygenation, and reduce endothelial dysfunction in pigs. 
| Conclusion|| |
Physicians who treat PH in the perioperative setting should be aware of the caveats of iNO and the iNO alternatives [Table 1]. The ideal pulmonary vasodilator for perioperative use which should be highly specific for the pulmonary circulation, free of side effects, inexpensive, and convenient to implement, has yet to be designed. iNO has the advantage of being recognized as a highly reliable pulmonary vasodilator that is approved by regulating authorities. The main disadvantages of iNO are its expense and cumbersome equipment. The inhaled forms of the prostanoids, PDE inhibitors, and NO donors (NTG, SNP) achieve reductions in PAP and PVR that are comparable to iNO and appear to be safe and well-tolerated. In addition, the iNO alternatives are typically inexpensive and rely on nebulization devices that many hospitals have on hand. Unfortunately, the cumulative experience with the iNO alternatives is substantially less than iNO. Routine use of a pulmonary-specific vasodilator must take into account how the drug will fit into a hospital's perioperative environment. Given that perioperative therapy for PH typically occurs in patients who are medically complex and unforgiving of misadventure, the choice of therapy should emphasize safety and reliability.
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| References|| |
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al
. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250-94.
Chin KM, Kim NH, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery Dis 2005;16:13-8.
Simon MA, Pinsky MR. Right ventricular dysfunction and failure in chronic pressure overload. Cardiol Res Pract 2011;2011:568095.
Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al
. Right ventricular function and failure: Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114:1883-91.
Rimar S, Gillis CN. Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 1993;88:2884-7.
Fernandes JL, Sampaio RO, Brandão CM, Accorsi TA, Cardoso LF, Spina GS, et al
. Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. Am J Cardiol 2011;107:1040-5.
Ardehali A, Hughes K, Sadeghi A, Esmailian F, Marelli D, Moriguchi J, et al
. Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation 2001;72:638-41.
Patel ND, Weiss ES, Schaffer J, Ullrich SL, Rivard DC, Shah AS, et al
. Right heart dysfunction after left ventricular assist device implantation: A comparison of the pulsatile HeartMate I and axial-flow HeartMate II devices. Ann Thorac Surg 2008;86:832-40.
Baumwol J, Macdonald PS, Keogh AM, Kotlyar E, Spratt P, Jansz P, et al
. Right heart failure and "failure to thrive" after left ventricular assist device: Clinical predictors and outcomes. J Heart Lung Transplant 2011;30:888-95.
Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, et al
. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: Incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316-24.
Lietz K, Long JW, Kfoury AG, Slaughter MS, Silver MA, Milano CA, et al
. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: Implications for patient selection. Circulation 2007;116:497-505.
Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, et al
. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29:S1-39.
Dang NC, Topkara VK, Mercando M, Kay J, Kruger KH, Aboodi MS, et al
. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1-6.
Bhorade S, Christenson J, O'connor M, Lavoie A, Pohlman A, Hall JB. Response to inhaled nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med 1999;159:571-9.
Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005;353:2683-95.
Young JD, Dyar O, Xiong L, Howell S. Methaemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intensive Care Med 1994;20:581-4.
Hugod C. Effect of exposure to 43 ppm nitric oxide and 3.6 ppm nitrogen dioxide on rabbit lung. A light and electron microscopic study. Int Arch Occup Environ Health 1979;42:159-67.
Kirmse M, Hess D, Fujino Y, Kacmarek RM, Hurford WE. Delivery of inhaled nitric oxide using the Ohmeda INOvent Delivery System. Chest 1998;113:1650-7.
Yahagi N, Kumon K, Tanigami H, Watanabe Y, Haruna M, Hayashi H, et al
. Cardiac surgery and inhaled nitric oxide: Indication and follow-up (2-4 years). Artif Organs 1998;22:886-91.
Augoustides JG, Ochroch EA. Pro: Inhaled prostaglandin as a pulmonary vasodilator instead of nitric oxide. J Cardiothorac Vasc Anesth 2005;19:400-2.
Dickstein ML. Con: Inhaled prostaglandin as a pulmonary vasodilator instead of nitric oxide. J Cardiothorac Vasc Anesth 2005;19:403-5.
Meadow W, Rudinsky B, Bell A, Hipps R. Effects of nebulized nitroprusside on pulmonary and systemic hemodynamics during pulmonary hypertension in piglets. Pediatr Res 1998;44:181-6.
Schütte H, Grimminger F, Otterbein J, Spriestersbach R, Mayer K, Walmrath D, et al
. Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation. J Pharmacol Exp Ther 1997;282:985-94.
Schreiber MD, Dixit R, Rudinsky B, Hipps R, Morgan SE, Keith RA, et al
. Direct comparison of the effects of nebulized nitroprusside versus inhaled nitric oxide on pulmonary and systemic hemodynamics during hypoxia-induced pulmonary hypertension in piglets. Crit Care Med 2002;30:2560-5.
Adrie C, Ichinose F, Holzmann A, Keefer L, Hurford WE, Zapol WM. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J Appl Physiol (1985) 1998;84:435-41.
Mestan KK, Carlson AD, White M, Powers JA, Morgan S, Meadow W, et al
. Cardiopulmonary effects of nebulized sodium nitroprusside in term infants with hypoxic respiratory failure. J Pediatr 2003;143:640-3.
Palhares DB, Figueiredo CS, Moura AJ. Endotracheal inhalatory sodium nitroprusside in severely hypoxic newborns. J Perinat Med 1998;26:219-24.
Moffett BS, Price JF. Evaluation of sodium nitroprusside toxicity in pediatric cardiac surgical patients. Ann Pharmacother 2008;42:1600-4.
Scheuch G, Kohlhaeufl MJ, Brand P, Siekmeier R. Clinical perspectives on pulmonary systemic and macromolecular delivery. Adv Drug Deliv Rev 2006;58:996-1008.
Lang BS, Gorren AC, Oberdorfer G, Wenzl MV, Furdui CM, Poole LB, et al
. Vascular bioactivation of nitroglycerin by aldehyde dehydrogenase-2: Reaction intermediates revealed by crystallography and mass spectrometry. J Biol Chem 2012;287:38124-34.
Bando M, Ishii Y, Kitamura S, Ohno S. Effects of inhalation of nitroglycerin on hypoxic pulmonary vasoconstriction. Respiration 1998;65:63-70.
Gong F, Shiraishi H, Kikuchi Y, Hoshina M, Ichihashi K, Sato Y, et al
. Inhalation of nebulized nitroglycerin in dogs with experimental pulmonary hypertension induced by U46619. Pediatr Int 2000;42:255-8.
Goyal P, Kiran U, Chauhan S, Juneja R, Choudhary M. Efficacy of nitroglycerin inhalation in reducing pulmonary arterial hypertension in children with congenital heart disease. Br J Anaesth 2006;97:208-14.
Omar HA, Gong F, Sun MY, Einzig S. Nebulized nitroglycerin in children with pulmonary hypertension secondary to congenital heart disease. W V Med J 1999;95:74-5.
Mandal B, Kapoor PM, Chowdhury U, Kiran U, Choudhury M. Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension. Ann Card Anaesth 2010;13:138-44.
Yurtseven N, Karaca P, Kaplan M, Ozkul V, Tuygun AK, Aksoy T, et al
. Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Anesthesiology 2003;99:855-8.
Yurtseven N, Karaca P, Uysal G, Ozkul V, Cimen S, Tuygun AK, et al
. A comparison of the acute hemodynamic effects of inhaled nitroglycerin and iloprost in patients with pulmonary hypertension undergoing mitral valve surgery. Ann Thorac Cardiovasc Surg 2006;12:319-23.
Singh R, Choudhury M, Saxena A, Kapoor PM, Juneja R, Kiran U. Inhaled nitroglycerin versus inhaled milrinone in children with congenital heart disease suffering from pulmonary artery hypertension. J Cardiothorac Vasc Anesth 2010;24:797-801.
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-67.
Madigan M, Zuckerbraun B. Therapeutic Potential of the Nitrite-Generated NO Pathway in Vascular Dysfunction. Front Immunol 2013;4:174.
Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: Therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res 2011;89:542-52.
Baliga RS, Milsom AB, Ghosh SM, Trinder SL, Macallister RJ, Ahluwalia A, et al
. Dietary nitrate ameliorates pulmonary hypertension: Cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation 2012;125:2922-32.
Dias-Junior CA, Gladwin MT, Tanus-Santos JE. Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism. Free Radic Biol Med 2006;41:1764-70.
Pluta RM, Oldfield EH, Bakhtian KD, Fathi AR, Smith RK, Devroom HL, et al
. Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. PLoS One 2011;6:e14504.
Blood AB, Schroeder HJ, Terry MH, Merrill-Henry J, Bragg SL, Vrancken K, et al
. Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation. Circulation 2011;123:605-12.
Hunter CJ, Dejam A, Blood AB, Shields H, Kim-Shapiro DB, Machado RF, et al
. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 2004;10:1122-7.
Zuckerbraun BS, Shiva S, Ifedigbo E, Mathier MA, Mollen KP, Rao J, et al
. Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 2010;121:98-109.
Endrys J, Belobradek Z, Petrle M, Steinhart L. Diagnosis of dominant mitral stenosis or regurgitation using amyl nitrite. Br Heart J 1964;26:250-4.
Muehlschlegel JD, Lobato EB, Kirby DS, Arnaoutakis G, Sidi A. Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs. Ann Card Anaesth 2007;10:113-20.
Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 2002;360:141-3.
Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, et al
. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999;103:1509-15.
Waxman AB, Zamanian RT. Pulmonary arterial hypertension: New insights into the optimal role of current and emerging prostacyclin therapies. Am J Cardiol 2013;111:1A-16A.
Haraldsson A, Kieler-Jensen N, Nathorst-Westfelt U, Bergh CH, Ricksten SE. Comparison of inhaled nitric oxide and inhaled aerosolized prostacyclin in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. Chest 1998;114:780-6.
Khan TA, Schnickel G, Ross D, Bastani S, Laks H, Esmailian F, et al
. A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. J Thorac Cardiovasc Surg 2009;138:1417-24.
Lowson SM. Inhaled alternatives to nitric oxide. Crit Care Med 2005;33:S188-95.
Dzierba AL, Abel EE, Buckley MS, Lat I. A review of inhaled nitric oxide and aerosolized epoprostenol in acute lung injury or acute respiratory distress syndrome. Pharmacotherapy 2014;34:279-90.
Mulligan C, Beghetti M. Inhaled iloprost for the control of acute pulmonary hypertension in children: A systematic review. Pediatr Crit Care Med 2012;13:472-80.
Vorhies EE, Caruthers RL, Rosenberg H, Yu S, Gajarski RJ. Use of inhaled iloprost for the management of postoperative pulmonary hypertension in congenital heart surgery patients: Review of a transition protocol. Pediatr Cardiol 2014;35:1337-43.
Denault AY, Lamarche Y, Couture P, Haddad F, Lambert J, Tardif JC, et al
. Inhaled milrinone: A new alternative in cardiac surgery? Semin Cardiothorac Vasc Anesth 2006;10:346-60.
Buckley MS, Feldman JP. Nebulized milrinone use in a pulmonary hypertensive crisis. Pharmacotherapy 2007;27:1763-6.
Hentschel T, Yin N, Riad A, Habbazettl H, Weimann J, Koster A, et al
. Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology 2007;106:124-31.
St-Pierre P, Deschamps A, Cartier R, Basmadjian AJ, Denault AY. Inhaled milrinone and epoprostenol in a patient with severe pulmonary hypertension, right ventricular failure, and reduced baseline brain saturation value from a left atrial myxoma. J Cardiothorac Vasc Anesth 2014;28:723-9.
Wang H, Gong M, Zhou B, Dai A. Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery. Adv Ther 2009;26:462-8.
Chen F, Zhang J, Aoyama A, Okamoto T, Fujinaga T, Bando T. Potential for pulmonary protection by nebulized milrinone during warm ischemia. Transplant Proc 2008;40:3335-8.
Zhang J, Chen F, Zhao X, Aoyama A, Okamoto T, Fujinaga T, et al
. Nebulized phosphodiesterase III inhibitor during warm ischemia attenuates pulmonary ischemia-reperfusion injury. J Heart Lung Transplant 2009;28:79-84.
Lamarche Y, Malo O, Thorin E, Denault A, Carrier M, Roy J, et al
. Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;130:83-92.
Haraldsson s 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 2001;93:1439-45.
Sablotzki A, Starzmann W, Scheubel R, Grond S, Czeslick EG. Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates. Can J Anaesth 2005;52:1076-82.
Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, et al
. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158-64.
Lopez-Meseguer M, Berastegui C, Monforte V, Bravo C, Domingo E, Roman A. Inhaled iloprost plus oral sildenafil in patients with severe pulmonary arterial hypertension delays the need for lung transplantation. Transplant Proc 2013;45:2347-50.
Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: Comparison with inhaled nitric oxide. Circulation 2002;105:2398-403.
Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, et al
. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-5.
Elias S, Sviri S, Orenbuch-Harroch E, Fellig Y, Ben-Yehuda A, Fridlender ZG, et al
. Sildenafil to facilitate weaning from inhaled nitric oxide and mechanical ventilation in a patient with severe secondary pulmonary hypertension and a patent foramen ovale. Respir Care 2011;56:1611-3.
Klodell CT Jr, Morey TE, Lobato EB, Aranda JM Jr, Staples ED, Schofield RS, et al
. Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices. Ann Thorac Surg 2007;83:68-71.
Lee JE, Hillier SC, Knoderer CA. Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease. J Intensive Care Med 2008;23:329-34.
Matamis D, Pampori S, Papathanasiou A, Papakonstantinou P, Tsagourias M, Galiatsou E, et al
. Inhaled NO and sildenafil combination in cardiac surgery patients with out-of-proportion pulmonary hypertension: Acute effects on postoperative gas exchange and hemodynamics. Circ Heart Fail 2012;5:47-53.
Mychaskiw G, Sachdev V, Heath BJ. Sildenafil (viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth 2001;13:218-20.
Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, et al
. Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 2005;79:194-7.
Al-Hesayen A, Floras JS, Parker JD. The effects of intravenous sildenafil on hemodynamics and cardiac sympathetic activity in chronic human heart failure. Eur J Heart Fail 2006;8:864-8.
Botha P, Parry G, Dark JH, Macgowan GA. Acute hemodynamic effects of intravenous sildenafil citrate in congestive heart failure: Comparison of phosphodiesterase type-3 and -5 inhibition. J Heart Lung Transplant 2009;28:676-82.
Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al
. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001;29:1000-5.
Aubin MC, Laurendeau S, Mommerot A, Lamarche Y, Denault A, Carrier M, et al
. Differential effects of inhaled and intravenous sildenafil in the prevention of the pulmonary endothelial dysfunction due to cardiopulmonary bypass. J Cardiovasc Pharmacol 2008;51:11-7.
Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, Arizona
Source of Support: None, Conflict of Interest: None