ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Inhaled nitric oxide in adults: Biology and indications for use

Inhaled nitric oxide in adults: Biology and indications for use
Literature review current through: Jan 2024.
This topic last updated: Jun 27, 2022.

INTRODUCTION — Nitric oxide (NO) is a naturally occurring vasodilator produced by vascular endothelial cells. Inhaled NO is currently approved for treatment of persistent pulmonary hypertension of the newborn (PPHN). In adult patients with pulmonary arterial hypertension (PAH), inhaled NO has an established role in acute pulmonary vasoreactivity testing during right heart catheterization. Inhaled NO has also been proposed as a long-term therapy for PAH and possibly other types of pulmonary hypertension (PH) [1] and is occasionally used as a rescue therapy for severely hypoxemic patients both with and without an established diagnosis of PH.

The role of inhaled NO in vasoreactivity testing and therapeutic uses of this agent in adults are discussed in this topic review. The use of inhaled NO in the management of infants with PPHN and the role of exhaled NO as a marker of disease activity in asthma and other chronic lung diseases are discussed separately. (See "Exhaled nitric oxide analysis and applications" and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Inhaled nitric oxide (iNO)'.)

BIOLOGY AND PHARMACOKINETICS — Endogenous nitric oxide (NO) is produced from L-arginine in vascular endothelial cells by endothelial nitric oxide synthase (eNOS; type III NOS), a constitutively expressed enzyme [2]. With the help of several key cofactors, eNOS catalyzes a multistep reaction in which L-arginine and oxygen are converted to L-citrulline and NO. NO that is synthesized by vascular endothelial cells diffuses into adjacent vascular smooth muscle and decreases vascular tone in the systemic and pulmonary circulation [3,4]. When administered by inhalation, it selectively dilates pulmonary vasculature in ventilated areas of the lung. The vasodilating effect of inhaled NO has a rapid onset of action and a short half-life that results in essentially no effect on systemic vessels, making it a highly selective, short-acting pulmonary vasodilator and an ideal agent for pulmonary vasoreactivity testing. (See 'Vasoreactivity testing' below.)

Mechanism of action – NO activates soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), which then activates cGMP dependent protein kinase (PKG) and results in the activation of several regulatory mechanisms that decrease intracellular calcium and relax vascular smooth muscle tone (ie, vasodilation) in precapillary resistance arterioles [2,5]. Additional effects of NO include suppression of both smooth muscle proliferation and platelet aggregation [6,7].

These properties have led to the development of inhaled NO and other agents that enhance the NO/cGMP signaling pathway such as sildenafil and tadalafil (phosphodiesterase type-5 [PDE5] inhibitors), or riociguat, a sGC stimulator. Inhaled NO has been shown to be effective at reducing pulmonary vascular resistance at doses as low as 1 part per million (ppm). A vasodilator effect of NO has been demonstrated with as little as 0.1 ppm, and there appears to be a peak effect for pulmonary vasodilation that occurs at a dose of approximately 10 ppm [8-10]. Administration of inhaled NO is discussed below. (See 'Procedure' below.)

Metabolism – NO is highly reactive and is rapidly inactivated by binding to a variety of heme moieties including those found in sGC, hemoglobin, myoglobin, and thiols. NO is also rapidly oxidized to the more stable metabolites nitrite dioxide (NO2-) and nitrite trioxide (NO3-). While the half-life of newly formed NO is in the order of 0.1 to 5 seconds, the vasodilator effect of the cGMP/PKG signaling induced by inhaled NO has a half-life of 15 to 30 seconds at a dose of 5 to 80 ppm. Due to its rapid inactivation and metabolism, inhaled NO selectively impacts the pulmonary vasculature with little effect on systemic arterial vessels, which, in contrast with other therapies for pulmonary arterial hypertension, makes it an attractive candidate as a "pure" pulmonary vasodilator [11]. (See 'Treatment' below.)

PULMONARY ARTERIAL HYPERTENSION (GROUP 1) — Pulmonary hypertension (PH) was defined at the 6th World Symposium on Pulmonary Hypertension (WSPH) as an mPAP ≥20 mmHg with a pulmonary vascular resistance (PVR) of ≥3 Wood units. This value for mPAP represents two standard deviations above mPAP in the general population [12]. The pulmonary hypertensive diseases have been classified into five groups by the WSPH (table 1). Group 1 includes those diseases that cause PH by obliterative vascular remodeling of the distal pulmonary circulation and are collectively referred to as pulmonary arterial hypertension (PAH). Groups 2 to 5 include diseases that elevate pulmonary arterial pressure due to left heart, lung, thromboembolic, and miscellaneous diseases, respectively. The use of inhaled nitric oxide (NO) in PH mostly applies to patients with pulmonary arterial hypertension (PAH; ie, group 1 PAH), although clinical trials are being conducted in patients with PH due to lung disease (group 3 PH). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Vasoreactivity testing — Acute vasodilator testing is the only well-established and widely accepted use of inhaled NO in adults with PAH. Guidelines for the treatment of PAH recommend acute vasoreactivity testing prior to the initiation of PAH-specific therapy [13]. Vasoreactivity testing identifies a minority of patients (less than 10 percent) in whom PAH is due primarily to increased pulmonary vascular tone as opposed to pulmonary vascular remodeling. These patients have a much better prognosis and respond well to treatment with high-dose calcium channel blockers alone (eg, nifedipine, amlodipine), agents considered to have a lower cost and toxicity profile when compared with other therapies for PAH. Vasoreactivity testing involves the administration of a short-acting vasodilator followed by measurement of the hemodynamic response during right heart catheterization that identifies this population.

Details regarding the procedure and efficacy of inhaled NO in vasoreactivity testing are discussed in this section. Details regarding indications for and interpretation of vasoreactivity testing are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Procedure — Vasoreactivity testing requires a pulmonary artery catheter (PAC) and is typically done in a catheterization laboratory and/or monitored setting (eg, intensive care unit). (See "Pulmonary artery catheters: Insertion technique in adults" and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults".)

Baseline hemodynamic parameters are measured (eg, central venous pressure, right atrial pressure, right ventricular pressure, pulmonary artery pressures, pulmonary capillary wedge pressure, systemic blood pressure, heart rate, and cardiac output). Pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output are measured again after inhalation of NO at 20 or 40 parts per million (ppm) for 5 minutes unless adverse symptoms develop.

How to administer NO, adverse effects, and interpretation of a positive and negative test are discussed separately. (See 'Administration' below and 'Adverse effects' below and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Efficacy — Inhaled NO, other inhaled agents (eg, nebulized epoprostenol, treprostinil, or iloprost), and intravenous agents (eg, epoprostenol, adenosine) can be used in vasoreactivity testing. Although no single agent has been established as superior [14], NO is typically used because of its rapid onset of action, short half-life, and ease of administration and because its effect on the pulmonary vasculature is highly selective [3,9,15-18].

The ability of vasoreactivity testing with inhaled NO to predict pulmonary vascular reactivity has been confirmed in several studies [15,16]. As examples:

One study demonstrated that vasodilation of the pulmonary vasculature induced by inhaled NO at a dose of 80 ppm predicted an acute hemodynamic response to nifedipine, a calcium channel blocker, with a sensitivity and specificity of 88, 100, and 94 percent, respectively [16].

Another study of 35 patients with PAH undergoing vasoreactivity testing reported similar pulmonary vasodilation with intravenous epoprostenol and inhaled NO, but only intravenous epoprostenol had detectable systemic hemodynamic effects [9].

Although the best dose of NO has not been established, there is concern that high doses of inhaled NO can induce acute pulmonary edema, especially in patients with concomitant pulmonary venous hypertension from left ventricular diastolic dysfunction, pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis, or PAH associated with connective tissue disease [19]. In patients with PAH, there does not appear to be any significant difference in vasodilator response between 20 and 40 ppm. Therefore, most PH centers of expertise usually do not use doses in excess of this range.

While vasoreactivity testing with inhaled NO (or any other agent) identifies patients who are vasoreactive, the results of testing do not reliably predict whether patients will experience clinical improvement with calcium channel blockade and close follow-up is required to ensure that patients are responding to this therapy. Patients with a positive acute vasodilator response who do not improve with calcium channel blockers should be considered for treatment with PAH-specific medications. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Calcium channel blockers (trial)'.)

Treatment — Inhaled NO remains an investigational agent for the treatment of patients with group 1 PAH (table 1). Randomized trials using enhanced delivery systems offer some promise, but there are no data yet to support its efficacy.

The rationale for the use of inhaled NO (and other inhaled agents) in PAH is local delivery of a potent pulmonary vasodilator with minimal systemic effects. In addition, it is thought that administration of a vasodilator by the inhaled route will result in preferential pulmonary vasodilation in areas of well-ventilated lung, resulting in decreased perfusion of poorly ventilated lung and a subsequent decrease in intrapulmonary shunt fraction resulting in an overall improvement in ventilation-perfusion (V/Q) matching (figure 1); this is in contrast with worsening V/Q mismatching that can result from a generalized increase in pulmonary flow to both poorly ventilated and well ventilated alveoli with systemically administered agents [20]. While in the past, enthusiasm for inhaled NO was driven by these potential advantages and a lack of alternative therapies, excitement has waned due to practical difficulties with its administration and the development of effective alternative systemic therapies with proven benefit, which are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Long-term inhaled NO has been successfully administered to patients with PAH (table 1) (ie, outpatients) via nasal prongs or face mask. Although hemodynamics (eg, mean pulmonary artery pressure and pulmonary vascular resistance) and exercise tolerance improve with inhaled NO, the effect is not consistent and the potential impact of long-term NO treatment on survival is unstudied. Evidence supporting its use is limited to case reports and small case series [21-24]. In one case report, prolonged inhaled NO was used successfully as a bridge to transplantation in a patient with idiopathic pulmonary arterial hypertension (IPAH) [21]. However, prospective randomized controlled trials of continuous inhaled NO in PAH have not been conducted. A phase 3, placebo-controlled, double-blind, randomized, clinical study did examine the safety and efficacy of intermittent inhaled NO therapy using a pulsed-dose delivery system as an add-on therapy in patients with group 1 PAH who were already being treated with approved PAH medications. However, this study was stopped early when an interim analysis found NO to be of no clinical benefit (NCT02725372).

Using inhaled NO to treat other types of PH (ie, patients belonging to group 2 through 5 PH (table 1)) is also not recommended, since small trials have shown limited or no benefit. In one small trial, 44 patients with PH associated with COPD were randomized to inhaled NO plus oxygen or oxygen alone. Inhaled NO improved pulmonary hemodynamics, cardiac output, and partial arterial pressure of carbon dioxide (pCO2), but there was no objective assessment of clinical endpoints, although more patients in the NO group reported improved physical performance on a questionnaire [25]. Pulse-dose inhaled NO is being developed as a potential treatment for PH associated with interstitial lung disease, chronic obstructive pulmonary disease, and pulmonary sarcoidosis, but the results of these trials have not yet been published. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Pulmonary arterial hypertension-directed therapy'.)

ACUTE HYPOXEMIC RESPIRATORY FAILURE

Patients with underlying pulmonary hypertension — Inhaled nitric oxide (NO) has been used successfully in patients with severe underlying pulmonary hypertension (PH) who become acutely hypoxemic and/or hemodynamically unstable. However, the data are of limited quality and NO is usually only attempted on a trial basis when other standard therapies have failed [26-35]. Hypoxemia in PH patients is often acutely worsened by factors that can induce acute pulmonary vasoconstriction (eg, alveolar hypoxemia, lung transplant related ischemia), which can potentially be ameliorated quickly by the vasodilatory function of inhaled NO.

Examples of PH patients where inhaled NO may be of benefit include:

PAH that worsened due to an acute illness (eg, pneumonia)

PH immediately following lung transplantation, lung resection, pulmonary endarterectomy, or cardiac surgery

PH is a recognized risk factor for increased morbidity and mortality after cardiac surgery. Inhaled NO is often used to reduce right heart failure intra- and postoperatively in these patients due to its lack of adverse effects on systemic arterial blood pressure and oxygen saturation. However, its ability to improve patient outcome in this setting is unclear. One meta-analysis reviewed 18 randomized controlled trials of 958 adult or pediatric cardiac surgery patients receiving inhaled NO versus any comparator. NO resulted in no meaningful clinical benefit in terms of duration of mechanical ventilation, intensive care unit stay, and survival [36].

Patients without underlying pulmonary hypertension — Inhaled NO has been used as a rescue therapy when standard therapy has failed in patients with severe acute hypoxemia and/or hemodynamic compromise who do not have underlying pulmonary hypertension. This indication is based upon the rationale that delivery of an inhaled pulmonary vasodilator may improve ventilation-perfusion (V/Q) matching (figure 1) [20]. However, inhaled NO usually has a small effect on V/Q and a larger effect on reducing shunt fraction. This is thought to occur because small increases in perfusion to areas of normal ventilation result in a "steal" phenomenon from areas that are perfused but not ventilated, thereby reducing intra-pulmonary shunt. It is prudent when selecting inhaled NO in these settings to consider whether vasoconstriction of the pulmonary vascular bed or intrapulmonary shunting are likely to be contributing to severe hypoxemia or hemodynamic compromise.

Evidence to support use in this population are limited and of poor quality [27,28,31,37,38]. Examples of such patients in whom inhaled NO may be successful include:

Acute right heart syndrome, in which a sudden deterioration in right ventricular function (eg, pulmonary embolism, acute respiratory distress syndrome [ARDS]) has decreased the left ventricular end-diastolic volume, causing systemic hypotension. In a randomized placebo-controlled, double blind study of inhaled NO in acute pulmonary embolism associated with right ventricular (RV) dysfunction, twice as many patients met the primary composite endpoint of normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL in the NO group than in the placebo group. Although the difference was not statistically significant (24 versus 13 percent), the study was only powered to detect a 30 percent or greater difference between treatment groups. In a post hoc analysis, there was a significant increase in the percentage of patients who resolved their RV dilation or hypokinesis by 24 hours [39].

ARDS, where inhaled NO theoretically decreases pulmonary vascular pressure and improves oxygenation. Clinical trials have demonstrated temporary improvements in oxygenation and better pulmonary function tests six months after treatment but no improvement in overall survival. Details regarding inhaled NO in patients with ARDS are provided separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults".)

In some clinical situations, inhaled NO can be used to improve hemodynamic parameters or oxygenation while the acute process leading to the deterioration is reversed or a more effective therapy safely initiated. However, prolonged administration of inhaled NO has not been shown to improve outcome and may be associated with worsening renal function or other adverse effects. As a result, the use of inhaled NO beyond several days is not recommended. (See 'Adverse effects' below.)

ADMINISTRATION — Inhaled nitric oxide (NO) is generally administered by mixing pressurized NO and oxygen and adjusting the amount of NO using bleeder valves. It is delivered using a specialized face mask or nasal prongs for spontaneously breathing patients, or via the ventilator for mechanically ventilated patients. Not all facilities have NO on their formulary due to its high cost, but it is more likely to be available in institutions that use it frequently in infants with persistent pulmonary hypertension of the newborn, where its therapeutic role is established. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Inhaled nitric oxide (iNO)'.)

When administered for more than several days, inhaled NO should not be abruptly discontinued but rather weaned slowly by gradually decreasing the dose in decrements of 10 parts per million (ppm) over several days. Once a dose of 10 ppm is reached, discontinuation is generally considered safe, although an increase in FiO2 may temporarily be required. Patients who demonstrate worsening oxygenation of hemodynamic compromise may need to be weaned to 5 or 1 ppm before discontinuing. (See 'Adverse effects' below.)

ADVERSE EFFECTS — Although inhaled nitric oxide (NO) is generally considered safe, there are some adverse effects that are typically short-lived and reversible due to its short half-life. Administration for more than several days may be associated with a greater risk of side effects.

Hemodynamic deterioration – Immediate side effects similar to those seen with other pulmonary vasodilators can rarely occur with inhaled NO and include decreased systemic vascular resistance, decreased systemic blood pressure, increased heart rate, pulmonary edema, and hypoxemia. Should these develop, NO should be discontinued immediately and consideration should also be given to the diagnosis of pulmonary veno-occlusive disease. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Hemodynamic findings of PAH'.)

Methemoglobinemia – Methemoglobinemia during acute or prolonged NO inhalation is unusual when NO is administered within the accepted dose range [40]. Nonetheless, it can occur in patients receiving higher doses of NO (usually in excess of 40 parts per million [ppm]) or in patients who are predisposed to the development of methemoglobinemia, or when it is administered for prolonged periods in the acute hospitalization setting. (See "Methemoglobinemia".)

Rebound pulmonary hypertension – Abrupt discontinuation of inhaled NO can precipitate rapid worsening of ventilation-perfusion mismatching and/or pulmonary hypertension, which typically manifests as hypoxemia and/or hemodynamic compromise [10,37]. In a study of 31 patients treated with inhaled NO for acute hypoxemic respiratory failure, approximately 25 percent had hemodynamic collapse when the NO was abruptly discontinued after 10 to 30 hours [37]. This was most common in older patients and patients whose blood pressure improved when the inhaled NO was started. Reinstitution of inhaled NO restored hemodynamic stability in all instances. Some evidence suggests that coadministration of sildenafil may ameliorate the effects of withdrawal [41]. Slow weaning over days is preferred when discontinuing this agent.

Inhaled NO may also have some theoretical adverse effects:

Cytotoxicity – NO and its oxidized derivatives (principally NO2) can be directly toxic to alveolar and vascular tissue [40,42]. NO should be stored in combination with nitrogen (at concentrations no higher than 1000 ppm) and blended with oxygen at the time of administration to prevent oxidation to toxic products [2,27]. In addition, there should be close surveillance for NO2 levels >2 ppm (usually performed by institutional environmental health departments by means of a detector device). Only some commercial administration systems measure NO2 levels. The formation of NO2 increases exponentially with the concentration of oxygen used. We measure NO2 levels continuously when NO is used with a fraction of inspired oxygen (FiO2) greater than 0.5.

NO released into the work environment can be potentially toxic. The limit of NO exposure for employees set by the Occupational Safety and Health Administration is 25 ppm as an eight-hour time-weighted average. This degree of exposure would be unlikely to occur by the accumulation of exhaled NO in a patient's room. However, it is recommended that patients receiving prolonged inhaled NO through a ventilator circuit have their expiratory gases ventilated to the outside environment or, if administered by nasal prongs or face mask, that it be done in a well-ventilated area.

Immunosuppression – NO has immunosuppressive properties, which theoretically could increase the risk of nosocomial infection.

Mutagenesis – Potentially mutagenic deoxyribonucleic acid (DNA) strand breaks and base alterations can be caused by NO [40].

Renal dysfunction – NO may increase the risk of renal dysfunction, especially with prolonged use and in patients with ARDS [43,44]. In a meta-analysis of 10 randomized controlled trials involving 1363 patients, the use of inhaled NO significantly increased the risk of acute kidney injury (AKI) compared with controls (RR 1.4, 95% CI 1.06-1.83) [43]. Four of the trials were conducted in patients with ARDS and four in surgical patients, including two in patients undergoing cardiac surgery. In a stratified analysis, a high cumulative dose of inhaled NO defined as >7 days significantly increased the risk of AKI, whereas lower cumulative doses did not. Subgroup analysis found an increased risk of AKI in patients with ARDS (RR 1.55, 95% CI 1.15-2.09) but not in the other patient groups (RR 0.90, 95% CI 0.49-1.67).

In contrast, limited use of inhaled NO has been shown to protect against AKI in patients requiring prolonged cardiopulmonary bypass. The mechanisms responsible for AKI with cardiopulmonary bypass are unclear but may include increased hemolysis leading to increased plasma levels of free oxyhemoglobin that binds to and depletes endogenous NO, leading to vasoconstriction, impaired tissue perfusion, and inflammation. In a large single-center study from China, 244 patients undergoing multiple valve replacement surgery were randomized to receive inhaled NO at 80 ppm or inhaled nitrogen during cardiopulmonary bypass and for 24 hours postoperatively [45]. Patients in the treatment arm had evidence of reduced plasma oxyhemoglobin and reduced AKI at 30 days, 90 days, and one year (RR 0.47, 95% CI 0.20-1.10 at one year).

SUMMARY AND RECOMMENDATIONS

Nitric oxide (NO) is a naturally occurring vasodilator. It selectively dilates the pulmonary vasculature when administered by inhalation. Its action is rapid in onset and effects are short-lived due to its short half-life (15 to 30 seconds). Inhaled NO is generally administered by mixing pressurized NO and oxygen and adjusting the amount of NO using bleeder valves. (See 'Biology and pharmacokinetics' above.)

Acute vasodilator testing is the only well-established and widely accepted use of NO in adult patients with pulmonary arterial hypertension (PAH). (See 'Vasoreactivity testing' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Continuous, prolonged inhaled NO is not accepted as a first-line agent for long-term treatment of PAH, because of logistical challenges in its delivery, limited data regarding its safety and efficacy, and availability of other agents. Occasionally, it has been used successfully to stabilize acutely ill and/or hemodynamically compromised patients with severe underlying pulmonary hypertension (PH) and, less commonly, to improve hypoxemia in those without PH. (See 'Treatment' above and 'Acute hypoxemic respiratory failure' above.)

Inhaled NO is generally considered safe. Adverse effects include hemodynamic compromise, methemoglobinemia, and rebound PH (when discontinued after prolonged administration). There are other theoretical adverse effects including cytotoxicity, immunosuppression, and mutagenesis. (See 'Adverse effects' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Darren Taichman, MD, PhD who contributed to an earlier version of this topic review.

  1. http://clinicaltrials.gov/show/NCT01457781 (Accessed on August 24, 2015).
  2. Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994; 149:538.
  3. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, et al. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338:1173.
  4. Ichinose F, Roberts JD Jr, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation 2004; 109:3106.
  5. Archer SL, Huang JM, Hampl V, et al. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 1994; 91:7583.
  6. Zapol WM, Rimar S, Gillis N, et al. Nitric oxide and the lung. Am J Respir Crit Care Med 1994; 149:1375.
  7. Nong Z, Hoylaerts M, Van Pelt N, et al. Nitric oxide inhalation inhibits platelet aggregation and platelet-mediated pulmonary thrombosis in rats. Circ Res 1997; 81:865.
  8. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111.
  9. Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151:384.
  10. Pearl JM, Nelson DP, Raake JL, et al. Inhaled nitric oxide increases endothelin-1 levels: a potential cause of rebound pulmonary hypertension. Crit Care Med 2002; 30:89.
  11. Rimar S, Gillis CN. Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 1993; 88:2884.
  12. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53.
  13. Klinger JR, Elliott CG, Levine DJ, et al. Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest 2019; 155:565.
  14. Preston IR, Sagliani KD, Roberts KE, et al. Comparison of acute hemodynamic effects of inhaled nitric oxide and inhaled epoprostenol in patients with pulmonary hypertension. Pulm Circ 2013; 3:68.
  15. Jolliet P, Bulpa P, Thorens JB, et al. Nitric oxide and prostacyclin as test agents of vasoreactivity in severe precapillary pulmonary hypertension: predictive ability and consequences on haemodynamics and gas exchange. Thorax 1997; 52:369.
  16. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: a safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol 1998; 32:1068.
  17. Morales-Blanhir J, Santos S, de Jover L, et al. Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Respir Med 2004; 98:225.
  18. Leuchte HH, Schwaiblmair M, Baumgartner RA, et al. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest 2004; 125:580.
  19. Preston IR, Klinger JR, Houtchens J, et al. Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome. Chest 2002; 121:656.
  20. Hill NS, Preston IR, Roberts KE. Inhaled Therapies for Pulmonary Hypertension. Respir Care 2015; 60:794.
  21. Snell GI, Salamonsen RF, Bergin P, et al. Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am J Respir Crit Care Med 1995; 151:1263.
  22. Koh E, Niimura J, Nakamura T, et al. Long-term inhalation of nitric oxide for a patient with primary pulmonary hypertension. Jpn Circ J 1998; 62:940.
  23. Channick RN, Newhart JW, Johnson FW, et al. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest 1996; 109:1545.
  24. Preston IR, Klinger JR, Landzberg MJ, et al. Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension. Chest 2001; 120:866.
  25. Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax 2003; 58:289.
  26. Jeffery M, Taichman DB. Management of the acutely ill patient with pulmonary arterial hypertension. In: Pulmonary Vascular Disease, Mandel J, Taichman DB (Eds), Elsevier Science, Philadelphia 2006. p.254.
  27. Mizutani T, Layon AJ. Clinical applications of nitric oxide. Chest 1996; 110:506.
  28. Bhorade S, Christenson J, O'connor M, et al. Response to inhaled nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med 1999; 159:571.
  29. 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 2004; 127:1058.
  30. Meade MO, Granton JT, Matte-Martyn A, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med 2003; 167:1483.
  31. Cornfield DN, Milla CE, Haddad IY, et al. Safety of inhaled nitric oxide after lung transplantation. J Heart Lung Transplant 2003; 22:903.
  32. Takaba K, Aota M, Nonaka M, et al. Successful treatment of chronic thromboembolic pulmonary hypertension with inhaled nitric oxide after right ventricular thrombectomy. Jpn J Thorac Cardiovasc Surg 2004; 52:257.
  33. Fattouch K, Sbraga F, Sampognaro R, et al. Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, double-blind study. J Cardiovasc Med (Hagerstown) 2006; 7:119.
  34. Trummer G, Berchtold-Herz M, Martin J, Beyersdorf F. Successful treatment of pulmonary hypertension with inhaled nitric oxide after pulmonary embolectomy. Ann Thorac Surg 2002; 73:1299.
  35. Solina A, Papp D, Ginsberg S, et al. A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients. J Cardiothorac Vasc Anesth 2000; 14:12.
  36. Sardo S, Osawa EA, Finco G, et al. Nitric Oxide in Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth 2018; 32:2512.
  37. Christenson J, Lavoie A, O'Connor M, et al. The incidence and pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled nitric oxide. Am J Respir Crit Care Med 2000; 161:1443.
  38. Rossaint R, Falke KJ, López F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328:399.
  39. Kline JA, Puskarich MA, Jones AE, et al. Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial. Nitric Oxide 2019; 84:60.
  40. Weinberger B, Laskin DL, Heck DE, Laskin JD. The toxicology of inhaled nitric oxide. Toxicol Sci 2001; 59:5.
  41. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91:307.
  42. Narula P, Xu J, Kazzaz JA, et al. Synergistic cytotoxicity from nitric oxide and hyperoxia in cultured lung cells. Am J Physiol 1998; 274:L411.
  43. Ruan SY, Huang TM, Wu HY, et al. Inhaled nitric oxide therapy and risk of renal dysfunction: a systematic review and meta-analysis of randomized trials. Crit Care 2015; 19:137.
  44. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev 2016; :CD002787.
  45. Lei C, Berra L, Rezoagli E, et al. Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am J Respir Crit Care Med 2018; 198:1279.
Topic 8264 Version 21.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟