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Ann Thorac Surg 1996;61:1856-1864
© 1996 The Society of Thoracic Surgeons

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Current Review

Inhaled Nitric Oxide: Therapeutic Applications in Cardiothoracic Surgery

Department of Surgery, University of Colorado, Denver, Colorado

	Abstract

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Hypoxemia and increased pulmonary vascular resistance can greatly complicate the management of cardiothoracic surgical patients. These complications are commonly found in the setting of thoracic organ transplantation, adult and pediatric cardiac surgical procedures, and general thoracic surgical procedures. Inhaled nitric oxide is a new therapy that promises to be extremely valuable to the cardiothoracic surgeon. It has been shown to improve oxygenation in the setting of acute lung injury and to selectively lower pulmonary vascular resistance, without producing unwanted systemic vasodilation. The purpose of this review is to discuss the biochemistry, toxicity, experimental studies, and therapeutic applications of inhaled nitric oxide administration in cardiothoracic surgical patients.

	Introduction

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Inhaled nitric oxide (NO) is a new therapy that promises to be extremely valuable to the cardiothoracic surgeon. It improves oxygenation in acute lung injury and selectively lowers pulmonary vascular resistance (PVR) without producing unwanted systemic vasodilation. The purpose of this review is to discuss the therapeutic applications of inhaled NO administration for cardiothoracic surgical patients.

	Vascular Physiology of Nitric Oxide

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Nitric oxide is an endothelial-derived relaxing factor. In arteries and veins, NO is synthesized in endothelial cells and smooth muscle cells. Endothelial cells contain the constitutive isoenzyme of nitric oxide synthase (NOS), which is responsible for the continuous production and release of NO from the amino acid precursor L-arginine (Fig 1) [1]. Calcium activates constitutive NOS in response to receptor stimulation on the endothelial membrane by agonists such as adenosine diphosphate, acetylcholine, bradykinin, and thrombin. The calcium ionophore A23187 stimulates NOS by opening calcium channels on the endothelial cell membrane, thus activating constitutive NOS in a receptor-independent manner. Under physiologic conditions, an important stimulant of constitutive NOS is the shear stress of blood flowing across the endothelium, which increases the influx of calcium into the endothelium to activate constitutive NOS. A second isoenzyme of NOS, inducible NOS, is calcium-independent. It is found in vascular smooth muscle and is undetectable under basal conditions. It is induced by endotoxin, tumor necrosis factor, and interleukins. Nitric oxide produced within vascular smooth muscle cells by inducible NOS may explain hypotension during sepsis.

View larger version (27K): [in this window] [in a new window]   Fig 1. . Endothelial-derived nitric oxide (NO) is synthesized by constitutive nitric oxide synthase (NOS) from the amino acid L-arginine. The NO then diffuses into the subjacent vascular smooth muscle cell to stimulate guanylate cyclase to generate cyclic guanine 3`,5` monophosphate (cGMP). (GTP = guanosine triphosphate.)

View larger version (23K): [in this window] [in a new window]   Fig 2. . The principal intracellular mechanisms of pulmonary vasorelaxation are ultimately mediated through cyclic guanine 3`,5` monophosphate (cGMP) or cyclic adenosine 3`,5` monophosphate (cAMP). The cGMP–mediated relaxation can be endothelial dependent (response to acetylcholine [ACh]) or endothelial independent (response to nitroprusside). (ß2 = type 2 ß-adrenergic receptor; M = muscarinic receptor; NO = nitric oxide.)

Inhaled NO is particularly well suited as a ``selective'' pulmonary vasodilator. Inhaled into the alveolus, it readily diffuses across the alveolar-capillary membrane to relax pulmonary vascular smooth muscle (Fig 3). As it diffuses into the blood vessel lumen, it is bound to hemoglobin and inactivated; the affinity of hemoglobin for NO is 3,000 times greater than it is for oxygen. In binding the NO, hemoglobin converts to nitrosyl-hemoglobin and then to methemoglobin. Methemoglobin converts to nitrates and nitrites by methemoglobin reductase found in erythrocytes. Most of the circulating nitrates and nitrites in blood derive from metabolism of endogenous NO. Because of the binding to hemoglobin, the actions of inhaled NO are clinically focused in the pulmonary circulation without producing unwanted systemic vasorelaxation. The vasodilating action of NO stops when inhaled NO is withdrawn from the breathing circuit. The half-life of cGMP is less than 1 minute. Thus the pharmacologic effects of NO are eliminated with cessation of the drug.

View larger version (39K): [in this window] [in a new window]   Fig 3. . Inhaled nitric oxide (NO) is rapidly bound and deactivated by hemoglobin after producing pulmonary vasodilation. In this way, the vasodilating actions of NO are focused in the pulmonary circulation. (Nitrosyl-Hb = nitrosyl-hemoglobin; MET-Hb = methemoglobin; RBC = red blood cells.)

	Toxicity of Nitric Oxide

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

However, studies in which the NO exposure was very carefully controlled demonstrated that NO₂ rather than NO was the toxic moiety. Rats breathing 1,000 ppm of NO (without NO₂) for 30 minutes were found to have no lung disease [6], nor did mice breathing 10 ppm of NO for 6 months [8] or rabbits breathing NO 43 ppm and NO₂ 3.6 ppm for 6 days [9]. Administration of NO for 53 days to a patient with ARDS produced pulmonary disease [10]. Nonetheless, pulmonary edema developed shortly after initiation of inhaled NO in a patient awaiting heart transplantation [11]. The Occupational Safety and Health Administration [12] recommended a limit of 25 ppm exposure to NO per 8 hours per 24 hours. However, there are virtually no data documenting the effects of long-term exposure to inhaled NO on the human lung. When NO is used clinically, the following must be monitored for toxicity: methemoglobin and NO₂.

Methemoglobin
Methemoglobin is produced when the iron of hemoglobin is converted from ferrous (Fe²⁺) to ferric iron (Fe³⁺). Ferric iron does not bind to oxygen, so methemoglobin cannot carry oxygen. In addition to methemoglobin's inability to bind to oxygen, it shifts the oxygen-hemoglobin dissociation curve to the left, thereby impairing the release of oxygen from hemoglobin. Normal methemoglobin concentrations range from 0% to 3%. Symptoms of hypoxemia result as the concentration of methemoglobin rises. Methemoglobin levels of 0% to 15% typically produce no symptoms. At levels of 15% to 20%, asymptomatic cyanosis may be noted. Methemoglobinemia at 20% to 25% produces weakness and progresses to acidosis and coma at methemoglobin levels of 50% to 70%. Levels greater than 70% are associated with death [13]. Despite inhalation of high doses of NO (80 ppm) for protracted periods, methemoglobinemia is uncommon. Nonetheless, Adatia and associates [14] reported methemoglobin levels of up to 9% in children receiving NO 80 ppm. Methemoglobin levels must be carefully monitored in infants; infants may be deficient in methemoglobin reductase [13].

Nitrogen Dioxide
With exposure to oxygen, NO is oxidized to NO₂. Nitrogen dioxide is very cytotoxic because it is rapidly converted by water into nitric acid. In an aqueous environment, NO₂ is also rapidly converted into peroxynitrite (OONO^-) which then rapidly degenerates into cytotoxic hydroxilanion. Early experiments erroneously attributed lung histopathologic conditions to NO when NO₂ probably produced those conditions. The rate at which NO is converted to NO₂ is dependent on the square of the concentration of NO and the inspired oxygen fraction (FIO₂) to which it is exposed. For example, 10,000 ppm of NO in an FIO₂ of 1.0 becomes 50% NO₂ in 24 seconds, but in concentrations used clinically, such as 10 ppm of NO and FIO₂ of 1.0, 7 hours is required to generate 50% NO₂.

To prevent the toxicity of NO₂, the concentration of inhaled NO and oxygen must be monitored. Inhaled NO is usually administered in concentrations of 1 to 80 ppm. The concentrations of inhaled NO administered to the patient and the amount of NO₂ must be monitored by chemiluminescence (discussed later) in a continuous fashion or by frequently checking the concentration of NO delivered. The Occupational Safety and Health Administration [12] has established a limit of 5 ppm per 8 hours per 24-hour interval as the upper limit of safe human exposure. As little as 2 to 3 ppm of NO₂ can be extremely cytotoxic in pulmonary histologic studies. The NO₂ to which the patient is exposed is minimized by placing a soda lime canister in the inhalational limb of the ventilator circuit.

When closely monitored, inhaled NO can be used safely. It may be prudent to ``scavenge'' the exhaled gas from patients treated with inhaled NO, but recent data [15] suggest that the exposure of hospital personnel to NO or its metabolites from these patients is minimal.

	Clinical Administration of Inhaled Nitric Oxide

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Inhalation circuits to deliver NO must ensure accurate delivery of NO while maintaining a low concentration of NO₂. The circuit must be capable of delivering concentrations from 1 to 100 ppm of NO at an FIO₂ of 21% to 100%. The circuit must permit adjustment of NO independently of the FIO₂, tidal volume, and airway pressure. Because the conversion of NO to NO₂ depends on the residence time of NO in the mixture of inhaled gas, the mixture of a stock gas of NO with the inhaled gas should take place immediately prior to inhalation. Stock tanks of NO are supplied as a mixture of NO in nitrogen. Concentrations up to 1,000 ppm of NO have been used in most clinical studies (common concentrations used, 400 and 800 ppm). We have recently used stock tanks of 2,200 ppm of NO (2,000 psi) (Scot Medical Products, Plumsteadville, PA) without safety problems. Nitric oxide gas is available as an investigational new drug according to the guidelines of the Food and Drug Administration.

The circuit to deliver inhaled NO uses two high-flow blenders (Bird Products, Palm Springs, CA). Nitric oxide from the source tank is fed to the first blender, designated the ``NO'' blender, at 50 psi (Fig 4). A stainless steel two-stage regulator (Victor, Inc, Denton, TX) and an ultralow flowmeter (Alborg Instruments and Controls, Inc, Monsey, NY) are used to ensure accurate delivery of the gas from the stock tank. A second blender is designated the ``oxygen'' blender and receives oxygen from a wall oxygen source. We have preferentially used the Puritan-Bennett 7200ae ventilator (Carlsbad, CA) because it maintains flow characteristics under adverse conditions, permits a variety of mode selections and flow patterns, and offers extensive monitoring capabilities [16]. However, inhaled NO can be delivered through other commonly used ventilators, such as a Servo (Siemens-Elema, Englewood, CO). Nitric oxide is fed to the oxygen inlet of the ventilator, and the O₂/air mixture is fed to the air inlet of the ventilator. Adjustment of the NO concentration is accomplished using the FIO₂ of the ventilator. The FIO₂ is adjusted with the oxygen blender. An oxygen analyzer is placed in the breathing circuit, which runs from the ventilator. A standard soda lime canister is placed in the circuit to remove NO₂.

View larger version (28K): [in this window] [in a new window]   Fig 4. . Clinical administration of inhaled nitric oxide (NO). See text for details. (Fio2 = inspired oxygen fraction; O2 = oxygen.) (Reprinted with permission from McIntyre RC Jr, Moore FA, Moore EE, Piedalue F, Haenel JS, Fullerton DA. Inhaled nitric oxide variably improves oxygenation and pulmonary hypertension in patients with acute respiratory distress syndrome. J Trauma 1995;39:418–25.)

	Clinical Applications of Inhaled Nitric Oxide

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Cardiothoracic surgical patients who may benefit from inhaled NO therapy have pulmonary hypertension secondary to increased PVR. Acute pulmonary hypertension results from pulmonary vasoconstriction, which may or may not be associated with hypoxemia. Chronic pulmonary hypertension results from a combination of pulmonary vasoconstriction (``reactive component'') and pulmonary vascular remodeling (``fixed component'') from either chronic elevation of pulmonary blood flow or chronic pulmonary venous hypertension. For the purposes of this review, the clinical applications of inhaled NO therapy have been divided into acute and chronic pulmonary hypertension.

Acute Pulmonary Hypertension
PERSISTENT PULMONARY HYPERTENSION OF NEWBORN.
In persistent pulmonary hypertension of the newborn, increased PVR produces right-to-left shunting of blood at the atrium and the ductus arteriosus, thus resulting in hypoxemia. The markedly elevated PVR derives from pulmonary vascular spasm superimposed on smooth muscle hypertrophy and hyperplasia. Persistent pulmonary hypertension of the newborn can be idiopathic or associated with meconium aspiration or sepsis. Cardiothoracic surgeons participate in the care of these infants by providing extracorporeal membrane oxygenation (ECMO).

Inhaled NO may replace ECMO in the management of many of these infants. Inhaled NO selectively lowers PUR rather than systemic vascular resistance; blood preferentially follows the path of least resistance from the pulmonary artery into the lungs rather than through the ductus arteriosus. The magnitude of the right-to-left shunt is thereby reduced. Inhaled NO was used for persistent pulmonary hypertension of the newborn in 1992 by groups at Denver Children's Hospital [17] and Boston Children's Hospital [18]. On the basis of the report by Pepke-Zaba and colleagues [19] in which brief inhalation of NO successfully lowered PVR in adults with primary pulmonary hypertension, Kinsella and associates [17] administered inhaled NO 10 to 20 ppm to 9 infants who were otherwise candidates for ECMO. All infants had an arterial oxygen tension (PaO₂) of less than 40 mm Hg. Inhaled NO 20 ppm was administered initially with an immediate rise in mean PaO₂ to 80 mm Hg. Over the ensuing 12 hours, the dose of inhaled NO was decreased to 6 ppm and stopped after 12 to 24 hours. The improved PaO₂ was sustained after cessation of inhalational NO therapy. Extracorporeal membrane oxygenation was avoided in all of these infants.

HYPOXIC PULMONARY VASOCONSTRICTION.
Hypoxia is one of the most physiologically important pulmonary vasoconstrictors and is always present in acute lung injury. The mechanisms of hypoxic pulmonary vasoconstriction are unclear, but it is important in ventilation-perfusion matching. In hypoxia, pulmonary vasodilation by cAMP–mediated pathways is impaired [20]. Hypoxia also decreases endogenous NO production [21]; such deficiency of an endogenous vasodilator may contribute to pulmonary vasoconstriction in hypoxia. Administration of exogenous NO (inhaled NO) may replace this deficiency and achieve pulmonary vasodilation. After demonstrating in sheep that inhaled NO (40 to 80 ppm) could produce pulmonary vasorelaxation in hypoxia, Frostell and co-workers [22] demonstrated its efficacy in human volunteers. Nine adults breathed 12% oxygen for 30 minutes, decreasing the mean PaO₂ from 106 to 47 mm Hg; PVR rose from 70 to 125 dynes•sec•cm^-5. The volunteers then inhaled NO 40 ppm, and there was a prompt return of pulmonary artery pressure (PAP) and PVR to baseline. Interestingly, even after cessation of inhaled NO, PVR remained at baseline, although the volunteers continued to breath hypoxic gas. In a canine model of pulmonary vascular endothelial injury induced by monocrotaline, Van Camp and associates [23] demonstrated significant reduction in PVR with inhaled NO under normoxic and hypoxic conditions.

PROTAMINE SULFATE REACTION.
An adverse reaction to heparin reversal with protamine sulfate is characterized by severe pulmonary hypertension and systemic hypotension. Data from laboratory animals implicate thromboxane as an important mediator of this pulmonary vasoconstriction; thromboxane is one of the most potent pulmonary vasoconstricting agonists [24]. Fratacci and colleagues [25] demonstrated that inhaled NO could dilate the pulmonary vasoconstriction induced by protamine reversal of heparin in lambs. In control animals, PVR rose from 1 to 7 mm Hg•L^-1•min^-1 within 60 minutes of protamine administration. Over the ensuing 5 hours, PVR slowly returned toward baseline. Inhaled NO 180 ppm reduced this acute pulmonary constriction and lowered the peak PVR to 4 mm Hg•L^-1•min^-1.

ACUTE RESPIRATORY DISTRESS SYNDROME.
Pulmonary hypertension is universally present in the setting of acute lung injury [4]. Its etiology is multifactorial and results from a combination of the injury itself, the inflammatory response to the injury, increased local and circulating levels of vasoconstrictive substances, thromboembolic disease, and iatrogenic factors including ventilatory support. Impairment of the mechanisms of pulmonary vasorelaxation also contributes to increased PVR in ARDS [4]. In endotoxin-induced acute lung injury, cGMP–mediated mechanisms of pulmonary vasodilation are dysfunctional [26], yet systemic vasorelaxation is intact [27]. In addition, hypoxia produces dysfunction of cAMP–mediated pulmonary vasodilation [20, 27]. Dysfunctional mechanisms of vasodilation with intact vasoconstriction may shift net vascular tone toward constriction. This altered vasoreactivity may lead to alterations in pulmonary blood flow distribution with a resultant increase in the intrapulmonary shunt fraction and resultant hypoxemia.

Because pulmonary hypertension in acute lung injury plays a pivotal role in the pathophysiology, therapy to lower PVR is beneficial. Intravenous vasodilators such as nitroprusside, nitroglycerin, prostaglandin E₁, and prostacyclin lower PAP and PVR. However, their use leads to systemic hypotension in up to 15% of patients. Further, intravenous vasodilators increase the intrapulmonary shunt and worsen hypoxemia. Selective pulmonary vasodilation by inhaled NO has been demonstrated in several models of acute lung injury including endotoxin, oleic acid, and smoke inhalation [28, 29]. Inhaled NO effectively vasodilates well-ventilated regions of the lung. In acute lung injury, animal studies [29] demonstrated inhaled NO significantly lowers PAP, improves ventilation-perfusion matching, and increases PaO₂.

Rossaint and associates [10] reported the use of inhaled NO in ARDS in 1993. Inhaled NO reduced mean PAP from 37 to 30 mm Hg and decreased intrapulmonary shunting from 36% to 31%. The ratio of PaO₂ to FIO₂ increased from 152 to 199. neither mean arterial pressure nor cardiac output changed. patients received inhaled no for 3 to 53 days. there may be a discordant effect of no on oxygenation and pulmonary hypertension in ards [30]. bigatello and co-workers [30] reported the effect of inhaled NO on mean PAP but not on arterial oxygenation was dose related. Inhaled NO at low concentrations (<10 ppm) was more effective in increasing arterial oxygenation than higher concentrations. Conversely, higher NO concentrations (5 to 40 ppm) progressively lowered PAP.

Gerlach and associates [31] found that patients responded to and stabilized with inhaled NO within 5 to 8 minutes; the effective doses for improvement of oxygenation and pulmonary hypertension were low (<10 ppm). This group found that low concentrations of inhaled NO improved oxygenation with an effective dose in half the patients of 0.1 ppm, whereas the effective dose in half the patients for reduction of mean PAP was 2 to 3 ppm. Despite a paucity of clinical data, NO has been enthusiastically touted as an important advance in the therapy for ARDS. However, the role of NO in this therapy is uncertain. In studies by Rossaint [10] Gerlach [31], and their co-workers, the majority of patients had ARDS as the result of direct lung injury. Two thirds of the patients also were treated with ECMO. Thus, it is unclear if these results extend to patients with ARDS caused by systemic etiologies not treated with ECMO.

To address these concerns, we [32] studied the effects of inhaled NO in a series of surgical patients with ARDS who had a PaO₂ to FIO₂ ratio lower than 150 and a mean pap higher than 30 mm hg. inhaled no was delivered at 20 and 40 ppm in 16 trials involving 14 patients. inhaled no caused a 42% increase in the pao₂ to fIO₂ ratio at 20 ppm. however, the response was variable; only 69% of patients had a clinically significant improvement in arterial oxygenation (increase in pao₂ to fIO₂ ratio greater than 20% of baseline). overall, there was a 15% decrease in the mean pap at 20 ppm of no. again the response was variable with only 69% of patients having a significant clinical response (drop in mean pap of greater than 10% of baseline). this variable response to inhaled no has also been observed by other investigators [33, 34]. the reason for this variable response is unknown. improvement in arterial oxygenation and pulmonary hypertension by inhaled no does not seem to correlate well with the baseline pap, pvr, shunt, or cardiac output [35].

The response to inhaled NO in animal models of acute lung injury may explain the variable response in humans. As noted already, inhaled NO significantly attenuated both pulmonary hypertension and hypoxemia in a porcine model of endotoxin-induced acute lung injury [29]. These investigators [28, 36] also examined the effect of inhaled NO in a model of lung injury caused by smoke inhalation. Inhaled NO significantly attenuated the pulmonary hypertension, but the effect on oxygenation was not as significant as in the endotoxin-induced lung injury.

Inhaled NO may not cause a significant reduction in PAP or improvement in arterial oxygenation if vascular smooth muscle soluble guanylate cyclase is unresponsive to NO. We [26] demonstrated significant impairment of cGMP–mediated pulmonary vasorelaxation by pathways that require generation of cGMP. Thus, impaired activity of pulmonary vascular smooth muscle guanylate cyclase may lead to an impaired response to inhaled NO.

Pulmonary hypertension in ARDS may lead to right ventricular dysfunction and limit cardiac output. Fierobe and associates [37] reported a reduction in PAP and PVR with inhaled NO (5 ppm) in 13 patients with ARDS who had a mean PAP greater than 30 mm Hg. Right ventricular ejection fraction increased from 32% to 36%, and end-systolic and diastolic volumes decreased significantly, as did right atrial pressure. These data suggest that inhaled NO improves right ventricular function in patients with ARDS by reducing the right ventricular afterload.

Rossaint and colleagues [35] compared the mortality of 30 patients with ARDS treated with inhaled NO versus that of matched patients not receiving inhaled NO. Inhaled NO increased the PaO₂ to FIO₂ ratio by more than 10 mm hg in 83% of patients, decreased the venous admixture by more than 10% in 87% of patients, and decreased the mean pap by more than 3 mm hg in 63% of patients. the 30 patients were treated with no for a mean of 17 ± 2.4 days (range, 2 to 53 days). during that period, neither tachyphylaxis nor an increase in the response to no was observed. nonetheless, survival in patients treated with no did not differ from that in the matched patients who did not receive no.

The niche that inhaled NO will occupy in the treatment of ARDS is not well defined. Although NO improves oxygenation and pulmonary hypertension in the majority of patients with ARDS, it may fail to improve gas exchange or to reduce pulmonary hypertension in a subset of patients with ARDS. The reason for this lack of response is not clear at present. Ultimately the effect of inhaled NO on patient survival will require a multicenter prospective, randomized trial.

ADULT CARDIAC SURGICAL PATIENTS.
The pulmonary vasoconstricting effects of cardiopulmonary bypass are well recognized; after cardiopulmonary bypass, increased pulmonary vascular tone may be due to increased levels of circulating or local vasoconstricting agonists. Data suggest that pulmonary vascular endothelial cell dysfunction contributes to pulmonary vasoconstriction after cardiopulmonary bypass; impairment of endothelial-dependent cGMP–mediated pulmonary vasorelaxation has recently been described after cardiopulmonary bypass [38]. Inhaled NO achieves pulmonary vascular smooth relaxation independently of the endothelium and may offer a mechanistic advantage as a pulmonary vasodilator after cardiopulmonary bypass.

Few studies have examined the effect of inhaled NO in adult cardiac surgical patients. In a recent study [39] of patients undergoing aortocoronary bypass procedures, inhaled NO (20 and 40 ppm) consistently lowered PAP and PVR without a change in systemic arterial pressure or systemic vascular resistance. Mean PAP fell from 29 ± 1 mm Hg to 21 ± 1 mm Hg with inhaled NO; PVR was lowered from 343 ± 30 to 233 ± 25 dynes•s•cm^-5 during inhalation of NO. This pulmonary vasodilation produced a significant reduction in transpulmonary gradient and right ventricular stroke work index. Hemodynamic variables returned to baseline after cessation of inhaled NO (Fig 5).

View larger version (20K): [in this window] [in a new window]   Fig 5. . Hemodynamic effects of inhaled nitric oxide (NO) after cardiac operation. (A) Inhaled NO produced a significant reduction in mean pulmonary artery pressure (MPAP) without a change in mean systemic arterial pressure (MAP). (B) Inhaled NO produced a significant reduction in pulmonary vascular resistance (PVR) without a change in systemic vascular resistance (SVR). (* = p < 0.05.)

THORACIC ORGAN TRANSPLANTATION.
Inhaled NO may be valuable in the management of thoracic organ transplant recipients. The transplanted lung endures the obligatory injuries of ischemia and reperfusion, which are exacerbated by the use of cardiopulmonary bypass. These injuries produce pulmonary vasomotor dysfunction that may contribute to increased PVR in the transplanted lung [42, 43]. In addition to increased PVR, lung allograft dysfunction is marked by severe hypoxemia and may require ECMO or independent lung ventilation [44]. Inhaled NO is effective for both the increased PVR and the hypoxemia. Adatia and colleagues [14] successfully treated 6 patients (aged 5 to 21 years) who had acute allograft lung dysfunction with inhaled NO. Cardiopulmonary bypass was used in 5 of the 6 patients. In 5 patients with pulmonary hypertension, inhaled NO (80 ppm) lowered mean PAP from 38 ± 1.6 to 29 ± 3.1 mm Hg. The intrapulmonary shunt fraction was lowered from 29% to 21%, and this was associated with improved PaO₂ in 4 patients.

Increased PVR is a strong relative contraindication to heart transplantation; potential heart transplant recipients must be carefully evaluated to determine if elevated PAP is lowered with vasodilator therapy. Pharmacologic provocation is typically performed using nitroprusside or prostaglandin E₁. Adatia and co-workers [45] and Kierler-Jensen and associates [46] have used inhaled NO to examine the reactivity of the pulmonary vascular bed in patients undergoing evaluation for heart transplantation. When administered at up to 80 ppm, inhaled NO lowered PVR without producing systemic vasodilation, particularly in patients with severe pulmonary hypertension [45, 46]. However, because most patients considered for heart transplantation have severe left ventricular dysfunction, lowering the PVR may increase the preload of the left ventricle (left atrial pressure) in a patient unable to increase left ventricular output. This may produce an unwanted elevation in left atrial pressure [47]. This phenomenon was seen using inhaled NO in the study by Kierler-Jensen and associates [46]. Until further data are available, the routine use of inhaled NO to determine the reactivity of the pulmonary circulation in patients under consideration for heart transplantation is inadvisable.

Postoperatively, increased PVR may produce right ventricular failure. Inhaled NO has been used to lower right ventricular afterload and optimize right ventricular function in a patient with right ventricular dysfunction after orthotopic heart transplantation [48]. In a direct comparison with other pulmonary vasodilators after heart transplantation, inhaled NO produced a reduction in PAP and PVR comparable with that obtained with intravenous infusions of nitroprusside, prostaglandin E₁, and prostacyclin [49]. Unlike the intravenous vasodilators, inhaled NO ``selectively'' lowered PVR without producing systemic vasodilation.

Chronic Pulmonary Hypertension
PRIMARY PULMONARY HYPERTENSION.
The pathophysiology of chronic pulmonary hypertension differs from that of acute pulmonary vasoconstriction. In the latter, the pulmonary arterial circulation is simply constricted; it is ``reactive.'' In the former, structural changes within the pulmonary vascular smooth muscle contribute to increased PVR. In chronic pulmonary hypertension, at least part of the resistance to blood flow is ``fixed'' and therefore less amenable to vasodilator therapy. In addition to the structural changes found in chronic pulmonary hypertension, data from animal models suggest the ability of pulmonary vascular smooth muscle to respond to NO is markedly reduced [50].

Pepke-Zaba and colleagues [19], however, demonstrated that inhaled NO may be useful in at least lowering PAP and PVR in adults with primary pulmonary hypertension. In 8 patients with primary pulmonary hypertension, inhaled NO was compared with intravenous infusion of prostacyclin. Infusion of prostacyclin at progressively increasing dosages successfully reduced PVR from 15 to 10 mm Hg•L^-1•m^-1. However, this decrease in PVR was accompanied by a decline in systemic vascular resistance from 25 to 17 mm Hg • L^-1•m^-1. Particularly in patients with major pulmonary hypertension, such nonselective reduction of systemic and pulmonary arterial pressures is potentially life threatening. On the other hand, inhaled NO (40 ppm) produced a ``selective'' reduction in PVR from 15 to 10 mm Hg•L<sup>-1</sup>•m<sup>-1</sup>, comparable with the reduction achieved with prostacyclin. Inhaled NO, however lowered PVR without a change in systemic vascular resistance. This ``selective'' pulmonary vasorelaxation avoided the potential hazards of nonselective pulmonary and systemic vasodilation. This application of inhaled NO has been used successfully in a patient with primary pulmonary hypertension as a bridge to heart-lung transplantation [51].

CONGENITAL HEART SURGERY.
Pulmonary hypertension secondary to increased PVR frequently complicates the perioperative management of patients undergoing surgical correction of congenital heart disease. This increased PVR is derived in part from the structural changes induced by excessive pulmonary blood flow (``fixed component''). However, pulmonary vasoconstriction contributes to the pulmonary hypertension (``reactive component''). Data from laboratory animals [52] and children with congenital heart disease [53] suggest that dysfunction of the vascular endothelium is produced with chronic excessive pulmonary blood flow and contributes to pulmonary hypertension.

In 10 patients studied in the cardiac catheterization suite preoperatively, Roberts and colleagues [54] successfully lowered PVR with inhaled NO. Six of these patients had a left-to-right shunt (averaging 2:1), and the other 4 patients had pulmonary hypertension from increased left-sided pulmonary venous outflow pressures. The patients were studied in the cardiac catheterization laboratory to examine the response to both inhalational oxygen as well as NO. The PVR was 570 dynes•s•cm^-5 on room air without NO and was lowered to 400 dynes•s•cm^-5 by breathing an FIO₂ of 0.9. inhalation of 20 ppm and then 40 ppm of no reduced pvr only slightly when combined with an 0.9 fIO₂. however, inhaled no at 80 ppm combined with an fIO₂ of 0.9 did lower PVR to 320 dynes•s•cm^-5. These data suggest that at least prior to surgical correction, the ``reactive'' component of the PVR can be attenuated by a combination of oxygen and NO therapy.

Journais and associates [55] administered inhaled NO to 17 patients with refractory pulmonary hypertension in the early postoperative period after correction of congenital heart lesions. Inhaled NO lowered PAP in 12 of these 17 patients; 29% of the patients did not respond to inhaled NO. Prior to administration of inhaled NO (20 to 40 ppm), the ratio of mean PAP to mean aortic pressure was 0.75. Among the patients who did respond, inhaled NO successfully lowered this ratio to 0.5, where it remained for 12 hours during inhaled NO therapy. However, administration of inhaled NO was associated with a significant decrease in mean systemic arterial blood pressure in 4 (24%) of the 17 patients.

MITRAL VALVE SURGERY.
Pulmonary hypertension often complicates the perioperative management of patients undergoing operation for mitral valve disease, particularly mitral stenosis. The pulmonary hypertension in such patients is derived from both a vasoconstrictive component and from structural changes induced by chronic pulmonary venous hypertension. Because the increased PVR is largely produced from vascular remodeling induced by chronic pulmonary venous hypertension, pulmonary hypertension in patients with mitral valve disease is often refractory to vasodilator therapy. Perhaps not surprisingly, inhaled NO does not appear to be as effective in patients with pulmonary hypertension from mitral valve disease as it is in other clinical settings.

Girard and co-workers [56] studied 6 patients after mitral valve replacement for mitral stenosis and reported a modest reduction in PAP with inhaled NO 40 ppm. Preoperative mean PAP was 49 ± 16 mm Hg. Within 24 hours after mitral valve replacement, the mean PAP averaged 41 mm Hg and was successfully lowered to 37 mm Hg by inhaled NO 40 ppm. This attenuation of PAP was small but may be a reflection of the structural changes produced by chronic pulmonary venous hypertension.

	Conclusion

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Inhaled NO promises to be a valuable tool for the cardiothoracic surgeon in the management of patients with pulmonary hypertension and hypoxemia. However, a cautionary note is warranted. It is clear from the available literature that some patients do not respond to inhaled NO. Future research efforts should be focused on the identification of patients who may not respond to NO so that appropriate therapeutic strategies can be devised.

	Acknowledgments

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Supported by grant R29HL49398 from the National Institutes of Health.

	Footnotes

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 
Address reprint requests to Dr Fullerton, Cardiothoracic Surgery, University of Colorado Health Sciences Center, Campus Box C-310, 4200 E Ninth Ave, Denver, CO 80262.

	References

Top Footnotes Abstract Introduction Vascular Physiology of Nitric... Toxicity of Nitric Oxide Clinical Administration of... Clinical Applications of Inhaled... Conclusion Acknowledgments References

 

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