Treatment of Acute Pulmonary Hypertension With Inhaled Nitric Oxide

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1 Treatment of Acute Pulmonary Hypertension With Inhaled Nitric Oxide Martin Tonz, MD, Ludwig K. von Segesser, MD, Julian Schilling, MD, Thomas F. Luscher, MD, Georg Noll, MD, Boris Leskosek, BA, and Marko 1. Turina, MD Clinic for Cardiovascular Surgery, University Hospital, Zurich, and Division of Cardiology, University Hospital, Bern, Switzerland We examined the effectiveness of inhaled nitric oxide (NO) as a selective pulmonary vasodilator in acute pulmonary hypertension in an in vivo canine model with fixed cardiac output. In 5 dogs, total right heart bypass was instituted, and pulmonary hypertension was induced by infusion of the thromboxane analogue U During U infusion, NO was administered at 10 and 40 ppm for 5 minutes followed by breathing of the oxygen mixture without NO. Pump flow was held constant during the experiment. Infusion of the thromboxane analogue resulted in an increase in pulmonary vascular resistance and systemic vascular resistance from 147 ± 83 to 740 ± 126 dyne' s. cm- s and from 1,720 ± 113 to 2,407 ± 232 dyne' s. cm- s, respectively. During inhala- tion of 10 ppm NO, pulmonary vascular resistance significantly decreased to 613 ± 55 dyne' s. cm- s (p < 0.05) and further decreased to 527 ± 163 dyne' S' cm- s with 40 ppm NO inhalation (p < 0.05). Systemic vascular resistance did not change during NO treatment (2,300 ± 70 dyne s. em -s during 40 ppm NO). There was no increase in intrapulmonary shunting or methemoglobin levels during NO inhalation. In this setting, with a constant cardiac output throughout the experiment, NO acted as a selective pulmonary vasodilator without altering systemic vascular resistance. However, induced pulmonary vasoconstriction was only partially reversed by NO inhalation. (Ann Thome Surg ) N itric oxide (NO) was reported in 1987 to have activity identical to that of endothelium-derived relaxing factor [1, 2]. It is synthesized from L-arginine by the constitutive form of NO synthase in the vascular endothelium and has an important role in the regulation of the vascular system [3, 4]. Nitric oxide is a gas under atmospheric conditions. If inhaled, it can act as a selective pulmonary vasodilator in pulmonary artery hypertension. Inhaling low levels of NO was reported to reverse pulmonary vasoconstriction caused by hypoxemia or infusion of a thromboxane analogue in the lamb [5,6]. In a previous study, we [7] could confirm selective vasodilation with inhaled NO, but we were not able to demonstrate complete reversal of hypoxemia-induced pulmonary hypertension (unpublished data). This difference might be due to the fact that in these studies, induction of pulmonary hypertension and NO treatment not only influenced pulmonary vascular tone but also cardiac performance. As vascular resistance was calculated by two variables, pressure and flow, an increase in cardiac output compared with baseline might have contributed to the reduction in pulmonary vascular resistance. To determine the true vascular effects of NO, we chose an in vivo canine model with fixed cardiac output to study the proper effect of inhaled NO as a selective pulmonary vasodilator in acute pulmonary artery hypertension. Accepted for publication March 19, Address reprint requests to Dr Tonz, Clinic for Pediatric Surgery, University Hospital, 3010 Bern, Switzerland. Material and Methods Experimental Preparation Five dogs (mean weight, 28 ::':: 2 kg; age, 2 ::':: 0.3 years) were studied in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). After premedication, the animals were anesthetized with volatile anesthetics and mechanically ventilated in the volume-controlled mode with a nitrous oxide-oxygen mixture (inspired oxygen concentration, 0.35). After instrumentation with the electrocardiographic leads, an arterial pressure line (femoral artery), a venous sampling and pressure line (femoral vein), and a pulmonary artery thermodilution catheter (Swan-Ganz Oximetry thermodilution catheters; Baxter, Irvine, CA), a right thoracotomy was performed. The pericardium was opened and a catheter placed into the left atrium for pressure monitoring. After systemic heparinization (300 IU /kg) (Liquemin; F. Hoffmann-La Roche & Co, Basel, Switzerland), the pulmonary artery and superior and inferior venae cavae were cannulated. Ties were passed around both venae cavae and snared during the experiment to guarantee total drainage of the venous return with the exception of the venous blood from the coronary sinus. The right heart bypass system was composed of %-inch (0.94-cm) polyvinyl chloride tubing and a calibrated roller pump (Stockert, Munich, Germany) filled with crystalloid prime. Total right heart bypass was established with a constant flow of 1.9 ::':: 0.2 L/min by The Society of Thoracic Surgeons /94/$7.00

2 1032 TONZ ET AL Ann Thorac Surg To induce a generalized vasoconstriction, the thromboxane analogue U (Cayman Clinical Co, Ann Arbor, MI) was infused directly into the right heart bypass circuit. The NO-N 2 gas mixture (350 ppm NO in pure N 2 ) (AGA AG, Pratteln, Switzerland) was administered directly into the inspiration limb of the breathing circuit, 30 cm proximal to the connection with the endotracheal tube. With a volumetrically calibrated flowmeter, flow of the NG-N 2 gas mixture was adjusted to obtain the desired NO concentrations. Inspired NO concentrations were measured just proximal to the endotracheal tube with chemoluminescence analysis (Eco Physics, Durnten, Switzerland). Inspired oxygen concentration was held constant at 0.35 during the experiment by reducing nitrous oxide flow according to the NO-N 2 gas flow during NO inhalation. Measurements Inferior vena cava pressure (central venous pressure), pulmonary artery pressure (PAP), mixed venous oxygen saturation, left atrial pressure, and aortic pressure (systemic arterial pressure) were continuously recorded on a 16-channel computerized recording system (Hellige GmbH, Freiburg im Breisgau, Germany). Blood samples were analyzed with a BGElectrolyte Analyser and IL 482 co-oximeter (Instrumentation Laboratories Spa, Milan, italy). Carbon dioxide tension, oxygen tension, and ph were monitored and appropriate adjustments made as required throughout the study. The pulmonary vascular resistance (PVR), systemic vascular resistance, and intrapulmonary shunt were computed by standard formulas as described previously [7]. Maximal changes in PAP were calculated as follows: PAP (% max) = (PAP u - PAPNO)!(PAP u - PAP B ) X 100 where PAP (% max) change in PAP induced by NO inhalation expressed as a percentage of the maximal change in PAP induced by infusion of U-46619, PAPu PAP recorded during infusion of U-46619, PAP N O PAP recorded during NO inhalation and infusion of U-46619, and PAP» value recorded at baseline after institution of total right heart bypass and before infusion of U Maximal changes in PVR were calculated as follows: PVR (% max) = (PVR u - PVRNO)!(PVR u - PVR B ) X 100 where PVR (% max) change in PVR induced by NO inhalation expressed as a percentage of the maximal change in PVR induced by infusion of U-46619, PVR u PVR recorded during infusion of U-46619, PVR N O PVR recorded during NO inhalation and infusion of U-46619, and PVR B value recorded at baseline after institution of total right heart bypass and before infusion of U Baseline, Measurements,,,,,,,,,, [!iliqj U infusion Total right heart bypass [!iliqj I::iQIiQ] Fig 1. Experimental setup with several series of nitric oxide (NO) inhalations (10 ppm and 40 ppm NO) during total right heart bypass and infusion of U , C=====:J Experimental Protocol After institution of total right heart bypass, baseline measurements were obtained (Fig 1). Thereafter, the stable thromboxane analogue U was infused at a mean rate of 0.26 ± 0.2 /-Lg' kg-i. min- 1 to increase mean PAP to 30 mm Hg. After a stable period of pulmonary hypertension, dogs breathed the NO-N 2 mixture containing 10 ppm NO for 5 minutes followed by breathing of 40 ppm NO for another 5 minutes. Nitric oxide exposure was followed by breathing the oxygen mixture without NO for 5 minutes at the same inspired oxygen concentration, thereby allowing PAP to rise to levels measured before NO inhalation. These series of intermittent NO inhalations were repeated several times. Blood gas analyses were performed before and after each concentration of inhaled NO. Right heart bypass flow was held constant throughout the experiment at a flow of 1.9 ± 0.2 Lz'min. Statistical Analysis All values were reported as the mean ± the standard deviation and analyzed by means of the StatView 4.0 statistical system. Analysis of variance and paired or unpaired Student t tests were employed for comparison of data where appropriate. Differences were considered significant at a probability level of less than Results At both dose levels, NO inhalation produced a prompt reduction in pulmonary hypertension induced by U infusion. The dose-response curves to inhaled NO for PAP and PVR are shown in Figure 2. Inhalation of 10 ppm NO significantly reduced PAP and PVR from 28 ± 2 mm Hg to 25 ± 3 mm Hg (p < 0.05) and from 740 ± 126 to 613 ± 55 dyne' S' cm- 5 (p < 0.05), respectively. At a concentration of 40 ppm, PAP and PVR further decreased to 23 ± 2 mm Hg and 527 ± 163 dyne' S' cm- 5, respectively (p < 0.05). Note that neither PAP nor PVR reached baseline levels (12 ± 1 mm Hg and 147 ± 83 dyne s cm- 5, respectively). The PAP (% max) was 33% ± 5% and the PVR (% max), 36% ± 10% during inhalation of 40 ppm NO (Fig 3). Systemic arterial pressure and systemic vascular resistance remained unchanged throughout the period of NO treatment (systemic arterial pressure: baseline, 52 ± 2 mm Hg; U infusion, 68 ± 6 mm Hg; and additional 40 ppm NO, 67 ± 3 mm Hg; systemic vascular resistance: baseline, 1,720 ± 113 dyne' S' cm- 5 ; U infusion, 2,407 ± 232 dyne' s. em -5; and additional 40 ppm NO, 2,300 ± 70 dyne s. em-5) (Fig 4). Mean methemoglobin

3 Ann Thorac Surg TONZ ET AL ~ ~ 0 25 "C ~800 < ~ 01 ::<' 01 ::<' ::t: 20 0: :I: S -e S ~ f t! 0: g 600 g ~ " ~ Q., ~ 15 Q., t <C Q., " 3 <C C/O " ~ v SAP 1000 J!> PAP -+- SVR -+- PVR mean ± sd 500 mean ± sd! Baseline U ppm NO 40 ppm NO Baseline U ppm NO 40 ppm NO + U U U U Fig 2. Pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) after institution of right heart bypass (Baseline), during infusion of U-46619, and during infusion of U plus inhalation of 10 and 40 ppm nitric oxide (NO). U induced a marked increase in PAP and PVR, which was significantly reduced by simultaneous inhalation of NO (* = P < 0.05, inhalation of 10 ppm NO versus no NO; = P < 0.05, inhalation of 40 ppm NO versus 10 ppm NO and versus no NO). (sd = standard deoiaiion.) levels did not change (baseline, 0.6% ::'::: 0.2%; U infusion, 1.0% ::'::: 0.3%; and 40 ppm NO, 1.3% ::'::: 0.3%), nor did left atrial pressures, central venous pressures, arterial and mixed venous oxygen saturations, and intrapulmonary shunts (Table 1). Comment Our study demonstrates that inhaled NO can act as a selective pulmonary vasodilator without causing systemic vasodilation and without increasing the intrapulmonary shunt. Nitric oxide inhalation decreased pulmonary hyper- 50, , 40 >< oj E E 0 30 <.l:: <I) 0/) c oj..c o 20 ~ 10 0 l1li PAP (% change from max) 0 PVR (% change from max) is mean± sd!oppm NO 40 ppm NO + U U Fig 3. Reduction in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) during 10 and 40 ppm nitric oxide (NO) inhalation expressed as percent reduction in maximal changes in PAP and PVR induced by infusion of U (sd = standard deoiaiion.) Fig 4. Systemic arterial pressure (SAP) and systemic vascular resistance (SVR) after institution of right heart bypass (Baseline), during infusion of U-46619, and during infusion of U plus inhalation of 10 and 40 ppm nitric oxide (NO). Both variables remained unchanged throughout the period of NO inhalation. (sd = standard deoiation.) tension induced by infusing the stable endoperoxid analogue U in this in vivo model with fixed cardiac output without affecting systemic arterial pressure. There was a direct dose-dependent relationship with an increase in the vasodilator response with higher concentrations of inhaled NO. Because of its lipophilic characteristics, inhaled NO diffuses readily into subjacent vascular smooth muscle cells. Intracellular NO binds to the heme group present in soluble guanylyl cyclase. This in turn activates the guanylyl cyclase, thus resulting in an increased synthesis of the second messenger, cyclic guanosine monophosphate, with consequent relaxation of the smooth muscle cells [8-11]. Nitric oxide has a very short half-life (only seconds) [12]. If it penetrates the intravascular space, it rapidly binds to Table 1. Effects of U Infusion and Inhalation of 40 ppm Nitric Oxide on Hemodynamics, Gas Exchange, and Levels of Methemoglobin. n b NO 40 ppm plus Variable Baseline U U CVP(mmHg) 8±3 7±2 7±3 LAP (mm Hg) 9::': 1 10::': 1 10 ::': 2 Sa0 2 (%) 98 ::': 1 98::': 2 97 ± 2 Sv0 2 (%) 48 ± 12 55::': ± 16 QVA/QT (%) 2.5 ± ± ± 0.7 Met Hb (%) 0.6 ± ± ± 0.3 Pump flow (L!min) 1.9 ± ± ± 0.2 a Data are shown as the mean ± the standard deviation. b By repeated measures analysis of variance, there were no significant differences between measurements for any variable. CVP = central venous pressure; LAP = left atrial pressure; Met Hb = methemoglobin; NO = nitric oxide; QVA/QT = venous admixture; Sa0 2 = arterial oxygen saturation; Sv0 2 = mixed venous oxygen saturation.

4 1034 TONZ ET AL Ann Thorae Surg hemoglobin and thereby becomes inactivated. These two mechanisms restrict inhaled NO-induced vasodilation to vessels in the lung and prevent systemic vasodilation. Several studies postulated total reversal of induced acute pulmonary hypertension with inhalation of low levels of NO. Frostell and co-workers [5, 13] reported selective and complete reversal of pulmonary vasoconstriction in awake lambs either during infusion of the stable thromboxane analogue U or while breathing a hypoxic gas mixture and total reversal of hypoxic pulmonary hypertension in adult volunteers without altering systemic vascular resistance. Roberts and associates [6] found similar results in the hypoxic and acidotic newborn lamb. The present study, however, could not completely confirm these results. Inhaled NO caused selective pulmonary vasodilation, but its effectiveness was markedly less than that reported in the already mentioned studies. Nitric oxide treatment reduced pulmonary vasoconstriction induced by the thromboxane analogue (ie, the increase in PVR resulting from the infusion of U-46619) by only one third. Therefore, PVR was far from reaching baseline levels. Although inhaled NO concentrations of greater than 40 ppm may further reduce PVR, the additional effect is but small [5, 6, 14; Tonz, unpublished data) and is not likely to account for the difference observed. The following reasons may be of greater importance. Pulmonary vascular resistance is a calculated parameter and depends on both degree of vasodilation and cardiac performance. Changes in heart rate and contractility may therefore alter vascular resistance without any changes in vascular tone. As in the studies of Frostell and colleagues [5, 13], hypoxic pulmonary vasoconstriction was associated with a significant increase in cardiac output of up to 40%; the reduction in PVR may have been due in part to this augmentation in cardiac performance. In the studies with infusion of U [5], changes in hemodynamics were not reported. In an attempt to eliminate these confounding factors, we used an in vivo model with constant cardiac output. In this model, changes in PAP directly reflect alterations in PVR, ie, changes in pulmonary vascular tone and diameter. Nitric oxide exerts its vasodilator actions through activation of soluble guanylyl cyclase in vascular smooth muscle with concomitant formation of cyclic guanosine monophosphate. Cyclic guanosine monophosphate reduces intracellular calcium and dephosphorylates myosin light chains [15]. Cyclic guanosine monophosphate is particularly effective in reducing intracellular calcium levels if the calcium is released from intracellular stores, eg, after activation of phospholipase C by receptor-operated agonists with concomitant formation of inositol trisphosphate and diacylglycerol. Indeed, in porcine coronary arteries studied in vitro, NO and particularly prostacyclin are not very efficient in reversing potassium chloride-induced contractions [16, 17]. Potassium chloride depolarizes vascular smooth muscle cells and thereby opens voltageoperated calcium channels [16, 17]. The influx of large amounts of calcium through these channels can be only partially compensated by increases in intracellular cyclic guanosine monophosphate levels. Of particular interest fact that in small vessels, nitrovasodilators are less potent in inhibiting particularly endothelin-l-induced contractions but also those induced by the thromboxane analogue U compared with larger vessels, as smaller vessels are more dependent on extracellular calcium for their contractile responses [18]. The contribution of extracellular and intracellular calcium may not only differ among different vascular beds but also among different species. Hence, in blood vessels or in species in which the thromboxane analogue mainly causes contraction through the release of intracellular calcium, nitrovasodilators and inhaled NO may be particularly efficient in fully reversing contractile responses, whereas in other vascular beds or in species in which extracellular calcium also contributes importantly to contractile responses, only a partial reversal of the response may be achieved. Thromboxane is preferentially a venoconstrictor in canine and ovine lungs [19]. Administration of U to canine lungs increased vascular resistance only in the small and large vein segments [20]. The precise site of action of inhaled NO, however, has not yet been shown. Considering lung anatomy, it seems most probable that inhaled NO exerts its effects on the arterial side of the pulmonary vasculature. The precapillary arteries are closely related to the respiratory bronchioles and alveolar ducts, whereas postcapillary veins lie in the interlobular and intersegmental tissue. This probable mode and site of action perhaps explain the fact that inhaled NO did not completely reverse pulmonary vasoconstriction during infusion of U in our experimental setup. Even though the effectiveness of lowering the PVR might have been overestimated in previous reports, there is no doubt about the capacity of inhaled NO to selectively decrease PVR in pulmonary hypertension. Several clinical studies [21-26] suggest that inhaled NO might become a valuable therapeutic tool in the management of acute pulmonary hypertension and hypoxemia in the period after cardiac surgical intervention, especially after correction of congenital cardiac malformations and in disease states such as adult respiratory distress syndrome and persistent pulmonary hypertension of the newborn. References 1. 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