Aubin, Marie-Claude MSc*; Laurendeau, Steve MD†; Mommerot, Arnaud MD†‡; Lamarche, Yoan MD†; Denault, André MD§; Carrier, Michel MD†; Perrault, Louis P MD, PhD*†
The physiological alterations, including the induction of a systemic inflammatory response, following cardiopulmonary bypass (CPB) were recognized early after its introduction in the 1950s. During CPB, the blood flow is diverted from the right atrium to the CPB pump and is pumped back into the aorta. Since there is reduced flow in the pulmonary arteries, the lungs are perfused only by the bronchial arteries for the duration of CPB and are therefore submitted to ischemia. At separation from CPB, as ventilation and flow to the pulmonary arteries are resumed, lungs undergo reperfusion and suffer from ischemia-reperfusion injury due to exposure to oxygen free radicals. Activated neutrophils and platelets contribute to the pulmonary damage. The “postpump syndrome” is characterized by an increase in pulmonary capillary permeability leading to decreased oxygenation, manifested by an increase in the alveoloarterial gradient in O2 associated with decreased pulmonary compliance and increased pulmonary vascular resistance.1 A pulmonary arterial endothelial dysfunction occurs following CPB2 and contributes to pulmonary hypertension which increases right ventricular work. Right ventricular dysfunction following CPB carries a poor prognosis with a perioperative mortality ranging from 44% to 86%.3 This highlights the importance of finding new effective treatment to prevent this condition.
The endothelium has an important role in regulating the vascular tone, inhibiting platelet aggregation and neutrophil adhesion through the release of vasorelaxing and vasocontracting factors. Endothelial dysfunction can be defined as an imbalance between relaxing factors and contracting factors, resulting in the loss of the normal protective role of the endothelium on the homeostasis of the vascular wall.4
Several pharmacological agents have been used to limit the occurrence of pulmonary hypertension following cardiac surgery including intravenous nitroglycerin, inhaled nitric oxide (NO), inhaled prostacyclin and intravenous milrinone. Milrinone, a type III phosphodiesterase inhibitor, increases intracellular levels of cAMP by limiting its degradation. In a previous study using intravenous administration of milrinone, systemic vascular resistances decreased, causing hypotension.5 This can be hazardous in the hours following cardiac surgery and may require support with vasopressor drugs. Moreover, intravenous milrinone does not prevent pulmonary endothelial dysfunction and is associated with an increased alveoloarterial gradient in O2 60 min after bypass (P < 0.05), most likely due to shunting. Inhaled milrinone prevented the alterations in relaxation of pulmonary arteries to acetylcholine caused by CPB and improved relaxations to bradykinin.5 No positive effects on the pulmonary artery pressure or resistance were observed. Trials in patients undergoing cardiac surgery are ongoing to explore the effects of this mode of administration in the clinical area.
Sildenafil is a type V phosphodiesterase inhibitor mainly used in the treatment of erectile dysfunction. Phosphodiesterase V inactivates cyclic guanosine monophosphate (cGMP) synthesized by guanylate cyclase after stimulation by NO in the vascular smooth muscle. By inhibiting phosphodiesterase V, sildenafil limits the metabolism of NO end-products, thus enhancing its vasodilatory effect. Type V is seldom found in tissue6 and appears more specific to the lung. Several authors have reported the use of sildenafil in the treatment of pulmonary hypertension, relaxing isolated human vessels7 and reducing the pulmonary hypertension in animal models.8-10 Zhao and colleagues used a model of hypoxic pulmonary vasoconstriction in humans after inhalation of 11% oxygen. The control group showed a 50% increase in pulmonary artery pressures and the sildenafil group (100 mg PO) developed no pulmonary hypertension.11 Intravenous sildenafil was used in a study by Shekerdemian and colleagues in a model of meconial aspiration in the pig, which showed a 40% decrease in pulmonary vascular resistance and a 30% increase in cardiac output without change in oxygenation.12
The purpose of the present study was to evaluate the effects of inhaled and intravenous sildenafil, administered prior or after CPB, on pulmonary artery endothelial function.
Experimental Preparation for All Groups (Anaesthesia)
All experiments were performed using Landrace swine (McGill University, Montreal, QC, Canada) of either gender, aged 8 weeks and weighing 26 ± 2.5 kg. Animals were maintained and tested in accordance with the recommendations of the Guidelines on the Care and Use of Laboratory Animals issued by the Canadian Council on Animals. The piglets were fasted for 12 hours prior to surgery and sedated with intramuscular ketamine hydrochloride (25 mg/kg; Ayerst Veterinary Laboratories, Guelph, ON, Canada) and xylazine (10 mg/kg; Boehringer Ingelheim, Burlington, ON, Canada) and induction was achieved using mask ventilation with 2% isoflurane (Abbott Laboratories Limited, St-Laurent, QC, Canada). They were subsequently intubated and mechanically ventilated with a constant oxygen and air mixture (3:2, or FiO2 = 0.66) at 14 breath strokes/min and tidal volume of 6-8 mL/kg. Anesthesia was maintained with 1% isoflurane inhalation. Arterial and venous blood gases were measured at regular intervals and maintained within physiological limits by adjusting the ventilation rate and tidal volume.
Group 1: Control (n = 6)
After skin preparation, the mediastinum was exposed via a median sternotomy and 300 UI/kg heparin (Leo Pharma Inc. Ajax, ON, Canada) was given intravenously. After 1 hour of general anaesthesia with 1% isoflurane, the animal was exsanguinated and the lungs harvested.
Group 2: Cardiopulmonary Bypass (n = 6)
After skin preparation and draping with sterile fields, a median sternotomy was performed and the pericardium opened. After heparin administration (400 UI/kg), a double purse string was made on the proximal ascending aorta and a single purse string on the right atrium. A blood sample was drawn from the right atrium and anticoagulation assessed using an activated coagulation time (ACT) with Hemochron 801 (Technidyne, NJ). The aorta and right atrium were cannulated when ACT was superior to 300 sec, with a 22-Fr and a 29/29-Fr double staged cannulas (DLP Inc., Grand Rapids, MI), respectively. After cannulation, CPB was initiated when ACT was superior to 400 sec. Ventilation was stopped throughout the CPB period. Anaesthesia was maintained using the jugular vein line with a continuous infusion of propofol (0.1 to 0.2 mg/kg/min; Pharmascience Inc., Montreal, QC, Canada). The CPB circuit consisted of a hollow fiber membrane oxygenator with incorporated filtered hardshell venous reservoir (Monolyth, Sorin, Irvine, CA), a heater-cooler and a roller pump (Sarns 7000, Ann Harbor, MI). The circuit was primed with Pentaspan 500 mL (10% Pentastarch; DuPont Pharma Inc., Mississauga, ON, Canada), Ringer's lactate 250 mL, heparin 5000 UI, mannitol 12.5 g, and sodium bicarbonate 15 mEq. The pump flow was adjusted to maintain a cardiac index of 2.4 L/min/m2 and assessed by venous gases to maintain mixed venous saturation over 60%. Mean systemic arterial pressure was maintained between 50 and 70 mm Hg with crystalloid (Ringer's lactate) and boluses of 50 to 200 μg of neosynephrine (Cayman Chemical Company, Ann Arbor, MI). The temperature was allowed to drift to 36°C. The heart was left beating empty and no aortic cross clamping or cardioplegia was used. Before weaning of the CPB, swine were rewarmed to 38°C (normal porcine temperature). After 90 min of CPB, mechanical ventilation and isoflurane anaesthesia were reinstituted and CPB was weaned. Normal circulation was restored for 60 min, at which time the animal was exsanguinated. The beating heart and the lungs were excised en bloc and immediately immersed in a cold modified Krebs-bicarbonate solution (composition in mmol/L: NaCl 118.3, KCl 4.7, MgSO4 1.2, KH2PO4 1.2, glucose 11.1, CaCl2 2.5, NaHCO3 25, and ethylenediamine tetraacetic acid 0.026).
Group 3: Inhaled Sildenafil Before Cardiopulmonary Bypass (n = 6)
The same procedure was followed as in the CPB group (Group 2), except for administration of a 10-mg bolus of sildenafil (0.5 mg/kg; Viagra, Pfizer, Sandwich, UK) diluted in 20 mL of buffer (0.038 mol/L sodium acetate); this latest was given via the endotracheal tube through a nebulizer during the 30-min period preceding the initiation of CPB. The dosage was based on review of the literature.13-15 Sildenafil was given as sildenafil mesylate salt formulated for nebulizer administration. The drug was administered through a conventional in-line nebulizer kit (Salter Labs) connected to the inspiratory limb of the ventilator.
Group 4: Inhaled Sildenafil After Cardiopulmonary Bypass (n = 6)
The same procedure was followed as in the CPB group (Group 2), except for administration of a 10-mg bolus of sildenafil diluted in 20 mL of buffer given via the endotracheal tube through a nebulizer during 30 min following the weaning of CPB.
Group 5: Intravenous Sildenafil Before Cardiopulmonary Bypass (n = 5)
The same procedure was followed as in the CPB group (Group 2), except for administration of a 10-mg bolus of sildenafil diluted in 20 mL of buffer given intravenously during a 30-min period preceding the initiation of CPB.
Vascular Reactivity Studies
Less than 10 min after en bloc excision, the heart was removed and the primary pulmonary artery dissected. Branches of second degree of pulmonary arteries were isolated and dissected free of connective and adventitial tissue and divided into rings (4-mm wide; 16 rings per animal). All rings were placed in organ chambers (Emka Technologies Inc., Paris, France) filled with 20 mL of modified Krebs-bicarbonate solution continuously heated at 37°C and oxygenated with a carbogen mixture (95% O2 and 5% CO2). The rings were suspended between two metal stirrups with the upper one connected to an isometric force transducer connected to a signal amplifier and then allowed to stabilize for 30 min. Data were collected with biological signal data acquisition software (IOX 1.700; Emka technologies Inc., Paris, France). Each arterial ring was stretched to the optimal point of its active length-tension curve (4.0 g) as determined by measuring the contraction to potassium chloride (KCl; 30 mmol/L) at different levels of stretch (data not shown). The maximal contraction of rings was then obtained with addition of potassium chloride (KCl 60 mmol/L). After stabilization, all baths were washed twice with modified Krebs-bicarbonate solution and indomethacin (10−5 mmol/L; to exclude production of endogenous prostanoids) was added in each bath. After 45 min of stabilization, phenylephrine (PE, range 2 × 10−7 mol/L to 3 × 10−6 mol/L) was added to obtain a contraction averaging 50% of the maximal contraction to KCl.
The NO-mediated relaxation pathway was studied by constructing concentration-response curves to acetylcholine (ACh, 10−9 to 10−5 mol/L) and to bradykinin (BK, 10−12 to 10−6 mol/L).
At the end of the experiment, endothelium-independent relaxations were studied with the use of a bolus of 10−5 mol/L sodium nitroprusside (SNP), an NO donor.
All drugs were prepared daily. Acetylcholine, bradykinin, indomethacin, and SNP were obtained from Sigma Chemical (Mississauga, ON, Canada). Phenylephrine was obtained from Cayman Chemical (Ann Arbor, MI). Sildenafil was obtained from Pfizer (Sandwich, Kent, England).
The jugular vein and carotid artery were cannulated to obtain a central venous line and arterial pressure respectively. A Swan-Ganz catheter (Edwards Lifesciences, Irving, CA) was inserted through the jugular vein to measure wedge, central venous, and pulmonary artery pressure and cardiac output.
All values are expressed as means ± SEM. Contractions to PE (phenylephrine) are expressed as a percentage of the maximal contraction to KCl (60 mmol/L). Relaxations are expressed as the percentage of the maximal contraction to PE for each ring. Two-way repeated analysis of variance (ANOVA) were performed to compare each point of the concentration-response curves between control and CPB rings. Statistical analysis was performed with the computer software SAS (Cary, NC). A P value less than 0.05 was considered statistically significant.
The hemodynamics baseline values demonstrated the absence of significant variation among groups regarding different cardiac and pulmonary parameters evaluated (Table 1). On the other hand, a significant increase in mean pulmonary artery pressure was detected in the inhaled sildenafil group in comparison with the CPB group (P < 0.05).
The presence of sildenafil, independently of the route or the period of administration, significantly decreased the amplitude of contraction to KCl and PE in comparison to controls (Table 2). This may be the consequence of an increased NO bioavailability, which counteracts the contractions induced by both agonists at the pulmonary muscular level. On the other hand, the concentration of PE needed to reach the optimal contraction was not significantly different from controls as well as from CPB.
There was a statistically significant decrease of endothelium-dependent relaxations to ACh and to BK in the CPB group when compared to controls (P < 0.05). This endothelial dysfunction was prevented by the administration (intravenously or by inhalation) of sildenafil prior to or after CPB (Figs. 1 and 2). All sildenafil groups achieved maximal relaxation greater than controls. No difference in relaxation to SNP was observed between groups with all rings achieving 100% relaxation.
In the CPB untreated group, the mean pulmonary arterial pressure (mPAP) increased following CPB and reached statistical significance 30 min after weaning (P < 0.05; Fig. 3A). Administration of inhaled sildenafil prior to CPB prevented this statistically significant increase (P = 0.37) in mPAP. Intravenous sildenafil had the same effect. When given after the CPB, inhaled sildenafil decreased the mPAP. This decrease was more pronounced at 30 min of reperfusion (at the end of the nebulization) but never reached statistical significance (P = 0.24).
No statistically significant hypotension was observed after the administration of sildenafil (intravenously or by inhalation). The only significant decrease in the mean arterial pressure (MAP) was observed in the group receiving inhaled sildenafil prior to CPB at the time of reperfusion (Fig. 3B). The cardiac output was increased in all groups during reperfusion except for the inhaled sildenafil after CPB at 30 min of reperfusion (P = 0.16; Fig. 3C). No statistically significant tachycardia was noted with sildenafil administration either intravenously or by inhalation.
Following weaning from CPB, in the CPB-untreated group, the alveoloarterial gradient was statistically significantly increased (Fig. 3D). This was prevented by nebulization of sildenafil after the CPB and by the intravenous administration: in the inhaled sildenafil after CPB group, this gradient was decreased 30 min after reperfusion (P < 0.05) and increased at 60 min (P < 0.05), whereas it was only significantly increased after 60 min of reperfusion in the intravenous group.
The aim of the present study was to evaluate the effects of the use of sildenafil on the pulmonary artery endothelial function, hemodynamic profile, and oxygenation following exposure to CPB as well as to determine the best timing for administration of the treatment. The major findings of this study are that: 1) sildenafil administration, intravenous and inhaled (prior to or after CPB), prevents the occurrence of the pulmonary endothelial dysfunction after CPB; 2) sildenafil prevents the increase in mPAP after CPB with a safe hemodynamic profile; 3) nebulization of sildenafil after CPB and intravenous administration prevents the increase in alveoloarterial gradient secondary to CPB.
Postoperative pulmonary hypertension is a serious complication of cardiac surgery,16 which may increase right ventricular work and trigger right heart failure associated with a high mortality. Morita and colleagues demonstrated in a porcine model that CPB causes a significant increase in pulmonary vascular resistance and depresses the right ventricular function by more than 50%.17 During full CPB, pulmonary perfusion is decreased due to diversion of the systemic venous return to the aorta. The weaning of CPB completes the ischemia-reperfusion cycle, which causes injury to the lungs18 and further induces a significant decrease in endothelium-dependent relaxations to ACh. In our model, both Gi and Gq protein mediated pathways were altered (ACh and BK) upon reperfusion of the pulmonary tree after CPB.
In this model, CBP is associated with significant decreases in endothelium-dependent relaxations, suggesting the presence of an endothelial dysfunction. Because no significant differences in endothelium-independent relaxations to the exogenous NO donor SNP were observed, this suggests that the endothelial dysfunction is not due to an alteration of vascular smooth muscle cells, but is attributed to functional alterations of the signalling transduction mechanisms of the endothelial cells per se.19,20 These alterations in the endothelial cell signalling pathway involve both Gi and Gq protein mediated relaxations, as seen by the upward and rightward shift in the concentration-response curves to ACh and BK, respectively. ACh induces vasoconstriction under resting conditions and vasodilatation under conditions of elevated tone; NO pathway, as assessed by the Gi protein mediated agonist ACh, is preferentially damaged.17 Indeed, Gagnon and colleagues have shown that reperfusion of the pulmonary tree after CPB induces a decrease in endothelium-dependent relaxations mediated by muscarinic receptors.21 On the other hand, BK is an agonist that binds to B2 receptors, which causes release of NO in pulmonary endothelium but also stimulates prostacyclin release,22 resulting in vasodilatation independently of the preexisting vascular tone. However, all experiments in the present study were performed in presence of the cyclooxygenase inhibitor indomethacin to block the endogenous production of prostacyclin in order to focus on the NO pathway.
This study demonstrates the restoration of relaxations of the pulmonary rings with ACh and BK after sildenafil administration, through the inhaled and intravenous routes. This improvement can be explained by the inhibition of cGMP catabolism, which decreases calcium content in vascular smooth muscle cells, thus being less sensitive to the decreased NO content following CPB.23
Moreover, the CPB-induced systemic inflammatory response produces massive amounts of reactive oxygen species24 generated by pulmonary endothelial cells during reoxygenation after hypoxia.25 Oxidative injury causes functional uncoupling of the receptor/G-protein complex specific to the NO signal transduction pathway26 and of the eNOS by oxidation of an essential cofactor. This latest uncoupling leads to an increased production of free radicals at the expense of NO, accompanied by increased scavenging of NO by these radicals. The decrease in NO production and bioavailability caused by the presence of oxidative stress contributes to the endothelial dysfunction in pulmonary arteries following CPB. On the other hand, preservation of cGMP content by inhibition of its catabolism following sildenafil administration, explains the improvement in vascular relaxation.
Pulmonary Artery Pressure
Since numerous risk factors for postoperative pulmonary hypertension have been identified, some subsets of patients could probably benefit from the prophylactic use of agents to lower the risk of developing this complication with its deleterious consequences. In the present study, mPAP was lowered by the use of inhaled sildenafil when administered at the end of the CPB. Following weaning from CPB, mPAP increased significantly compared to pre-bypass levels and decreased less than 1 min after initiation of the nebulisation of sildenafil. Upon termination of the sildenafil inhalation after 60 min of reperfusion, the mPAP slightly reincreased suggesting a possible clinical application to reverse pulmonary hypertension after cardiac surgery. In fact, since the beneficial effect is seen shortly after the beginning of the administration, sildenafil could also be used once the pulmonary hypertension is established. A brief period of pulmonary hypertension would have little negative effect on right ventricular function.
In this porcine model, exposure to CPB induced a significant increase of the alveoloarterial gradient. Inhaled sildenafil, during reperfusion, prevented this increase during the duration of nebulization. Animals presented severe desaturation immediately after weaning of CPB as in two swine with oxygen saturations less than 60%, which was normalized less than 1 min after the beginning of the nebulization. However, the preventive effect lasted only during the duration of the nebulization, as seen with the increased alveoloarterial gradient after 60 min of reperfusion (30 min after the cessation of the nebulization).
The intravenous administration of sildenafil did not cause a significant decrease in the alveoloarterial gradient contrary to the one observed with nebulization post-CPB, and prevented the short rise (30 minutes) observed with CPB alone. The additional hemodynamic benefit seen with nebulization may come from that fact that, like NO,27 inhaled sildenafil diffuses rapidly across the alveolar-capillary membrane into the adjacent smooth muscle of pulmonary vessels causing vascular smooth muscle relaxation. Moreover, inhaled sildenafil has an impact exclusively on ventilated zone, improving the perfusion of these zones only, whereas intravenous sildenafil is delivered into perfused zones that may not be ventilated, increasing the shunt.
Possible side effects of intravenous administration of type III phosphodiesterase inhibitors include hypotension and tachycardia, which can be hazardous during the postoperative period. Intravenous administration of sildenafil did not significantly decrease the mean systemic arterial pressure or induce tachycardia, showing a higher specificity for the pulmonary vasculature. Similarly, inhaled sildenafil did not induce systemic hypotension demonstrating a safe and favorable hemodynamic profile by increasing the cardiac output without significant tachycardia.
The pharmacodynamics of the drug cannot be described extensively in the route of administration used. The dosages used in this study were extrapolated from literature and from clinical use; a dose-response curve was not obtained to determine the optimal dose. Finally, this model used young, healthy 8-week-old Landrace swine, which may not reflect the clinical situation of adult patients with long-standing cardiac and pulmonary diseases. The absence of cardioplegic arrest also differs from clinical CPB use. Inhaled sildenafil may not have the same beneficial effects in patients with heart failure, coronary artery disease, and pre-existing pulmonary diseases and may be contraindicated in patients receiving concomitant nitrates.
Exposure to CPB is associated with occurrence of pulmonary endothelial dysfunction, which contributes to clinically significant pulmonary hypertension and the potential for right ventricular failure with its attendant high mortality. The novel use presented in this study of a well-known drug is of definite clinical interest. Inhaled sildenafil in the prophylaxis of pulmonary hypertension in the postoperative setting could be an additional tool to prevent this important clinical problem. Moreover, sildenafil was able to reverse pulmonary hypertension once established. Since the effect occurs and ceases rapidly, it could be used once the pulmonary hypertension is established or in prophylaxis with continuous nebulization.
The authors would like to thank Marie-Pierre Mathieu and Dr. Olivier Bouchot for their skillful technical assistance and Karine Tétreault for her statistical expertise.
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