Production of nitric oxide during surgery involving cardiopulmonary bypass

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Abstract
Objectives: Surgery involving cardiopulmonary bypass induces an inflammatory response due to the contact of blood with the extracorporeal circuit. In some patients, this inflammatory response leads to multiple organ failure and death. Inflammatory states may increase the production of nitric oxide, either by increasing the activity of constitutive enzyme systems or by inducing of inflammation-specific systems. We hypothesized that surgery involving cardiopulmonary bypass would increase the production of nitric oxide in association with the inflammatory response. Design: Prospective, single center, observational study. Setting: University-affiliated, tertiary referral cardiothoracic center. Patients: Eleven adult patients undergoing routine myocardial revascularization. Interventions: Surgery for myocardial revascularization. Measurements and Main Results: Observations were made after induction of anesthesia, before bypass, after completion of the bypass, and on return to the recovery area. Parameters measured included hemodynamics, exhaled nitric oxide concentrations, plasma nitrate/nitrite concentration, plasma and bronchoalveolar lavage myeloperoxidase concentrations, and protein carbonyl conversion. All patients survived surgery. Oxygenation index fell significantly after bypass. Plasma myeloperoxidase increased significantly during the study period. Plasma carbonyl conversion also increased, although not significantly. Plasma nitrate/nitrite and airway nitric oxide concentrations did not change through the course of the study. Conclusion: Surgery involving cardiopulmonary bypass induced a demonstrable inflammatory response, but this response was not associated with increased nitric oxide production. (Crit Care Med 1998; 26:272-278) Surgery involving the use of cardiopulmonary bypass leads to systemic endotoxemia and the release of inflammatory cytokines, producing a generalized inflammatory state that, on a molecular level, resembles sepsis [1]. In most patients, this is a self-limiting process but a significant minority of patients develop profound organ dysfunction that may lead to multiple organ failure. After bypass, abnormalities of lung function are particularly common and can prolong postoperative recovery. Thus, significant increases in alveolar-arterial oxygen gradient, which may be accompanied by a gas transfer coefficient decrease by <or=to40%, have been demonstrated in the immediate postoperative period and cannot be attributed solely to the effects of anesthesia [2]. Although the reasons for these phenomena remain unclear, they may be attributable to the effects of the bypass-induced systemic inflammatory response on endothelial cells. Changes in the morphology and integrity of the pulmonary vascular endothelium have been described after bypass surgery [3], manifest in extreme cases in adults as the acute respiratory distress syndrome (ARDS), which develops in 1.5% of patients after cardiopulmonary bypass [4]. The endothelium is now recognized as an important regulator of vascular tone, releasing a wide variety of vasoactive substances, principal amongst which is the free radical nitric oxide (NO), generated by the enzyme nitric oxide synthase (NOS). Three distinct NOS complementary DNAs have now been cloned: Type I (nNOS), the constitutive NOS in neuronal tissues; Type II (iNOS) identified as being inducible by a variety of agents in macrophages and hepatocytes; and Type III (eNOS), the constitutive NOS in vascular endothelial cells. The eNOS and nNOS are functionally similar and distinct from iNOS. The genes coding for all three isoforms of NOS genes are transcriptionally regulated[5]. Although the iNOS gene is not transcribed under physiologic conditions, it can be expressed rapidly after inflammatory insults[6]. Thus, increased plasma or urine concentrations of nitrate/nitrite, the terminal metabolites of NO, have been observed in both clinical and laboratory studies of sepsis [7] and endotoxemia [8]. Further, concentrations of NO in exhaled breath are increased in inflammatory lung disease [9] and may decrease after anti-inflammatory therapy. Finally, changes in concentrations of airway NO have also been observed in patients undergoing cardiac surgery [10,11]. In clinical and experimental models, NO modulates systemic and pulmonary vascular tone, including the reflex of hypoxic pulmonary vasoconstriction which ensures the matching of ventilation/perfusion in damaged lungs. Hypoxic pulmonary vasoconstriction is lost after acute lung injury and in ARDS [12], thereby causing ventilation/perfusion mismatch and refractory hypoxemia. Inhaled NO has been used in these circumstances to improve ventilation/perfusion matching by recruiting blood to ventilated alveolar units [13]. However, the effects of endothelial injury on the endogenous generation of NO remain largely unexplored. The early identification of patients at risk of developing a clinically important inflammatory response syndrome after cardiopulmonary bypass may facilitate early therapeutic intervention. We hypothesized that the inflammatory insult of cardiopulmonary bypass would be associated with an increase in production of NO. Thus, the aims of this study were two-fold: a) to characterize the injury induced by cardiopulmonary bypass with particular reference to the lung by seeking evidence of neutrophil activation and oxidant stress in bronchoalveolar lavage and plasma; b) to demonstrate changes in endogenous NO production attributable to bypass-induced endothelial cell damage by measuring concentrations of exhaled NO and plasma concentrations and nitrate/nitrite.