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Ann Thorac Surg 1998;66:532-534
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Decreased exhaled nitric oxide may be a marker of cardiopulmonary bypass–induced injury

^a Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
^c Department of Anesthesia, The Hospital for Sick Children, University of Toronto, Toronto, Canada
^d Department of Critical Care Medicine, The Hospital for Sick Children University of Toronto, Toronto, Canada
^b Division of Respiratory Medicine and Departments of Pediatrics, Anesthesia, and Critical Care Medicine, University of Toronto, Toronto, Canada

Accepted for publication March 20, 1998.

Address reprint requests to Dr Adatia, Critical Care Medicine and Cardiology, The Hospital for Sick Children, 555 University Ave, Toronto, Ont M5J 1X8, Canada
e-mail: (iadatia{at}sickkids.on.ca)

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Background. Nitric oxide is an endothelium-derived vasodilator. Cardiopulmonary bypass may induce transient pulmonary endothelial dysfunction with decreased nitric oxide release that contributes to postoperative pulmonary hypertension and lung injury. Exhaled nitric oxide levels may reflect, in part, endogenous production from the pulmonary vascular endothelium.

Methods. We measured exhaled nitric oxide levels before and 30 minutes after cardiopulmonary bypass in 30 children with acyanotic congenital heart disease and left-to-right intracardiac shunts undergoing repair.

Results. Exhaled nitric oxide levels decreased by 27.6% ± 5.6% from 7 ± 0.8 to 4.4 ± 0.5 ppb (p < 0.05) 30 minutes after cardiopulmonary bypass despite a reduction in hemoglobin concentration.

Conclusions. The decrease in exhaled nitric oxide levels suggests reduced nitric oxide synthesis as a result of pulmonary vascular endothelial or lung epithelial injury. This may explain the efficacy of inhaled nitric oxide in the treatment of postoperative pulmonary hypertension. Furthermore, strategies aimed at minimizing endothelial dysfunction and augmenting nitric oxide production during cardiopulmonary bypass may decrease the incidence of postoperative pulmonary hypertension. Exhaled nitric oxide levels may be useful to monitor both cardiopulmonary bypass–induced endothelial injury and the effect of strategies aimed at minimizing such injury.

	Introduction

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The endothelial cell plays a pivotal role in the regulation of vascular homeostasis. Structural and functional damage to the pulmonary vascular endothelium has been demonstrated after cardiopulmonary bypass [1, 2]. This is thought to lead to a cascade of events resulting in increased pulmonary vascular resistance and platelet and neutrophil activation and sequestration. Endothelial-derived nitric oxide produces vasodilation and inhibits platelet aggregation and leukocyte activation [3]. Impaired production of nitric oxide may account for the increased pulmonary vascular resistance encountered after cardiopulmonary bypass and the efficacy of inhaled nitric oxide therapy for pulmonary hypertension and reperfusion injury [4, 5]. Exhaled nitric oxide is thought to be derived in part by the pulmonary vascular endothelium and can be detected in the exhaled breath during administration of nitric oxide donors [6–8]. Therefore, we measured exhaled nitric oxide levels before and after cardiopulmonary bypass in children undergoing repair of congenital heart defects.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We studied 30 children (15 girls; median age, 33 months; range, 1 to 146 months) with acyanotic congenital heart disease undergoing corrective surgical procedures. All patients had left-to-right intracardiac shunts (ventricular septal defect, n = 10; atrial septal defect, n = 9; atrioventricular canal defects, n = 9; unobstructed total anomalous pulmonary venous drainage, n = 2). No patient was receiving nitrovasodilators. Volatile anesthetics with effects on the endothelium were avoided [9], and anesthesia was maintained with fentanyl and midazolam. Ventilator parameters were kept constant before and after cardiopulmonary bypass.

Standardized cardiopulmonary bypass was performed with systemic cooling to 25° to 28°C, bicaval and ascending aorta cannulation, and cold blood cardioplegia administered through the aortic root.

Exhaled nitric oxide levels were measured before cannulation and 30 minutes after discontinuation of cardiopulmonary bypass with a rapid-response chemiluminescent analyzer (Sievers 270B, Boulder, CO) suitable for small samples. We calibrated the analyzer daily with serial dilutions of a standard nitric oxide gas. The lower limit of sensitivity was 2 ppb. Measurements of inspired gas in the operating room taken as a prelude to the present investigation suggested a level of 2 ppb nitric oxide. Furthermore, inspired nitric oxide levels were always less than expired.

We sampled exhaled gas using a 14-gauge, 2-inch catheter (Becton Dickinson Vascular Access, Sandy, UT) inserted into the nasotracheal tube through the end-tidal CO₂ port. Two consecutive samples of end-tidal expiratory gas were drawn from the intratracheal catheter into a 20-mL syringe to minimize airway nitric oxide uptake and approximate alveolar nitric oxide levels. Arterial blood gas and hemoglobin levels were measured concurrently. End-tidal CO₂ was monitored throughout, except during sampling times, and approximated arterial CO₂. Arterial blood gas and hemoglobin levels were measured concurrently. Sealed syringes were placed on ice and exhaled nitric oxide levels were measured within 15 minutes of sampling. We verified that this technique correlated (±5%) with immediate chemiluminescence measurement providing samples were analyzed within 1 hour. The mean of two samples was used for analysis.

The duration of cardiopulmonary bypass and aortic cross-clamping was recorded.

All results are expressed as the mean ± standard error of the mean. Exhaled nitric oxide levels were not normally distributed before and after cardiopulmonary bypass and were analyzed with a paired nonparametric test (Wilcoxon signed rank). A paired Student’s t test was used to assess the significance of changes in hemoglobin, pH, carbon dioxide tension, oxygen tension, heart rate, body temperature, and systemic blood pressure. The relationship between the change in exhaled nitric oxide and the duration of cardiopulmonary bypass and aortic cross-clamping was examined by correlation coefficient. Values of p of 0.05 or less were considered significant.

The research protocol was approved by the Hospital Human Ethics Committee and informed consent was obtained from the subjects or their parents.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Exhaled nitric oxide levels decreased in all but 3 patients after cardiopulmonary bypass with a mean change from 7.0 ± 0.8 to 4.4 ± 0.5 ppb (p < 0.05), a decrement of 27.6% ± 5.6% (Fig 1).

View larger version (24K): [in this window] [in a new window]   Fig 1. Exhaled nitric oxide (NO) levels decrease in children after cardiopulmonary bypass (CPB) and repair of left-to-right shunts.

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We found that exhaled nitric oxide levels decreased significantly after cardiopulmonary bypass in children undergoing repair of left-to-right shunts. This suggests that decreased lung nitric oxide production may be secondary to pulmonary vascular endothelial injury.

Preoperative exhaled levels in our study were similar to those measured in intubated patients about to undergo operations but not cardiopulmonary bypass [10]. However, in the study by Schilling and associates [10] exhaled nitric oxide levels increased after operation. This contrasts with the finding of decreased exhaled nitric oxide after cardiopulmonary bypass in the present study. Furthermore, Wessel and colleagues [4] demonstrated an attenuation of endothelial-dependent relaxation to acetylcholine, which acts by stimulation of endothelial nitric oxide release, in children with congenital heart defects undergoing cardiopulmonary bypass. This suggests that reduced levels of exhaled nitric oxide after cardiopulmonary bypass are the result of decreased endogenous nitric oxide production by an injured pulmonary vascular endothelium.

The correlation with duration of cardiopulmonary bypass and aortic cross-clamp strengthens the argument that the decrease in exhaled nitric oxide reflects pulmonary vascular injury rather than reduction in pulmonary blood flow and may be explained by the findings of Tsao and Lefer [11], who demonstrated that in a rat model, response to acetylcholine was depressed maximally after 20 minutes of reperfusion and remained comparably depressed thereafter.

The decrease in exhaled nitric oxide occurred despite lower hemoglobin levels after cardiopulmonary bypass, a change that might be expected to increase exhaled nitric oxide as nitric oxide avidly binds to hemoglobin [12]. An inverse relationship between exhaled nitric oxide and hemoglobin has been reported. Exhaled nitric oxide levels increased in exsanguinated rats [13] and conversely addition of autologous blood to a Krebs-dextran and albumin perfusate decreased exhaled nitric oxide in isolated pig lungs [8].

Decreased exhaled nitric oxide levels may indicate not only reduced production, but also increased breakdown. Free radicals are known to initiate lipid peroxidation and endothelial injury as well as inactivate nitric oxide [3], and they are increased after cardiac surgery, especially in pulmonary hypertensive patients [14]. Administration of free radical scavengers has been shown to prevent nitric oxide inactivation and to reduce ischemia and reperfusion injury [11]. Clearly, the present study cannot differentiate between decreased production and increased inactivation of nitric oxide.

Alternatively, exhaled nitric oxide levels may change with pulmonary blood flow and capillary blood volume [14]. Although Celermajer and coworkers [15] have demonstrated endothelial dysfunction in children with left-to-right shunts who did not undergo an operation, further attenuation of the response to acetylcholine after cardiac operation [4] supports endothelial injury, rather than reduction in pulmonary blood flow, as the cause of the decrease in exhaled nitric oxide levels.

Recent studies have shown that addition of nitric oxide or the precursor L-arginine [16] before reperfusion may ameliorate endothelial injury [17, 18]. Inhaled nitric oxide prevents microvascular injury, endothelial dysfunction, and pulmonary neutrophil accumulation in a piglet model of lung injury [18]. Thus exhaled nitric oxide levels may be useful to monitor both cardiopulmonary bypass–induced endothelial injury and the effect of strategies aimed at minimizing such injury.

Although high levels of exhaled nitric oxide may be measured in the nasopharynx [19], all of our patients were intubated and contamination from nasal air excluded. We minimized the contribution of bronchial nitric oxide by sampling with an intraairway catheter and by taking samples during free exhalation to minimize the transit time in the airway and contamination by dead space gas. A recent report suggests contamination of air piped to the operating room with environmental nitric oxide [20]. We verified that inspired nitric oxide levels were always lower than expired. It seems likely that in the present study exhaled nitric oxide levels reflect endogenous production by the pulmonary vascular endothelium as reported in the isolated pig lung [8] and human during cardiopulmonary bypass [21].

In conclusion, decreased exhaled nitric oxide levels may be a marker of pulmonary vascular injury in children undergoing surgical repair of congenital heart defects. Although the origin of postoperative pulmonary vascular complications is complex and multifactorial, decreased nitric oxide production may explain the efficacy of inhaled nitric oxide therapy of postcardiopulmonary bypass pulmonary hypertension and lung injury. Furthermore, exhaled nitric oxide levels may prove useful to monitor the effect of strategies to minimize endothelial dysfunction and augment nitric oxide production during cardiopulmonary bypass.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Maurice Beghetti is supported by a Bourse de relève du Fonds National Suisse pour la Recherche.

This study is supported by a grant from the Physicians Services Incorporated Foundation, Toronto, Canada.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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