Exhaled nitric oxide before and after cardiac surgery with cardiopulmonary bypass—response to acetylcholine and nitroglycerin

D. C. Törnberg1, M. Angdin2, G. Settergen2, J. Liska2, J. O. Lundberg3 and E. Weitzberg1

Department of Surgical Sciences, 1 Anaesthesiology and Intensive Care, 2 Cardiothoracic Surgery and Anaesthesiology, Karolinska Institute and Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden. 3 Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden

* Corresponding author. E-mail: danieltornberg{at}hotmail.com

Accepted for publication October 4, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Pulmonary endothelial dysfunction may occur after ischaemia–reperfusion injury and can be revealed as a reduced vasodilatory response upon administration of acetylcholine (ACh). ACh also releases the endothelium-derived vasodilator nitric oxide but direct measurements of this gas are difficult to perform in vivo. We wanted to study the effects of i.v. administration of ACh and the endothelium-independent vasodilator nitroglycerin on exhaled nitric oxide in relation to pulmonary endothelial dysfunction after open-heart surgery and cardiopulmonary bypass (CPB).

Methods. Basal exhaled nitric oxide and the response in exhaled nitric oxide to i.v. injections of ACh and nitroglycerin were measured with chemiluminescence in 10 patients before and after open-heart surgery.

Results. Exhaled nitric oxide decreased significantly after CPB. I.V. bolus injections of ACh induced a reproducible and dose-dependent increase in exhaled nitric oxide that was unaltered after CPB. In contrast, the increase in exhaled nitric oxide evoked by nitroglycerin was attenuated after CPB. The response in pulmonary vascular resistance index (PVRI) to an infusion of ACh decreased after CPB, indicating endothelial dysfunction. The decrease in PVRI response to ACh correlated to the duration of CPB.

Conclusions. Interestingly, pulmonary vascular dysfunction after CPB was accompanied by a reduction in the exhaled nitric oxide response to nitroglycerin and lower levels of basal exhaled nitric oxide. The ACh-induced responses in exhaled nitric oxide were unchanged, which could indicate nitric oxide-independent mechanisms behind the endothelial dysfunction in this study. The possibility of using exhaled nitric oxide dynamics to investigate pulmonary endothelial dysfunction merits further studies.

Keywords: heart, endothelium ; heart, endothelium-dependent relaxing factors ; heart, pulmonary vascular resistance ; heart, pulmonary vasodilation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Nitric oxide is a potent endothelium-derived vasodilator and thereby an important regulator of basal vasomotor tone in man.1 2 The endothelium is susceptible to ischaemia–reperfusion injury, which may affect the release of nitric oxide. Therefore, endothelial dysfunction is often demonstrated as impaired nitric oxide-mediated vasorelaxation in response to endothelium-dependent vasodilators, for example acetylcholine (ACh). Direct measurements of nitric oxide are difficult to perform in vivo because of rapid degradation of this reactive molecule. After open-heart surgery with cardiopulmonary bypass (CPB) an attenuated pulmonary vasodilation to infusion of ACh has been demonstrated both in children3 and adults.4 However, detecting this endothelial dysfunction requires the invasive procedure of pulmonary artery catheterization. A less invasive way of estimating pulmonary endothelial dysfunction could be to quantify changes in mediators responsible for vasodilation. Nitric oxide is detectable in exhaled air and has been extensively studied in relation to airway inflammation.5 6 We have previously demonstrated that i.v. ACh evokes a dose-dependent increase in exhaled nitric oxide in pig and man.7 This is also true for other vasoactive substances such as bradykinin, substance P, and endothelin.7 Exogenous nitric oxide donors such as nitroglycerin (glyceryl trinitrate, GTN) relax vascular smooth muscle cells via release of nitric oxide.8 Thus, GTN is an endothelium-independent nitric oxide releasing agent, which also induces the release of nitric oxide in exhaled air.9 Measurements of pulmonary vasoreactivity could have importance not only in ischaemia–reperfusion injury but also in patients with pulmonary hypertension, sepsis, and acute respiratory distress syndrome.

We performed a study of exhaled nitric oxide as a marker of pulmonary endothelial dysfunction after ischaemia–reperfusion injury. The hypothesis was that the exhaled nitric oxide response to ACh would be attenuated after CPB, as has been described for the vasodilatory response. If so it would be possible to non-invasively monitor the development of pulmonary endothelial dysfunction. The study was performed in patients undergoing open-heart surgery with CPB. The basal exhaled nitric oxide as well as the exhaled nitric oxide response evoked by i.v. administration of endothelium-dependent (ACh) and endothelium-independent (GTN) substances in relation to the vasodilatory response to ACh were analysed.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
The study was approved by the local ethics committee at the Karolinska Institute (Stockholm, Sweden) and 10 patients were included after informed consent. Open-heart surgery with aortic valve replacement (AVR) and/or coronary artery bypass grafting (CABG) was performed during CPB. Patients were not on continuous GTN treatment.

Anaesthesia, CPB, and surgical procedure
After pre-medication with morphine 10 mg i.m., a radial artery catheter was inserted under local anaesthesia. General anaesthesia was induced with fentanyl 0.5–0.7 mg and midazolam 3–4 mg and was followed by atracurium 0.5 mg kg–1 for muscular relaxation. After intubation, anaesthesia was maintained with a continuous infusion of propofol 3–4 mg kg–1 h–1 during initial measurements, isoflurane was used during surgery. During infusion of propofol norepinephrine was administered at 20–50 ng kg–1 min–1. The patients received volume-controlled ventilation with a tidal volume of 4 ml kg–1 plus 50 ml and a ventilatory frequency of 20 b.p.m. Fraction of inspired oxygen () was 0.50 and inhalation:exhalation ratio was 1:2. In the operation theatre a Julian Plus ventilator (Marquettes, Milwaukee, Wisconsin, USA) was used and after the operation the same ventilation was set with an Evita 4 ventilator (Dräger, Lübeck, Germany). The hospital compressed air used in the ventilators was filtered through a nitric oxide scavenger (a charcoal filter), to achieve zero nitric oxide concentration in the inspiratory air. A triple lumen central venous catheter was inserted via the right internal jugular vein, and through the same vessel a heparin-coated pulmonary artery catheter (Swan-Ganz 7.5 F, Edward Lifesciences, Irvine, California, USA) was inserted under pressure guidance. Heparin 300 u kg–1 was administered before the start of CPB. The target activated clotting time was at least 480 s. Non-pulsatile CPB was conducted with a centrifugal pump, crystalloid priming solution, and a membrane oxygenator. Antegrade or retrograde intermittent cold blood cardioplegia was used for myocardial protection. The lungs were not ventilated during CPB. Open-heart surgery was performed. After decannulation the patients received protamine 2–2.5 mg kg–1 to obtain an activated clotting time less than 120 s. After the operation infusions of propofol and norepinephrine were given in the same range as during initial measurements. No anticholinergic agents were administered before or during anaesthesia.

Nitric oxide recordings and calculations
Nitric oxide was detected with chemiluminescense technique. A linear pneumotachometer (Hans Rudolph, Missouri, USA) measuring pressure and flow was connected serially between the Y-piece from the ventilatory circuit and the humidifying antibacterial filter (Humid-Vent, Gibeck, Upplands Väsby, Sweden) leading to the tracheal tube. A thin suction catheter (Ch 12, Maersk, Denmark) was inserted in the tracheal tube in order to sample gas from the distal orifice of the tracheal tube to the nitric oxide-analysing system (Exhaled Breath Analyser, Aerocrine AB, Stockholm, Sweden) where the nitric oxide concentration, flow rate, and pressure were displayed online. Recordings were made during 30-s periods, before and after each drug injection and also during the last 30 s of the ACh infusion. During calculation of basal exhaled nitric oxide, the mean of all peak concentrations during 30 s was calculated and expressed as nitric oxide peak (parts per billion, ppb). Nitric oxide output (nl min–1) was calculated as nitric oxide concentration (nl litre–1=ppb)*flow (litre s–1)*60 for each data point during 30 s, after fitting the nitric oxide concentration curve to the corresponding exhalation flow curve (increase of nitric oxide adjusted to start of exhalation). After drug bolus injections and during infusions, nitric oxide peak delta, the absolute difference in nitric oxide peak concentration (evoked response minus basal) was determined. Nitric oxide output responses to bolus injections were calculated as the absolute difference in nitric oxide output (evoked response minus basal), expressed as nitric oxide output delta. All parameters were calculated during 30 s. The chemiluminescence analyser was calibrated with nitric oxide-free air and nitric oxide gas (10 ppm; AGA Linde, Lidingö, Sweden) before each experiment. The detection limit for the analyser was 1 ppb.

Vascular and pulmonary measurements
Cardiac output (CO) was measured as pulmonary artery flow by the thermodilution technique with a mean of two injections of 10 ml ice-cooled 5% glucose solution. The injections of glucose solution were randomly distributed through the respiration cycle. Mean of two CO measurements were used. Cardiac index (CI) was calculated as CO divided by body surface area. Pulmonary capillary wedge pressure (PCWP) was measured and pulmonary vascular resistance index (PVRI) was calculated as (MPAP – PCWP)*80*CI–1, where MPAP is mean pulmonary artery pressure. Every determination of PVRI was based on two determinations of MPAP – PCWP and four measurements of CO. The vascular response to an infusion of ACh was calculated as the relative reduction from PVRI measured before the start of infusion and PVRI measured during the infusion 2 min later. The infusion rate of ACh was based on the actual CO and 16.5 mg h–1 per litre min–1 was given in order to achieve an estimated 10–6 mol litre–1 concentration in the pulmonary artery.4 Patients were included only if the PVRI reduction before start of surgery was greater than 5%. One patient out of the 11 did not meet this criterion and was not included. Arterial and central venous blood samples were ran in a blood gas analyser (ABL, Radiometer, Copenhagen, Denmark). Alveolar–arterial (A–a) gradient was calculated assuming a respiratory exchange ratio of 0.8 as:

where is arterial oxygen tension in kPa. Arterial, venous, and end-capillary oxygen content (, , and ) was calculated as well as venous admixture (Qs/Qt, shunt):




where Hb is haemoglobin in g litre–1; and are arterial and venous saturation; and are venous and alveolar oxygen tension in kPa.

Study protocol
After induction of general anaesthesia but before the start of surgery measurements of MPAP, PCWP, and CO were made before and during infusion of ACh. Relative reduction of PVRI by infusion of ACh was determined and both central venous and arterial blood was sampled before and after 2 min infusion of ACh. Randomly ordered bolus doses of ACh (Clinalfa, Läufelfingen, Switzerland) 0.5, 1, and 2 mg were administered through the central venous catheter and exhaled nitric oxide was recorded. After a washout period of 5 min GTN was administered in the central venous catheter using the least dose (25 or 50 µg) that evoked an increase in exhaled nitric oxide. This protocol was repeated 2 and 3 h after the end of CPB.

Statistics
Non-parametric statistics were used. For the analysis of repeated measurements Friedman's analysis of variance (ANOVA) was used and, when significant, was followed by the Wilcoxon matched pairs test. The Spearman rank order test followed by multiple linear regression was used for correlation analysis. All statistics were made in Statistica 6.0 (Statsoft, Tulsa, Oklahoma, USA). P<0.05 was considered significant. Data are presented as median and interquartile range unless stated otherwise.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient data
Eleven patients (one smoker) were studied with an infusion of ACh before surgery. One patient was not included and studied further, as ACh caused no decrease in PVRI before surgery. Of the remaining 10 patients (nine male and one female) the median age was 74 (range 59–82) years. The surgical procedures were CABG and AVR in five, AVR in two, CABG redo in one, composite graft in one and CABG and composite graft in one patient. The duration of CPB was 102 (range 56–154) min and the duration of aortic occlusion was 69 (15–126) min. There were no complications related to the study and no in-hospital mortality.

Exhaled nitric oxide evoked by ACh
There was a reproducible dose–response relationship in the nitric oxide output delta and nitric oxide peak delta response to injection of ACh 0.5, 1, and 2 mg, which was unchanged after CPB (Figs 1 and 2). Also during infusion of ACh a minor but significant increase in evoked nitric oxide output was observed; 1.3 (0.2–3.8) nl min–1, P=0.03. The effect was unchanged after CPB (data not shown).



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Fig 1 Original tracings from one patient before open-heart surgery displaying the dose-dependent increase in exhaled nitric oxide (NO) evoked by (A) ACh (0.5, 1, and 2 mg, i.v.) and the response to (B) GTN (25 µg, i.v.).

 


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Fig 2 (A) Nitric oxide (NO) output delta and (B) nitric oxide peak delta responses to i.v. ACh (0.5, 1, and 2 mg) before, 2 and 3 h after CPB, respectively. Median and interquartile ranges are displayed. There were no significant differences in the response to ACh 2 and 3 h after CPB compared with before CPB.

 
Basal exhaled nitric oxide
Nitric oxide output decreased from 12.2 (7.8–20) to 8.0 (3.7–12.8) nl min–1 and 9.0 (5.4–13) nl min–1 (P=0.007 and 0.005), 2 and 3 h after CPB, respectively (Fig. 3). Nitric oxide peak also decreased from 3.2 (1.9–6.3) to 1.8 (1.1–3.2) ppb and 2.2 (1.5–4.5) ppb, 2 and 3 h after CPB, respectively (P=0.07 and P=0.02). Neither nitric oxide output nor nitric oxide peak increased during pulmonary capillary wedging.



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Fig 3 (A) Basal exhaled nitric oxide (NO) output and (B) nitric oxide output delta response to nitroglycerin before, 2 and 3 h after CPB, respectively. Median and interquartile ranges are displayed. **P<0.01 compared with before CPB.

 
Exhaled nitric oxide evoked by GTN
The nitric oxide output delta response to GTN decreased from 3.1 (1.9–4.1) nl min–1 before CPB to 1.2 (0.7–2.2) and 1.2 (1.1–2.3) nl min–1 (both P=0.009), 2 and 3 h after CPB, respectively (Fig. 3). Nitric oxide peak delta response to GTN also decreased from 1.0 (0.7–1.9) to 0.5 (0–0.9) ppb 2 h after CPB (P=0.009) and 0.8 (0.6–1.2) at 3 h (P=0.17). There was a correlation between the relative evoked nitric oxide output by GTN and the vascular response to ACh infusion (R2=0.46, P=0.03).

Vascular and pulmonary effects by ACh
Infusion of ACh had no systemic vascular effects (Table 1). PVRI decreased by 27 (19–31)% during the infusion of ACh before CPB, because of decreased MPAP and unchanged PCWP and CI. Two and three hours after CPB the ACh-induced reduction of PVRI was only 17 (0–29) and 16 (3–23)% (P=0.06 and P=0.04, compared with before CPB). The decrease in PVRI response (difference between 3 h after CPB and before CPB) correlated to the duration of CPB (R2=0.66, P=0.004) and of aortic cross-clamping (R2=0.59, P=0.01, Fig. 4).


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Table 1 Basal compared with ACh induced parameters (median [interquartile range]) before, respectively, 2 and 3 h after CPB. =ratio between arterial partial pressure for oxygen and fraction inhaled oxygen; ACh-infusion=parameter after 2 min i.v. ACh (16.5 mg h–1 per litre min–1 CO); basal=parameter before administration of any nitric oxide releasing agent;

 


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Fig 4 Linear regression analysis describing the relation between the decrease in PVRI response before and after (3 h) CPB and duration of (A) CPB (time CPB) and (B) aortic cross-clamping (time AXC).

 
Vascular and pulmonary effects by CPB
After open-heart surgery with CPB, heart rate and CO increased, MAP decreased, while MPAP, PVRI, and PCWP were unchanged (Table 1). Arterial oxygenation ratio () decreased, A–a gradient of oxygen increased, while venous admixture, arterio-venous oxygen content difference (Table 1) and airway pressure (not shown) were unchanged after CPB.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After open-heart surgery with CPB the PVRI reduction upon ACh was attenuated and arterial oxygenation was impaired, indicating both endothelial and pulmonary dysfunction. The reproducible dose–dependent response in exhaled nitric oxide after administration of ACh was unchanged. These findings indicate that CPB-induced endothelial dysfunction, defined as a reduced vascular response to ACh, is not primarily related to exhaled nitric oxide release. In contrast, both GTN-induced and basal exhaled nitric oxide were attenuated after CPB, which suggests a diminished conversion of GTN to nitric oxide or an increased scavenging of nitric oxide after ischaemia–reperfusion.

ACh-induced effects
In a previous study by our group nitric oxide release in response to injections of ACh was detected in exhaled air but this response in humans with endothelial dysfunction has not been investigated.7 Infusion of ACh induced only a minor increase in exhaled nitric oxide while the bolus doses of ACh increased nitric oxide substantially. Thus, injections of ACh had a larger impact on exhaled nitric oxide than infusions, which might be expected because of the higher intravascular concentration. The release of nitric oxide increased dose-dependently and yet the detected levels in exhaled air might only be the ‘tip of the iceberg’, representing nitric oxide escaping the rapid and powerful scavenging by circulating haemoglobin. We have no indication of reaching a threshold in the nitric oxide synthase (NOS) ability to respond to ACh as a 3 mg dose in a similar setting was able to further increase nitric oxide exhaled in air.7

All patients included in the current study had a vasodilatory response to ACh before CPB. Even though patients with coronary artery disease often have a systemic endothelial dysfunction the pulmonary circulation may be less affected.10 This is supported by the fact that the magnitude of basal nitric oxide output was similar to that of a group of healthy anaesthetized young females.11

Reduced vasodilation by ACh after CPB has been demonstrated before and interpreted as endothelial dysfunction but our findings of an unaltered exhaled nitric oxide response to ACh indicate an intact ability of the tissues involved to release nitric oxide.3 4 This suggests that the attenuated vasodilatory response could be partly independent of alterations in nitric oxide release. The mechanism behind these diverging responses to ACh was not further studied here but one could speculate in intercellular scavenging, preventing the produced nitric oxide from reaching the vascular smooth muscle or a diminished release of other mediators responsible for vasodilation, for example endothelium-derived hyperpolarizing factor.12 13

We chose to use ACh as the endothelium-dependent agonist in this study as it is rapidly degraded by acetylcholineesterases in the blood, thereby reducing the risk of systemic side effects and indeed, no such effects were observed.14

Basal exhaled nitric oxide
Both exhaled nitric oxide output and nitric oxide peak were reduced after CPB. Exhaled nitric oxide is highly flow dependent and according to the ‘two compartment model’ suggested by several investigators, it originates from alveolar and bronchial sources.1517 Changes in nitric oxide peak, which appears at end expiratory low flow rates (see Fig. 1), are more sensitive to changes in bronchial nitric oxide release while nitric oxide output represents both alveolar and bronchial sources.15 Our findings indicate a reduction in both alveolar and bronchial nitric oxide release after CPB.

The decreased ratio and the increased A–a gradient were probably caused by alveolar collapse and formation of atelectasis, which could explain the decrease in basal exhaled nitric oxide. Other explanations could be an attenuated NOS activity, an increased scavenging of nitric oxide or an increased diffusion barrier to the airway lumen. However, from the design of the current study we cannot fully explain the cause of the basal exhaled nitric oxide reduction.

Previous studies of exhaled nitric oxide in open-heart surgery and CPB reported decreased18 or unchanged19 20 exhaled nitric oxide. It is notable that the duration of CPB varied significantly between these studies and that endothelial function was not investigated. In the current study endothelial dysfunction correlated to the duration of CPB and of aortic occlusion. Thus, the diverging findings regarding basal nitric oxide after CPB could be caused by differences in duration of CPB and aortic occlusion. Taken together, changes in basal exhaled nitric oxide seem to be related to the severity of the ischaemia–reperfusion injury in this group of patients.

GTN-induced effects
After CPB, GTN-induced nitric oxide output decreased by more than 50% and the relative response correlated to the ACh-induced PVRI reduction. Since the enzymatic generation of nitric oxide from GTN is generally assumed to take place in the vascular smooth muscle cells (VSMC) GTN-induced nitric oxide is likely to be produced in regions where these cells are predominant, that is the pre-capillary small arteries.21 Our findings may suggest a reduced metabolic capacity of the enzymes involved in GTN conversion to nitric oxide. However, in a study by Kövesi and co-workers reduced exhaled nitric oxide and unchanged vasodilation upon GTN administration after CPB was reported, indicating intact nitric oxide formation within the VSMC.20 Therefore, other explanations are plausible; nitric oxide may react with free oxygen radicals, haem or sulphydryl groups during the ischaemia–reperfusion injury before reaching the airway lumen for detection in exhaled air. Tachyphylaxis to GTN cannot be excluded but seems unlikely as infusions of GTN were not administered and GTN bolus doses were low and repeated only three times over several hours.

A limitation of the current study was that we could not continue the measurements to follow reversal of the endothelial dysfunction, as the patients were weaned from the ventilator early after surgery. Reversal has been described after 8 h, a time period wherein most of our patients were already extubated.4 Another limitation was that the transient nature of the pulmonary vascular response to bolus injections of ACh did not allow for simultaneous measurements of PVRI and exhaled nitric oxide. Furthermore, it had been reported that exhaled nitric oxide increased considerably during occlusion of the pulmonary artery catheter in pigs.22 However, we did not see any such effect in this human study.

We conclude that in patients with open-heart surgery, pulmonary vascular dysfunction after CPB was accompanied by lower levels of basal exhaled nitric oxide and a reduction in the exhaled nitric oxide response to nitroglycerin. In contrast, the ACh-induced responses in exhaled nitric oxide were unchanged by CPB, which suggest that the endothelial dysfunction in these patients is not primarily related to nitric oxide release. We suggest that exhaled nitric oxide dynamics after pharmacological stimulation might be used to investigate pulmonary vascular dysfunction.


    Acknowledgments
 
This study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Research Council and funds from the Karolinska Institute. We wish to thank Professor Matteo Sofia for valuable comments.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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15 Tsoukias NM, George SC. A two-compartment model of pulmonary nitric oxide exchange dynamics. J Appl Physiol 1998; 85: 653–66[Abstract/Free Full Text]

16 Jorres RA. Modelling the production of nitric oxide within the human airways. Eur Respir J 2000; 16: 555–60[Abstract/Free Full Text]

17 Silkoff PE, McClean PA, Slutsky AS, et al. Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am J Respir Crit Care Med 1997; 155: 260–7[Abstract]

18 Ishibe Y, Liu R, Hirosawa J, Kawamura K, Yamasaki K, Saito N. Exhaled nitric oxide level decreases after cardiopulmonary bypass in adult patients. Crit Care Med 2000; 28: 3823–7[ISI][Medline]

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