Eur J Cardiothorac Surg 2003;23:1040-1045
© 2003 Elsevier Science NL
Does sodium nitroprusside reduce lung injury under cardiopulmonary bypass?
Omer Cakira*,
Ahmet Oruca,
Sevval Erena,
Huseyin Buyukbayramb,
Levent Erdincc,
Nesimi Erena
a Department of Thoracic and Cardiovascular Surgery, Dicle University, School of Medicine, Diyarbakir, Turkey
b Department of Pathology, Dicle University, School of Medicine, Diyarbakir, Turkey
c Department of Biochemistry, Dicle University, School of Medicine, Diyarbakir, Turkey
Received 18 October 2002;
received in revised form 2 March 2003;
accepted 12 March 2003.
* Corresponding author. Fax: +90-412-248-8440
e-mail: omercak{at}dicle.edu.tr
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Abstract
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Objective: We hypothesized that direct pulmonary arterial infusion of sodium nitroprusside (SNP) would ameliorate lung injury under cardiopulmonary bypass. Methods: Experiments were performed on 12 adult mongrel dogs of both sexes weighing 20–28 kg. The animals were randomly divided into two groups of six animals each. All animals were subjected to total cardiopulmonary bypass (CPB) and moderate hypothermia (28°C core temperature). During total CPB, the aorta was clamped together with the pulmonary artery to prevent any antegrade flow to the lungs. After cardioplegic arrest for 120 min, the animals were rewarmed, weaned from CPB, and their condition stabilized for another 90 min. After the release of the aortic cross-clamp, the dogs received either a 5% glucose solution as a placebo (group I) or SNP (0.5 µg/kg per min) (group II), both infused into the pulmonary arterial line. The infusion was stopped after 60 min. To measure lung tissue malondialdehyde (MDA), water content and polymorphonuclear leukocytes count, lung tissue samples were taken before CPB and after weaning from CPB. In addition, alveolar-arterial oxygen difference (AaDO2) for tissue oxygenation was calculated by obtaining arterial blood gas samples. Results: Values of MDA before CPB of 42.0±5.3 nmol/g of tissue rose to 67.6±5.7 nmol/g of tissue after weaning from CPB in group I (P=0.028). In group II MDA values also increased from 43.1±4.3 to 52.4±5.7 nmol MDA/g of tissue after weaning from CPB (P=0.046). The MDA increase in group II after CPB was found to be significantly lower than that for group I (P=0.004). The wet-to-dry lung weight ratio in the sodium nitroprusside group was 5.1±0.2, significantly lower than in the control group (6.8±0.4), (P=0.01). AaDO2 increased significantly in group I (P=0.028). There was no statistically significant difference (P=0.065) between groups I and II. During histopathological examination it was observed that neutrophil counts in the lung parenchyma rose significantly after CPB in both groups. The increase in group I was significantly larger than that in group II (P<0.001). Conclusions: The results represented in our study indicate that pulmonary arterial infusion of sodium nitroprusside during reperfusion can reduce lung injury under cardiopulmonary bypass.
Key Words: Lung injury • Cardiopulmonary bypass • Sodium nitroprusside
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1. Introduction
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Despite extensive research into cardiopulmonary bypass (CPB), postoperative dysfunction of the lung remains a life-threatening problem. Previous studies have demonstrated that the direct contact of blood with the synthetic surface of the CPB circuit induces systemic inflammatory responses and a progressive accumulation of neutrophils in the pulmonary circulatory system, which are presently known to result in tissue injury mediated by neutrophil-endothelium interaction and oxygen-derived free radicals [1].
In experimental studies nitric oxide (NO) has been shown to reduce reperfusion injury [2,3]. In a clinical study of pediatric patients undergoing cardiac operations for congenital malformations, a reduction in complement activation during CPB was observed with sodium nitroprusside (SNP) [4]. This was responsible for the diminished rise in inflammatory parameters noted by the authors. This action seems to be independent of vasodilatation, but may be related to the capacity of NO to act as an oxygen radical scavenger [5]. The hypothesis of the present study was that the application of a NO donor reduces lung injury under cardiopulmonary bypass. In this study we investigated the effects of SNP administration on histopathologic neutrophil sequestration, water content, and malondialdehyde (MDA) values from lung tissue samples obtained before CPB and after from weaning CPB. In addition, alveolo-arterial oxygen difference (AaDO2) was calculated as an index of tissue oxygenation.
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2. Materials and methods
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All animals received humane care in compliance with the European Convention on Animal Care. The study was approved by the Institutional Ethics Committee.
2.1. Surgical procedure
Adult mongrel dogs of both sexes weighing 20–28 kg were initially anesthetized with intravenous sodium thiopental (20 mg/kg) followed by a continuous infusion of fentanyl citrate (0.3 µg/kg per min) and diazepam (0.03 mg/kg per min). Each dog was endotracheally intubated and the lungs ventilated with an oxygen fraction (FiO2) of 1.0 at a rate of 12 breaths/min. Esophageal and rectal temperatures were continuously recorded. The right femoral artery and vein were cannulated for arterial blood sampling and fluid administration, respectively. Heart rate, mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, pulmonary vascular resistance, and thermodilution cardiac output were recorded. Arterial blood gas and pH were measured at regular intervals during the experiment using the alpha-stat strategy. The left femoral artery was isolated and canulated with a 10F arterial cannula. After right lateral thoracotomy and heparinization (300 U/kg), the pericardium was opened and tented. The vena cavae were isolated, and the azygous vein was ligated. Superior and inferior vena caval cannulas (24F) were inserted transatrially into the right atrium and poised in the atrium so as not to impair venous return. A double-lumen aortic root cannula was inserted for cardioplegia delivery. The pump prime consisted of a balanced electrolyte solution. CPB was completed with a roller pump (Sarns 7000, USA), hollow fiber membrane oxygenator (Cobe, USA) and moderate hypothermia (28°C core temperature). During total CPB, the aorta was clamped together with the pulmonary artery to prevent any antegrade flow to the lungs. Ventilation was stopped at this stage. Full bypass flow was set at 100 ml/kg per min. Myocardial preservation was achieved through the antegrade administration of cold hyperkalemic blood (30 mEq/l K+) cardioplegic solution. After cardioplegic arrest for 120 min, the animals were rewarmed, weaned from CPB, and their condition stabilized for another 90 min. Ventilation was restarted 10 min before weaning from CPB, with an inspired oxygen fraction of 1.0. Intravenous protamine was administered.
2.2. Experimental protocol
The dogs were randomly divided into two groups. After the release of the aortic cross-clamp, the dogs received either a 5% glucose solution as a placebo (group I) or SNP (0.5 µg/kg per min) (group II); both were infused into the pulmonary arterial line. The infusion was stopped after 60 min.
Pulmonary vascular resistance (dynes/s per cm5)= 79.92xmean pulmonary arterial pressure – mean left atrial pressure/cardiac output) was measured before CPB and 60 min after CPB.
To measure lung tissue MDA, water content and polymorphonuclear leukocytes (PMNs) count, lung tissue samples were taken before CPB and 30 min after weaning from CPB. Samples (1x1 cm) were taken from the lower lobe of the left lung. One of the halves was kept at -70°C until needed for biochemical examination. The other half was placed in formalin solution for histologic examination.
2.3. Histologic evaluations
Tissue samples were fixed in 10% formolin and embedded in paraffin after a routine follow-up procedure. Sections with a width of 4 µm were cut from paraffin blocks and colored with hematoxylin and eosin (HE) before examination under light microscope (Olympus BX 50, Japan). For each sample, PMNs were counted for 20 different magnification areas. The total number of PMNs was divided by 20 to find the average number of PMNs per area.
2.4. Biochemical analyzes
To determine lipid peroxidation, the lung tissue samples were homogenized in a 1.15% KCl solution with an Ultraturrax homogenizer, after which 10% homogenized material was prepared. After this, 0.2 ml of 8.1% sodium dodecyl sulphate, 1.5 ml of 20% acetic acid, and 1.5 ml of 8.1% thiobarbituric acid solution were added to 0.2 ml of 10% homogenized material. After this mixture was expanded volumetrically to 4 ml with distilled water, it was kept in a boiling water bath for 1 h. Following these procedures, the mixture was cooled in a tap water bath, and 1 ml of distilled water and a 5 ml N-butanol/pyridine mixture were added. This newly formed mixture was shaken vigorously. The butanol phase was separated by centrifugation at 4000 rpm for 10 min, and absorbance of the colored complex was measured at 535 nm with a Shimadzu UV-1201 spectrophotometer. Lipid peroxidation was determined in the lung tissue homogenates with the thiobarbituric acid test as described by Ohkawa et al. [6], and the results were expressed in nanomoles of MDA, a last product of lipid peroxidation, per gram of wet tissue using a molar extinction coefficient of 1.56x105 at 535 nm for calculation purposes.
2.5. AaDO2 calculation
The alveolar-arterial oxygen difference for tissue oxygenation was calculated by obtaining arterial blood gas samples before CPB and 30 min after weaning from CPB according to the following formula:
where Pbar is the barometric pressure, FiO2 is the inspiratory oxygen fraction, and PaO2 and PcO2 are the arterial partial pressures for O2 and CO2, respectively.
2.6. Water content
The water content of the lung tissue was determined by taking lung biopsy samples and placing them on tissue paper to absorb the blood for 10 s. Samples were then weighed and desiccated for 3 days at 80°C. Postdessication weights were measured. The ratio of the weight before and after drying was calculated. This measure reflects lung water or pulmonary edema.
2.7. Statistical analysis
The results were evaluated as mean±SD. For statistical analysis, the Mann–Whitney U-test was used between the groups and the non-parametric Wilcoxon signed rank test was used for comparisons within the groups. The results were considered statistically significant for P<0.05.
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3. Results
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3.1. Hemodynamics parameters
Hemodynamic data for the two groups at baseline and at 60 min after CPB are summarized in Table 1. There were no group differences in any of the parameters at baseline.
3.2. MDA
There was no significant difference between the groups for the lung tissue values of MDA before CPB (P=0.57). MDA values before CPB of 42.0±5.3 nmol/g of tissue rose to 67.6±5.7 nmol/g of tissue after weaning from CPB in group I (P=0.028). In group II MDA values also increased from 43.1±4.3 to 52.4±5.7 nmol MDA/g of tissue after weaning from CPB (P=0.046). The MDA increase in group II following CPB was found to be significantly lower than in group I (P=0.004) (Fig. 1)
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Fig. 1. MDA levels in lung tissue, before CPB and after CPB in both groups. The MDA increase in group II after CPB was found to be significantly lower than in group I (P=0.004).
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3.3. PMN count
The PMN count in lung parenchyma was similar in both groups before CPB (P=0.6). After weaning CPB, the PMN count increased from 2.6±0.9/high power field to 9.1±4/high power field in group I (P<0.001) and from 2.4±0.9/high power field to 3.5±1.8/high power field in group II (P=0.039). After weaning from CPB, the count was significantly lower in group II than in group I (P<0.001) (Figs. 2 and 3)
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Fig. 2. PMN count in lung tissue, before CPB and after CPB in both groups. After CPB, the PMN count was significantly lower in group II than group I (P<0.001).
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Fig. 3. Microscopic findings of lungs after CPB (HE x200). A, Control group; and B, NAC group. Neutrophil infiltrations were marked in control group compared to NAC group.
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3.4. AaDO2
There was no statistically significant difference between the AaDO2 values of group I (244±18) and group II (237±20) before CPB (P=0.81). These values were 326±22 in group I (P=0.028) and 282±60 mmHg in group II (P=0.17) 30 min after weaning from CPB. There were statistically significant differences between the before and after CPB values in group II. Although the increase in group II was lower than in group I, this was not a statistically significant difference (P=0.065) (Fig. 4)
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Fig. 4. AaDO2 before CPB and after CPB. The values significantly increased in group I (P=0.028) after CPB. Although the increase in group II was lower than group I, there were not statistically significant difference (P=0.065).
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3.5. Water content
The wet-to-dry lung weight ratio in the sodium nitroprusside group was 5.1±0.1, significantly lower than in the control group (5.6±0.3), (P=0.01).
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4. Discussion
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It is a widely accepted concept that the exposure of blood to CPB is a cause of lung injury. An increasing number of studies have endorsed the view that the cessation of blood flow in the pulmonary arteries during total CPB has aggravated lung injury. Indeed, experimental studies have found that lung injury was much less severe at a lower level of blood flow deprivation in the pulmonary arteries during CPB or partial CPB than during total CPB. This could be ascribed to the hemodynamic features during total CPB, when the lung is perfused solely by the bronchial arterial system, with the lung being exposed to the risk of ischemic insult [7].
Despite a large number of studies, the specific pathophysiologic mechanism of ischemia-reperfusion injury remains unclear. However, it has been demonstrated that endothelial dysfunction, neutrophil activation, oxygen free radicals, platelet activation, and various cytokines are involved in ischemia-reperfusion injury [8–10]. The endothelium appears to play a critical role in maintaining vascular homeostasis in the ischemic heart [11] and lung [12].
Nitric oxide, identified as an endothelium-derived relaxing factor, has been recently purported to be an important physiologic regulator of microcirculation, as well as of vascular permeability [8,13]. Nitric oxide released from endothelial cells maintains vascular homeostatic properties by relaxing vascular smooth muscle cells [11]. NO interacts at the blood-endothelial interface to prevent the adhesion of both platelets and neutrophils to the normal vascular endothelium. Clinically, inhaled NO offers decreased ventilation-perfusion mismatch, improved oxygenation, and decreased pulmonary artery hypertension in patients with both acute lung injury and early allograft dysfunction following pulmonary transplantation [14]. In experimental studies NO has been shown to reduce reperfusion injury and, therefore, to act as a cardioprotective agent [5]. We hypothesized that low doses of SNP (0.5 µg/kg per min), a potent NO donor, would ameliorate lung injury under CPB.
Neutrophils play an important role in inflammatory response and in the damage that occurs with reperfusion. White cell depletion or neutrophil adhesion blockade before the reperfusion of ischemic hearts decreases infarct size. On leukocyte-depleted blood reperfusion, Breda and associates [15] reported improved myocardial function after ischemia, and Wilson and colleagues [16] reported reduced myocyte damage and better ventricular systolic function following global myocardial ischemia.
With respect to post-CPB lung injury, Johnson and associates [17] demonstrated that dogs treated with either indomethacin or a leukocyte filter before partial CPB had better arterial oxygenation after CPB than untreated dogs. Bando and associates [18] found that leukocyte depletion can reduce lung injury after total CPB. The tissue samples from control dogs showed intravascular leukocyte aggregation, perivascular hemorrhaging, and focal alveolar injury. These changes were minimal or absent in the leukocyte-depleted group. Gillinov and colleagues [19] demonstrated a significant reduction in lung injury with NPC 15669 (neutrophil adhesion blocker), manifested by a lack of pulmonary vasoconstriction, improved arterial oxygenation, absence of neutrophil sequestration, and lower lung edema. We detected a clear increase in the number of lung neutrophils after weaning from CPB in both groups (control group: from 2.6±0.9 to 9.1±4.0 and SNP group: from 2.4±0.9 to 3.5±1.8). However, this increase in the SNP group was significantly lower than in the control group (P<0.001). In our study, AaDO2 increased in the control group after separation from CPB compared to the SNP group; however, this increase was not statistically significant (P=0.065).
Malonaldehyde, an important decomposition product of lipid peroxides, is an indirect measure of free radical activity [20]. Increased lipid peroxidation, a marker of free oxygen radical damage, was indeed observed in our study after CPB tended to increase these products, as would be anticipated. Clark et al. [21] have experimented with single lung transplantation models, using pentoxifylline in the reperfusion infused intravenously. In this study, malonaldehyde values were significantly higher in the lungs of the control group compared with those of the pentoxifylline group. Johnson and associates [17] demonstrated that dogs treated with a leukocyte filter before partial CPB had significantly lower malonaldehyde values than those of the control group.
In cardiac patients, the optimal timing for intervention with a donor of NO is unclear in the literature. Inhibiting the production of endogenous NO was found to have the greatest effect when started with postischemic reperfusion [22]. On the other hand, it was reported that reperfused heart recovery was greatest when NO was supplemented before cardioplegia, and that application during reperfusion may even be detrimental [23]. In another study performed on the basis of animal studies the best results were obtained with a short-term postischemic application of a NO donor [5]. Massoudy and colleagues [2,24] in two separate studies found that the administration of SNP (0.5 µg/kg. min) for both the first 20 min and first 60 min of reperfusion to patients undergoing coronary artery bypass grafting led to a reduction in the acute inflammatory response. In these studies, the effect was achieved without any systemic hemodynamic changes being observed.
Yamashita and associates [3] demonstrated that SNP administration in the flush solution and during reperfusion improves lung allograft function and blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. In addition, King and colleagues [25] demonstrated that a pulmonary arterial infusion of low-dose SNP (0.5 µg/kg per min) during lung reperfusion alone significantly improved pulmonary hemodynamics, oxygenation, compliance, and edema formation. In our study, pulmonary vascular resistance in group I was higher than group II after CPB, but there were not statistically significant difference (P>0.05).
In conclusion, an anti-inflammatory action is described for SNP in total cardiopulmonary bypass. However, we believe that the effect of SNP in lung tissue after CPB needs to be further evaluated. A larger cohort of cases is needed to draw better conclusions, and further experiments with lower and/or higher doses of SNP are required to obtain more reliable results.
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Abstract
1. Introduction
