Eur J Cardiothorac Surg 2004;25:766-771
© 2004 Elsevier Science NL
Effects of aminophylline on cytokines and pulmonary function in patients undergoing valve replacement
Wan-Jun Luo*,
Xiang Ling,
Ri-Mao Huang
Department of Cardiothoracic Surgery, Xiang Ya Hospital, Hunan Medical University, Changsha, Hunan 410008, China
Received 21 November 2003;
received in revised form 18 February 2004;
accepted 23 February 2004.
* Corresponding author. Tel.: +86-731-4327247; fax: +86-731-4327332
e-mail: luowanjun{at}yahoo.com
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Abstract
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Objective: This study is to evaluate the effects of aminophylline on systemic inflammatory response after cardiopulmonary bypass in patients undergoing valve replacement. Methods: Thirty patients undergoing elective valve replacement were randomized to receive either aminophylline treatment (aminophylline, n=15) or no aminophylline (control, n=15). Administration of aminophylline (5 mg/kg) was injected intravenously after induction of anesthesia and maintained with 0.5 mg/kg per h until the end of cardiopulmonary bypass. Perioperative cytokines (interleukin-8 and interleukin-10, tumor necrosis factor-
) and respiratory function, blood neutrophil count ratio of right atrium to that of left atrium, plasma malondialdehyde were measured during the experiment. Results: Interleukin-8 and tumor necrosis factor- levels after cardiopulmonary bypass were significantly lower in the aminophylline group than that in the control group (P<0.05, for each group), and interleukin-10 level in aminophylline group was significantly higher than in control (P=0.001). The respiratory index was greater in the control than in aminophylline group (P<0.05). Neutrophil count ratio of right atrium blood to left atrium blood and plasma malondialdehyde level in aminophylline group were much lower (P=0.02 and 0.001, respectively) than in the control 30 min after aortic declamping. Compared with control group, the duration of ventilation and intensive care unit stays were shorter in aminophylline group (P=0.032 and 0.013, respectively). Conclusions: Intraoperative administration of aminophylline had anti-inflammatory effect and improved pulmonary oxygenation in patients undergoing valve replacement.
Key Words: Cardiopulmonary bypass • Lung preservation • Aminophylline • Cell signaling protein
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Introduction
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The cardiac operations using cardiopulmonary bypass (CPB) cause the release of proinflammatory cytokines such as tumor necrosis factor-, interleukin-8 [1–4]. The release of proinflammatory cytokines were associated with the incidence of postoperative organ dysfunction or failure [5]. The previous study have showed that pulmonary dysfunction is associated closely with the release of proinflammatory cytokines [4]. Aminophylline, a xanthine derivative, has been used to treat asthma and chronic obstructive pulmonary disease for many years all over the world. Recently, aminophylline has been shown to have anti-inflammatory effects [6] and it inhibited the neutrophil adhesion to the capillary endothelium and reduce the generation of oxygen-derived free radicals [7]. The agent also suppressed the release of tumor necrosis factor- and interleukin-8 from human blood mononuclear cells [8] and improved functional recovery of isolated rat lungs after hypothermic preservation [9].
However, to date, effects of aminophylline on systemic inflammatory response (SIR) in open heart operations with CPB have not been investigated. We hypothesize that aminophylline also has anti-inflammatory effects and improve postoperative pulmonary function in patients undergoing valve replacement with CPB. The present prospective, randomized study was to evaluate the effects of aminophylline on the release of cytokines and pulmonary function in the patients undergoing valve replacement with CPB.
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1. Patients and methods
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1.1. Patients and operation
Between November 2002 and May 2003, thirty consecutive adult patients with rheumatic heart valve disease undergoing elective isolated valve replacement were randomly divided into two groups of 15 each. The patients were randomized by drawing prearranged cards in an envelope before anesthesia. A nurse of operating room performed the randomization and prepared the syringes of blinded solution. Only anesthesiologist and one nurse of operating room were aware of the treatment groups. All operations were performed by one surgeon (L.W.-J.). The patients signed a consent form approved by our hospital research committee before operation. Exclusion criteria for the experiment were infective valve disease, valve disease with coronary artery disease, reoperation of valve, chronic obstructive pulmonary disease. No patients received aspirin or corticosteroids preoperatively. Anesthesia was induced with midazolam and vecuronium bromide intravenously, and maintained with intravenous fentanyl intermittently and inhalation of isoflurane. All patients received aprotinin (50 000 u/kg) in the CPB priming solution. The operations were performed using standard hypothermic (28–31 °C) CPB with bicaval cannulation and left vent via right superior pulmonary vein. The myocardium was protected using intermittent antegrade cold blood cardioplegia via the aortic root or orifice of coronary artery. The mitral valve replacement was carried out via right atrial septal incision using continuous suture and aortic valve replacement was performed via aortic incision using intermittent suture. The criteria for extubation include the following: patients awake and obeying commands; stable hemodynamic state; urine flow of larger than 30 ml/h; no significant arrhythmia; no significant bleeding from chest tubes; rectal temperature of higher than 36 °C; arterial oxygen pressure of more than 75 mmHg on FiO2 of 0.4 and IMV of 6 breaths/min; normal arterial carbon dioxide pressure and pH.
The criteria in our hospital for discharge from the ICU include the following: no mechanical ventilation and arterial oxygen pressure of more than 75 mmHg and oxygen saturation as measured by pulse oximetry of 95% or higher with FiO2 of 0.4 or less; normal arterial carbon dioxide pressure; stable hemodynamic state without significant inotrope support (<5 ug/kg per min); no newly occurred arrhythmia; normal chest X-ray; no severe incisional pain and no significant fever (rectal temperature <38 °C); blood potassium of larger than 4.5 meq/l. The patients were usually discharged from the ICU after 24 h stay in the ICU if they meet above criteria; otherwise, the patients would stay in the ICU for another 1 night.
The aminophylline group (n=15) received aminophylline (5 mg/kg) intravenously immediately after induction of anesthesia at over 5 min period, and maintained with continuous intravenous administration of aminophylline at a rate of 0.5 mg/kg per h until the end of CPB. This dose of aminophylline is based on routine dose recommended for anti-asthma in the literature [25] and our results of pilot experiment before the present study. In the control group (n=15), the patients received same volume of normal saline instead of aminophylline. The hemodynamic data including heart rate, cardiac rhythm, blood pressure and airway pressure were monitored continuously during the administration of aminophylline or saline. The other side effects such as nausea, tremor, and seizure of aminophylline were also monitored.
1.2. Cytokines measurements
Blood samples were collected from the peripheral arterial lines after anesthesia induction but before administration of aminophylline at 1, 8, and 24 h after termination of CPB. All blood samples were drawn in vacuum tubes containing ethylenediamine tetraacetic acid for determination of interleukin-8, interleukin-10 and tumor necrosis factor-. The samples were immediately centrifuged at –4 °C. The plasma was transferred to a sterile polypropylene tube and stored at –70 °C until assayed. Interleukin-8, interleukin-10 and tumor necrosis factor- were measured by means of commercially available enzyme-linked immunosorbent assays according to the supplier's recommendations with checking standard curves for the Elisa measurements of the cytokines above (JingMei Biologic Engineering Company Ltd, Shenzhen, China). All samples were measured in duplicate. The correction of value was made for hemodilution.
1.3. Neutrophil count ratio and plasma malondialdehyde
The blood samples in the left and right atrium were drawn, respectively, for the routine neutrophil count before CPB and 30 min after aortic declamping. The plasma level of malondialdehyde (MDA) in the left atrium was determined by modified thiobarbituric acid method [10] at the same time as that of measurement of neutrophil count.
1.4. Hemodynamic and pulmonary function measurement
Mean arterial pressure, heart rate, central venous pressure, pulmonary artery pressure, cardiac index (CI, by thermodilution) were recorded routinely during the experiment. Arterial blood gas analysis was determined by standard techniques using automated analyzer (OPTI, USA) at anesthesia induction at 1, 8, and 24 h after termination of CPB. The respiratory index (RI) was calculated as follows: RI=A–aDO2/PaO2.
1.5. Statistical analysis
All data were expressed as mean±SD. Statistical analysis was performed with SPSS10.0 software (SPSS Inc, Chicago, IL). The unpaired Student's t-test or Mann–Whitney test and one- or two-way repeated measures analysis of variance (ANOVA) followed by Student–Newman–Keuls test if appropriate were used to test the difference for continuous variables. Catalogic data were analyzed using the 
2-test. Correlation between cytokine levels and RI at different time point of measurement was established by linear regression models. A P-value less than 0.05 was considered significant.
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2. Results
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2.1. Clinical outcomes
The preoperative clinical data are shown in Table 1. No significant differences were noted with regard to age, gender, NYHA class, liver and renal function in both groups.
The operative and postoperative data are shown in Table 2. Patients were similar with regard to type of procedures, bypass time, aortic claming time, chest drainage, transfusion and perioperative water balance between two groups. However, the duration on ventilator and length of intensive care unit stay in the aminophylline group were significantly shorter than that in the control group (P=0.03 and 0.01, respectively). Repeated measures ANOVA revealed that differences were not significant over time within groups and between groups for heart rate, mean arterial pressure, central venous pressure and CI (Table 3).
Early postoperative complications are shown in Table 4. There were no operative deaths in two groups. One patient in aminophylline group needed reopening for bleeding. One in control group had prolonged ventilation. No side effects related to aminophylline such as tachycardia, arrhythmia, and hypotension were observed in patients receiving aminophylline.
2.2. The levels of plasma cytokines
The plasma levels of cytokines are shown in Table 5. Repeated measures ANOVA revealed that differences were significant over time within groups in the plasma levels of tumor necrosis factor- (P=0.021) and the levels were much lower in aminophylline group than in control group. The differences between groups were found at 1, 8 and 24 h after CPB (P<0.05, respectively). Interleukin-8 was significantly different over time within groups (P=0.01) and were much higher in the control group at 1 and 8 h after CPB (P<0.05, respectively). The significant difference between groups (P=0.023) in the levels of interleukin-10 was found with repeated measures ANOVA and the interleukin-10 was much higher only at 1 h after CPB in the aminophylline group than in the control (P=0.001).
2.3. Neutrophil count ratio and malondialdehyde content
The changes of blood neutrophil count ratio (right atrium/left atrium) and malondialdehyde in two groups are shown in Table 6. The neutrophil count ratio and MDA content were much lower in the aminophylline group than that in the control group at 30 min after aortic declamping (P=0.02 and 0.001, respectively).
2.4. Pulmonary function
There are no significant differences with regard to the RI before CPB between two groups (Table 3). Repeated-measures ANOVA revealed that differences were significant over time within groups (P=0.025) and between groups (P=0.042). RI was much lower in the aminophylline group. Differences between groups in RI were at 1, 8 and 24 h after CPB (P<0.05, respectively). A significant correlation was found between RI and IL-8 (r=0.618, P<0.05) and TNF- (r=0.724, P<0.05) only at 1 h after CPB. No significant relationship was found between RI and IL-10.
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3. Comment
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Although coronary artery bypass operations can be performed without CPB, the CPB cannot be avoided in valve replacement operation. Many studies have proved that CPB induces SIR that leads to postoperative organ dysfunction especially for the lungs [4,5]. The SIR is characterized with the release of proinflammatory factors such as interleukin-6, interleukin-8 and tumor necrosis factor- during and after CPB [1,3], and this study further confirmed other authors' results [3]. Many approaches to reduce the CPB-induced SIR were investigated during open heart operation including depletion of leukocytes [11], heparin-coating of the extracorporeal circuit [12], and pretreatment with steroids [13].
Aminophylline is one of the most commonly used, effective and inexpensive agent to treat asthma. The recent study has shown that theophylline attenuated TNF- release from lipopolysaccharide-stimulated human peripheral blood mononuclear cells, and augmented release of interleukin-10, one of the anti-inflammatory factors [6]. In in situ animal study, theophylline given by intraperitoneum injection also inhibited the production of TNF- induced by lipopolysaccharide [14] and provided protective effect on hypothermic preservation of rat lungs [15]. To date, however, the effects of aminophylline on cytokines production in patients undergoing open heart operation with CPB have not been studied. In present study, we found that the plasma levels of TNF- and interleukin-8 after CPB were significantly suppressed in patients receiving aminophylline, whereas interleukin-10, one of an anti-inflammatory factor, was increased significantly in the aminophylline group patients. The patients receiving aminophylline also had better oxygenated function after CPB. The results suggested that aminophylline also had inhibitory effect on the release of proinflammatory factors in patients undergoing valve replacement.
The proinflammatory cytokines play an important role in pulmonary injury. The TNF- is one of the important proinflammatory factors to activate other synthesis of cytokines and to induce the expression of adhesive molecules in endothelial cells [16]. Interleukin-8 can induced neutrophil adhesion to the endothelium [16], whereas monoclonal antibody against IL-8 prevented lung from reperfusion injury in rabbits [17]. The previous study demonstrated that theophylline at a concentration of 10–3 M inhibited adhesion of neutrophil to the capillary wall, and reduced generation of oxygen-free radical from the neutrophil by 85% when compared with the control [7]. Yasui et al. [18] reported that theophylline induced neutrophil apoptosis and inhibited its migration to the pulmonary tissue. The present study showed that administration of aminophylline before and during CPB significantly ameliorated the sequestration of neutrophil in the lungs at 30 min after aortic declamping. Compared with the control group, the plasma MDA content representing partly the extent of lipid-oxidation also decreased significantly in patients receiving aminophylline. Whether the aminophylline ameliorate neutrophil sequestration in the lung by inhibiting the release of proinflammatory cytokines such as IL-8 and TNF- [19] or not deserved further study.
The mechanism of action of aminophylline in present study was not clear. It is well known that aminophylline is a phosphodiesterase inhibitor which elevates the intracellular cAMP levels [20]. The previous study in cardiac operation patients receiving aminophylline reported the plasma levels of cAMP were increased by more than two-fold times [21]. The increase of cAMP played an important role in modulating the cytokine production [22]. However, the mechanism of aminophylline in modulating the release of cytokines during open heart operations needs further investigation.
Because relatively low dose of aminophylline was used, no adverse effects such as hypotension, arrhythmia of aminophylline were observed in the present study except that the heart rate slightly increased when aminophylline was administered before CPB (data were not showed). Compared with other agents such as aprotinin and steroids, aminophylline is safe and cost-effective, and has no risk of increasing potential infection, thromoembolism, and allergic reactions. In addition, aminophylline was also used to neutralize the adverse effect of protamine in cardiac operation [23], improved the sinus node dysfunction in heart transplantation [24]. We think that anti-inflammatory effect of aminophylline may also be beneficial for the patients undergoing open heart operation.
This study is limited by the use of aprotinin. Aprotinin is well known to modulate the SIR associated with CPB. Although all patients in both groups received low dose of aprotinin, we cannot deny the possibility that aminophylline has an interaction with aprotinin which might interfere with the purity of the study. Second limitation of small size of our study is not sufficient to assess clinical outcomes such as intubation time, stay in ICU and postoperative pulmonary morbidity being low in our young low-risk patients. In addition, the mitral and aortic valve patients were not analyzed separately for the two groups of treatment due to the small number of patients, which may decrease the power of conclusion in present study, however, the types of procedure in both groups matched well. Aminophylline may be more beneficial for high-risk patients with complex, prolonged surgical procedures or with compromised pulmonary function. However, the final conclusion needs well-planned, large size and multicentric clinical trials. The third limitation is that serum levels of aminophylline and transpulmonary gradient of cytokines were not measured and so the working mechanism of aminophylline for its effect on lung injury cannot be clearly evaluated.
In conclusion, our primary study suggested that intraoperative administration of aminophylline reduced the release of proinflammatory factors and improved pulmonary function in patients undergoing valve replacement with CPB.
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Abstract
Introduction
