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Ann Thorac Surg 2001;71:631-635
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Cardiac ischemic preconditioning improves lung preservation in valve replacement operations

Guohu Li, MDa, Shenxi Chen, MDa, Erxiong Lu, MDa, Wanjun Luo, MDa

a Department of Cardiothoracic Surgery, Xiangya Hospital, Hunan Medical University, Changsha, Hunan, China

Accepted for publication June 28, 2000.

Address reprint requests to Dr Li, Department of Cardiothoracic Surgery, Xiangya Hospital, Hunan Medical University, Changsha 410008, Hunan, China
e-mail: guohu-li{at}cs.hn.cn


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Previous work has shown that cardiac ischemic preconditioning reduces cardiac reperfusion injury. We investigated whether cardiac ischemic preconditioning can improve lung preservation in patients who undergo valve replacement.

Methods. Forty patients with rheumatic heart disease requiring valve replacement were randomly divided into two groups. Twenty patients received two cycles of 3 minutes of aortic cross-clamping and 2 minutes of reperfusion before cardioplegic arrest (group IP), and 20 patients underwent 10 minutes of cardiopulmonary bypass (group C, control group). Blood samples from the pulmonary vein were collected to measure levels of polymorphonuclear leukocytes, superoxide dismutase, malonedialdehyde, and thromboxane B2, and arterial oxygen tension. Blood samples from the coronary sinus were used to measure calcitonin gene–related peptide values. Hemodynamic data were recorded by a pulmonary artery Swan-Ganz catheter. Lung tissue was collected after 1 hour of reperfusion to evaluate morphology. Clinical outcome data were recorded.

Results. In group C (cardiopulmonary bypass and cardioplegic arrest), the levels of polymorphonuclear leukocytes, thromboxane B2, malonedialdehyde, and calcitonin gene–related peptide were increased after 1 hour of reperfusion, whereas the value for superoxide dismutase was decreased. In group IP, preconditioning attenuated the increase in polymorphonuclear leukocytes, thromboxane B2, and malonedialdehyde (p < 0.05) and increased superoxide dismutase and calcitonin gene–related peptide levels (p < 0.05). Preconditioning also increased arterial oxygen tension and cardiac index compared with controls (p < 0.05) and decreased mean pulmonary artery pressure and pulmonary vascular resistance index (p < 0.05). Histologic findings showed less lung injury and a lower polymorphonuclear leukocyte count in group IP than in group C (p < 0.05). Group IP had fewer postoperative pulmonary complications and a shorter intubation time.

Conclusions. Cardiac ischemic preconditioning improves lung preservation in patients having valve replacement. The mechanism may be that cardiac ischemic preconditioning reduces the accumulation of polymorphonuclear leukocytes in lung tissue and decreases the formation of oxygen free radicals.Key Words: Ischemic preconditioning; lung injury; open heart surgery; calcitonin gene–related peptide.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Although technical progress has made valve replacement operations for rheumatic heart disease safer than before, postoperative pulmonary dysfunction still develops in many patients even after successful intracardiac procedures [1]. This may be associated with damage caused by cardiopulmonary bypass (CPB). During CPB and cardioplegic arrest, the lungs have virtually no circulation except for the limited perfusion provided by the bronchial arteries, and the temperature of the lungs is not reduced much during hypothermic CPB; thus, lung tissue undergoes normothermic ischemia and is subjected to ischemia-reperfusion injury.

Many studies have focused on the role of neutrophils in postbypass pulmonary injury and pulmonary ischemia-reperfusion injury [2–5]. We [4, 5] have recently shown that ischemic preconditioning of the lungs can reduce pulmonary reperfusion injury and that inhibition of neutrophil activation is one of the main protective effects. It is well known that ischemic preconditioning of the heart improves myocardial protection [6, 7], and in 1999, it was reported that preconditioning of other organs such as the kidneys [8] and the intestine [9] protects the myocardium. In the present study, we investigated whether cardiac ischemic preconditioning could protect the lungs of patients undergoing valve replacement.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
The clinical trial was approved by both the university scientific association and the local ethics committee of Hunan Medical University. Written informed consent was obtained from each patient before inclusion in the study.

Patient selection
Forty patients with rheumatic heart disease undergoing valve replacement with a mechanical prosthesis were prospectively entered into the study. None of the patients were smokers, none were having a reoperation, and none were receiving medication affecting neutrophil function or free radical generation. They did not have coronary artery disease, a major noncardiac-related illness, or primary pulmonary disease. Preoperative lung function was not reduced and was similar between patients. The patients were randomly divided into two equal groups, the treatment group receiving ischemic preconditioning (group IP) and the time-matched control group (group C).

Operative procedures
Anesthesia was uniformly induced with a standard combination of fentanyl citrate and pancuronium bromide and maintained with intravenously administered propofol and inhalation of isoflurane. The lungs were mechanically ventilated with a volume-cycled respirator (Ohmeda Excel-210) with an inspired oxygen fraction in air of 0.5. Arterial pressure was monitored through the left radial artery. A pulmonary artery Swan-Ganz catheter was introduced through the right internal jugular vein and connected to a monitor (Spacelabs Inc model 90303B). The electrocardiogram and body temperature were also monitored. The extracorporeal circuit was primed with a crystalloid-albumin-blood solution, and CPB was conducted with nonpulsatile flow (Stöckert III) employing a membrane oxygenator (Sarns Inc).

After initiation of CPB, group IP underwent two cycles of 3 minutes of aortic cross-clamping (effective left ventricular decompression by intracardiac drainage) followed by 2 minutes of reperfusion. Group C underwent 10 minutes of CPB under the same conditions of flow and left ventricular venting, which was accomplished through a right superior pulmonary vein catheter, as in group IP. Thereafter, the venae cavae were snared, the aorta was cross-clamped, and cardioplegic arrest was started with intermittent cold (4°C) blood cardioplegia and maintained by reinfusion every 15 minutes during the valve replacement period of cardiac arrest. After operation, ventilation was continued in the intensive care unit with a volume-cycled respirator (inspired oxygen fraction, 0.5).

Measurement of hemodynamic data
Before CPB and after 1 hour of reperfusion hemodynamic data (cardiac index, mean pulmonary artery pressure, pulmonary vascular resistance index) were recorded from the pulmonary artery Swan-Ganz catheter.

Collection and assay of blood samples
Before CPB and after 1 hour of reperfusion, blood samples were collected from the right superior pulmonary vein to measure levels of superoxide dismutase and malonedialdehyde (chemical analysis with commercial kits; Nanjing Jiangzheng Biological Engine Institute, China), polymorphonuclear leukocytes, and thromboxane B2 radioimmunoassay commercial kit; East Asia Immune Technological Institute, Beijing, China) and to perform blood gas analysis (Ciba Corning model 288, blood gas system). Blood samples were collected from the coronary sinus before CPB, after ischemic preconditioning or after 10 minutes of CPB, at the beginning of reperfusion, and after 1 hour of reperfusion to measure calcitonin gene–related peptide levels (radioimmunoassay commercial kit; Beijing East Asia Immune Institute, China)

Microscopic observation of lung tissues
After reperfusion for 1 hour, lung tissue from the same location in 10 patients in each group was collected. The biopsy specimens were stained with hematoxylin and eosin. For quantitative analysis of tissue damage, the sections were examined in blind fashion by a pathologist. Each section was coded randomly, and 50 microscopic fields using a magnification x400 were employed for analysis. The number of alveoli in each field was totaled, and the presence of exudate, erythrocytes, and leukocytes was determined in each alveolus. An alveolus was considered damaged when it contained exudate, more than two leukocytes, or more than two erythrocytes. The overall severity of alveolar injury was evaluated as the ratio of the number of damaged alveoli to the total number of alveoli in the 50 microscopic fields along with a morphologic evaluation of disruption in alveolar structure.

Statistical analysis
All data are presented as the mean ± the standard deviation. Comparisons between groups were made by Tukey’s test and {chi}2 test where appropriate. Differences were considered significant when the p value was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
There were no significant differences between groups with respect to sex, age, preoperative cardiac function, aortic cross-clamp time, and time on CPB (Table 1).


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  		Table 1. Summary of Patient Dataa,b

 
Biochemical variables
After 1 hour of reperfusion, polymorphonuclear leukocyte count, malonedialdehyde level, and thromboxane B2 value increased in both groups, but ischemic preconditioning reduced these increases (p < 0.05). Group IP had higher superoxide dismutase and arterial oxygen tension values than controls after 1 hour of reperfusion (p < 0.05) (Table 2). Calcitonin gene–related peptide levels were similar between groups before CPB, but the value was increased in group IP at the end of the preconditioning period, at the beginning of reperfusion, and after reperfusion for 1 hour compared with controls (p < 0.05) (Table 3).


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  		Table 2. Summary of Biochemical and Hemodynamic Data for the Two Groupsa

 

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  		Table 3. Changes in Calcitonin Gene–Related Peptide Levelsa,b

 
Hemodynamic data
Cardiac index tended to increase in group C after 1 hour of reperfusion, but the rise was much more apparent in group IP (p < 0.05). Mean pulmonary artery pressure increased after 1 hour of reperfusion in controls, whereas ischemic preconditioning attenuated this increase (p < 0.05). At the same measurement time, pulmonary vascular resistance index was significantly lower in group IP than in group C (p < 0.05) (see Table 2).

Lung histological findings
In control patients, lung tissue obtained after 1 hour of reperfusion showed multifocal areas of interstitial and intraalveolar pulmonary edema, intraalveolar hemorrhage, and intravascular and perivascular neutrophil accumulation. In preconditioned patients, there was less pulmonary edema and hemorrhage, and the number of polymorphonuclear leukocytes in lung interstitium was reduced (Table 4).


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  		Table 4. Quantification of Alveolar Injury and Polymorphonuclear Leukocytes in Lung Interstitiuma

 
Early clinical observations
There were no operative deaths (up to 30 days postoperatively) in either group. Patients in group IP had fewer postoperative pulmonary complications, a shorter postoperative period of mechanical ventilation, and a reduced need of pharmacological inotropic support than patients in group C (Table 5).


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  		Table 5. Early Clinical Outcomea,b

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Ischemic preconditioning has been described not only for the myocardium [6, 7] but also for the lungs [4, 5] and other organs [8–10]. Beneficial cardiac effects of preconditioning the human heart during open heart surgical procedures have been demonstrated [6, 7], It has been shown that regional ischemic preconditioning protects remote virgin ischemic myocardium [11] and that ischemia in remote organs, such as the kidneys and intestine, can protect the myocardium against infarction. The mechanism may be mediated by adenosine, activation of a neurogenic pathway, or capsaicin-sensitive nerves [8, 9, 12]. Our results indicate that cardiac ischemic preconditioning reduces mean pulmonary artery pressure, pulmonary vascular resistance, lung tissue injury, and postoperative pulmonary complications. In this study, preconditioning also increased arterial oxygen tension and reduced intubation time. On the basis of our research, we believe cardiac ischemic preconditioning can improve lung preservation in patients undergoing valve replacement.

Pulmonary injury associated with CPB is complex and multifactorial in pathogenesis. The accumulation and activation of neutrophils in inflammatory and ischemic-reperfused lungs may be important mediators of injury [13]. When blood comes in contact with the foreign surfaces of the CPB circuit, neutrophils can be activated by complement split products, proinflammatory cytokines, platelet-activating factor, and arachidonic acid metabolites [13]. Activated neutrophils can damage lung tissues by release of proteolytic enzymes, generation of oxygen free radicals, and production of arachidonic acid metabolites [13]. Some researchers have used mechanical leukocyte filtration [2], heparin coating of the bypass circuit [14], or drugs that inhibit neutrophil adhesion [3] to reduce pulmonary injury in CPB and have found that neutrophils are important mediators of CPB–associated pulmonary damage. Inhibition of neutrophil–endothelial cell adhesion is a promising new modality for reducing lung injury associated with CPB, as it leads to suppression of alveolar and interstitial edema, microatelectasis, and other pulmonary abnormalities [13].

Thromboxane B2, the stable metabolite of thromboxane A2, can be produced by activated endothelial cells or by platelet-leukocyte interaction. The lungs are a major site of thromboxane synthesis. Thromboxane A2 induces pulmonary vascular contraction and platelet aggregation, which can lead to pulmonary hypertension and can increase microvascular permeability [15]. Inhibition of thromboxane synthesis in sheep undergoing CPB reduced lung injury [16].

In the present study, cardiac ischemic preconditioning decreased the number of neutrophils in the pulmonary venous blood and lung interstitium, which can reduce the activation of polymorphonuclear leukocytes. Preconditioning reduced oxygen free radical formation in pulmonary venous blood, as evidenced by decreased contents of the lipid peroxidation product malonedialdehyde and increased superoxide dismutase levels. Further, preconditioning reduced thromboxane B2 formation. These findings suggest that cardiac ischemic preconditioning can reduce lung injury and improve lung function through these protective mechanisms.

Calcitonin gene–related peptide may be an endogenous myocardial protective substance. It has been proposed that the effects of calcitonin gene–related peptide on the myocardium may result from a reduction in calcium overload and inhibition of lipid peroxidation [17]. Calcitonin gene–related peptide inhibits the response of human neutrophils to substance P through the inhibition of IP3 (inositol 1,4,5-triphosphate)–induced Ca2+ release from intracellular Ca2+ stores, and reduces substance P–induced superoxide anion production [18]. Pretreatment with calcitonin gene–related peptide or exogenous oxygen free radicals can protect the myocardium against injury elicited by oxygen free radicals, and this effect is related to the activation of protein kinase C [19]. Activation of protein kinase C is believed to be a key event in ischemic preconditioning [20]. Calcitonin gene–related peptide also has a protective effect on renal ischemia-reperfusion injury by decreasing membrane lipid peroxidation [21]. Tang and colleagues [9] showed that a brief period of anterior mesenteric artery occlusion caused an increase in the plasma level of calcitonin gene–related peptide–like immunoreactivity and reduced myocardial infarct size. In the present study, ischemic preconditioning of the heart increased the production of calcitonin gene–related peptide, and this may have contributed to reducing lung tissue injury and preserving lung function in group IP.

In summary, the results presented here suggest that cardiac ischemic preconditioning may improve lung preservation in patients having valve replacement. The possible mechanism is that ischemic preconditioning reduces both the accumulation of polymorphonuclear leukocytes in lung tissue, and the formation of oxygen free radicals.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by a grant from the Scientific Committee of Hunan Province, China.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  8. Takaoka A., Nakae I., Mitsunami K., et al. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of "remote preconditioning". J Am Coll Cardiol 1999;33:556-564.[Medline]
  9. Tang Z.L., Dai W., Li Y.J., Deng H.W. Involvement of capsaicin-sensitive sensory nerves in early and delayed cardioprotection induced by a brief ischaemia of the small intestine. Naunyn Schmiedebergs Arch Pharmacol 1999;359:243-247.[Medline]
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  11. Przyklenk K., Bauer B., Ovize M., Kloner R.A., Whittaker P. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893-899.[Abstract/Free Full Text]
  12. Gho B.C., Schoemaker R.G., van den Doel M.A., Duncker D.J., Verdouw P.D. Myocardial protection by brief ischemia in noncardiac tissue. Circulation 1996;94:2193-2200.[Abstract/Free Full Text]
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