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A prospective randomized trial to determine the effects of steroid on the incidence of postoperative… Prasongsukarn, Kriengchai 2002

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A PROSPECTIVE RANDOMIZED TRIAL TO DETERMINE THE EFFECTS OF STEROID ON THE fc INCIDENCE OF POSTOPERATIVE ATRIAL FIBRILLATION AFTER CORONARY ARTERY BYPASS GRAFTING SURGERY (CABG) B Y KRIENGCHAIPRASONGSUKARN, MD M.D., Mahidol University, Thailand, 1992 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF SURGERY We acceptftfiis thesis a$ conforming to the required standard UNIVERSITY OF BRITISH COLUMBIA VANCOUVER, BRITISH COLUMBIA DECEMBER 2001 © Kriengchai Prasongsukarn, 2001 I ABSTRACT Background Atrial fibrillation remains one of the most common postoperative complications of coronary artery bypass grafting (CABG). Because of the additional hospital costs associated with this arrhythmia, owing to increased use of antiarrhythmic medications, diagnostic studies, and prolonged hospitalization, this subject continues to draw the interest of cardiac surgeons and cardiologists. Despite many clinical studies, there is still no consensus regarding the best prevention strategy for this arrhythmia. There are several mechanisms that explain why atrial fibrillation occurs after C A B G , still the pathophysiological mechanism remains unclear, and therefore mutifactorial causes are likely. One of the mechanisms that we believe is inflammation around the sac of the heart and surgical trauma, including the generalized inflammation response induced by the heart-lung machine. As we know, steroid can decrease the body's response to trauma and inflammation and may reduce the chance of atrial fibrillation occurring. For this reason we design the study to assess the short-term effect of steroid on the incidence of postoperative atrial fibrillation after C A B G . Methods This study was done during the time from August 2000 to February 2001 .Eighty-eight consecutive consenting patients were prospectively entered into a randomized, double blind, placebo-controlled trial to determine the efficacy of steroid on the incidence of atrial fibrillation after elective coronary artery bypass grafting. No patient had documented or suspected arrhythmias preoperatively. Two patients were excluded from the study due to Off-PumpCABG, forty-three patients 11 received 1 gm of methyprednisolone before surgery and 4 mg of dexamethasone every 6 hours for one day after surgery, and forty-three patients received only placebo. Results Postoperative atrial fibrillation occurred in 9 of the 43 patients in the steroid group (21 percent) and 22 of the 43 patients in the placebo group (51 percent) (p=0.003). Minor postoperative complications occurred in 15 steroid patients (34 percent) and in 6 patients receiving placebo (14 percent). Major complications occurred in 4 patients who received steroid (9 percent) and in 2 who received placebo (5 percent) (p=0.052) Patients with atrial fibrillation were hospitalized for significantly longer days than were patients with normal sinus rhythm (median 8Vs.6 days, p=0.002); however, the length of hospital stay in Steroid group was 6 days compare with 7 days in Placebo group (p=0.337). Conclusions The use of prophylactic Short-Term Steroid Administration in patients undergoing coronary bypass grafting surgery reduced the incidence of postoperative atrial fibrillation by approximately 50 percent. Patients without postoperative atrial fibrillation had a shorter length of hospital stay. Overall, there was no significant difference between Steroid Group and Placebo Group with regard to the length of hospital stay. In this study, we found that Steroid had higher complications which may contribute to prolonged hospitalization. • * « 111 Table of contents Abstract \L Table of Contents l v . List of Tables ^ List of Figures Vlll Acknowledgements X Chapter 1. INTRODUCTION Overview 1 Epidemiology 1 Pathophysiology 6 Potential Preoperative Markers for the Risk of developing.Atrial Fibrillation after CABG 19 Sequelae 29 Prophylaxis 34 Chapter 2. OBJECTIVE OF THE THESIS 39 Possible mechanism of inflammatory response of cardiopulmonary bypass 40 Steroid and inflammatory response process 42 Research plan 44 Study hypothesis 44 Primary outcome 45 Secondary outcome 45 Benefit 45 Study design 46 Material and Methods Sample size Patient Selection Steroid administration Operative technique Hemodynamic Measurement and Monitor Statistics Breaking the code-Interim analysis Estimated duration of study Data base form Result Postoperative atrial fibrillation Complication Length of Hospital stay Risk Factors of Postoperative AF Discussion References List of Tables Table 1. Risk Factors by Univariate Logistic Regression Analysis. 23 Table 2. Independent Risk Factors for the Development of Postoperative Atrial Arrhythmias. 24 Table 3. Patient Characteristics. 58 Table 4. Number of Atrial Fibrillation patients of two groups. 59 Table 5. Number of Episode of Atrial Fibrillation of two groups. 59 Table 6. Number of sex of Patients of two groups. 61 Table 7. Number of Congestive Heart Failure Patients of two groups. 61 Table 8. Number of Myocardial Infarction Patients of two groups. 62 Table 9. Number of Chronic Obstructive Lung Disease Patients of two groups. 62 Table 10. Number of Asthma Patients of two groups. 63 Table 11. Number of Smoking Patients of two groups. 63 Table 12. Number of Chronic Renal Failure Patients of two groups. 64 Table 13. Number of Hypertension Patients of two groups. 64 Table 14. Number of A-Pacing Patients of two groups. 65 Table 15. Number of AV-Pacing Patients of two groups. 65 Table 16. Number of Bypass Grafts in Patients of two groups. 66 Table 17. Left Ventricular Ejection Fraction of Patients in Each Group in Detail. 66 Table 18. Patients Characteristics in Age, Cross clamp time, and Bypass time. 67 Table 19. Complications in Each Group in Detail. 69 Table 20. Number of Complication Patients in Detail. 70 Table 21. Number of White Blood Cell Count at 12-hour postoperative period of two groups. 71 Table 22. Number of White Blood Cell count at 24-hour postoperative period of two groups. 72 Table 23. Length of Hospital stay compare between normal sinus rhythm and atrial fibrillation patient. 73 Table 24. Length of hospital stay compare between steroid group and placebo group. 75 Table 25. Risk factors by multivariate logistic regression analysis 77 Table 26. Univariate analysis in myocardial infarction between NSR and AF patient. 78 Table 27. Univariate analysis in congestive heart failure between NSR and AF patient. 78 Table 28. Univariate analysis in A-pacing between NSR and AF patient. 79 Table 29. Univariate analysis in AV-pacing between NSR and AF patient. 79 Table 30. Univariate analysis in chronic obstructive lung disease between NSR and AF patient. 80 Table 31. Univariate analysis in age, cross-clamp time, and bypass-time between NSR and AF patient. 80 vii List of Figures Figure 1. Time of occurrence of atrial fibrillation after coronary artery bypass grafting. 4 Figure 2. Atria showing a composite map of the distribution of effective refractory periods (ERPs) in 14 dogs before cardiopulmonary bypass. 10 Figure 3. (A) Distribution of the preoperative ERPs in a dog. 12 Figure 3. (B) Distribution of the postoperative ERPs in the same dog. 12 Figure 4. Simultaneous measurement of the temperatures of the atrial septum and the ventricular septum during the first 10 minutes of cardioplegic arrest in a C A B G patient. 14 Figure 5. Univariate logistic regression analysis in age and incidence of postoperative atrial arrhythmia. 21 Figure 6. Univariate logistic regression analysis in aortic cross-clamp time and incidence of postoperative atrial arrhythmia. 22 Figure 7. (A) ICU and nursing ward hospitalization compare between NSR and atrial arrhythmia patients. 31 Figure 7. (B) Number of ventricular arrhythmia patients, permanent pacemaker implantation, and postoperative stroke compare between NSR and atrial arrhythmia patients. 32 Figure 8. Relationship between duration of hospitalization and development of postoperative atrial fibrillation. 33 Figure 9. Incidence of postoperative atrial fibrillation compare between steroid - and placebo group. 60 Vill Figure 10. Percentages of major and minor complication in steroid and placebo group. Figure 11. Mean score length of hospital stay compare between NSR and AF patient. Figure 12. Mean score length of hospital stay compare between steroid and placebo group. ACKNOWLEDGEMENTS I dedicate this thesis to my mother and father, Porntip and Prasong Prasongsukarn, who have always encouraged me to strive, and to Taddao and Amie Prasongsukarn, who understand and had the patience to see this journey through with me. I 'm much obliged to Anandamahidol Foundation who sponsors me to pursue my study in Cardiac Surgery in Canada. I am grateful to Samuel V. Lichtenstein MD.PhD.FRCSC, James G. Abel MD.MSc.FRCSC who educated me in the science and art of the profession and taught me the operations, including giving their constant guidance and support. In particular, special thanks to my Supervisory committee James A. Russell MD.FRCPC, Keith R.Walley MD.FRCPC, Stanley K K . Tung MD.FRCPC, who have provided much encouragement, support and constructive criticism as my experiments and my thesis took shape. I would like to thank the ICU research nurse (Carol), Kanya R N for helping me collect the data. Finally, I would like to thank Min, Lilian for her expertise in the statistical analysis, and to Donny for his help in the computer program. X CHAPTER 1 Introduction Overview Few problems are more common or recalcitrant than atrial fibrillation after cardiac surgery. This postoperative complication is the major reason for hospital stays that exceed 4 days after coronary artery bypass surgery. Partly because of its frequency, and therefore its familiarity, postoperative atrial fibrillation is commonly considered to be more nuisance than a potentially serious complication. Nowadays the increased mean age of patients undergoing open-heart surgery is expected to result in an increase incidence of postoperative atrial fibrillation and greater costs for the management of these patients. Epidemiology Supraventricular arrhythmias are common after all major surgical procedures, including thoracic and abdominal surgical procedures. The incidence of atrial fibrillation and atrial flutter was reported by Favaloro et al. to be 12 % in the first 100 patients undergoing C A B G at the Cleveland clinic from 1967 to 1968(1). The incidence of supraventricular arrhythmias was reported to be 4% by Goldman in a large registry of patients undergoing major noncardiac surgery (2). A multicenter study of patients undergoing 1 abdominal aortic aneurysm repair reported an incidence of supraventricular arrhythmias of 3.2%, and in a prospective study of 295 patients undergoing thoracotomy for lung cancer, the incidence of supraventricular arrhythmias was almost 13% (3,4). Data published during the past decade show an incidence of atrial fibrillation after C A B G that varies considerably between studies, ranging from 5% to 40% (5). A recent preliminary report from the Cleveland Clinic cited an incidence of postoperative atrial fibrillation of 19% in 42 patients undergoing minimally invasive cardiac surgery, which was similar to the incidence of atrial fibrillation for patients undergoing C A B G using standard techniques (6). Two recent prospective multicenter studies of C A B G from the 1990s reported an incidence of postoperative atrial fibrillation between 27% and 33% (7,8). The incidence of atrial fibrillation is higher in patients undergoing valve replacement with or without C A B G , occurring in 30% to 70% of patients. The incidence of postoperative atrial fibrillation has varied markedly between trials owing mostly to the intensity and duration of postoperative monitoring. A meta-analysis by Andrews et al (9) reported a 27% incidence of postoperative atrial fibrillation in the control group. However, atrial fibrillation was documented in 41% of patients using continuous electrocardiographic (Holter) monitoring compared with only 20% in patients using other forms of electrocardiographic monitoring. Mathew et al(10) also reported an incidence of 27% in a multicenter trial involving 2,265 patients undergoing elective coronary artery bypass graft surgery. Creswell et al reviewed 6 years of data and reported an incidence of 32% in 2,833 patients 2 undergoing coronary artery bypass surgery (11). Of note, this incidence was 60% in patients undergoing coronary plus aortic valve surgery and 64% in patients having combined coronary and mitral valve surgery. We looked at the incidence of atrial fibrillation postoperative C A B G in our province. The data from B.C. Cardiac registry from 1993 to 1998 showed the incidence of atrial fibrillation after Coronary artery bypass surgery at St.Paul's hospital was 43.5%. Atrial fibrillation may occur at any time after C A B G , but generally occurs 2-4 days after open-heart surgery (7,8). The episodes generally tend to be transient, short-lived, frequent, and recurrent. Atrial fibrillation occurs less commonly immediately (less than 24 hours) or late (greater than 5 days) after bypass surgery with a time course approximating a bell-shaped curve and the peak occurring 2-4 days after surgery (Fig 1). Episodes may recur or persist for weeks before finally resolving spontaneously. Up to 10% to 15% of patients with post-CABG atrial fibrillation are discharged from the hospital with atrial fibrillation. It is rare for chronic atrial fibrillation to develop after C A B G . 3 30 0 1 2 3 4 5 6 6+ Post Op Day Figure 1 Time of occurrence of atrial fibrillation after coronary artery bypass grafting. (From Aranki SF, Shaw DP, Adams DH, et al: Predictors of atrial fibrillation after coronary artery bypass surgery. Current trends and impact on hospital resources. Circulation 94:390-397.1996) Patients undergoing cardiac surgery may be categorized into 3 groups, depending on their vulnerability to the development of postoperative atrial fibrillation (12). The percentages quoted below are all approximate but are based on those reported in the literature. Groupl. Five percent of patients undergoing any type of surgery will develop postoperative atrial fibrillation. These are patients who undergo peripheral 4 vascular surgery, abdominal surgery, orthopedic surgery, and so forth, and develop postoperative atrial fibrillation. Clearly, these patients enter surgery with an underlying propensity to develop postoperative atrial fibrillation regardless of the type of surgery performed. Group 2. Thirty-five percent of patients develop atrial fibrillation after cardiac surgery if untreated, but atrial fibrillation can be controlled in all but 5% of patients by a variety of prophylactic measures. This irreducible level of 5% postoperative atrial fibrillation represents the patients in Group I. The remaining patients, with a rate of around 30%, represent those patients in Group 2 whose postoperative atrial fibrillation can be prevented by appropriate prophylactic measures. Group3. The remaining 65% of patients will not develop atrial fibrillation after cardiac surgery no matter the complexity of the surgical procedure. Clearly, these patients do not have the underlying vulnerability, whatever that may be, that makes Group 1 patients invariably have postoperative atrial fibrillation and that makes Group 2 patients have it unless prophylaxed against it. Because Group 1 patients invariably develop postoperative atrial fibrillation and Group 3 patients never develop it, the only patients in whom prophylactic measures are of any potential importance are those in Group 2, ie, in only 30% of patients undergoing cardiac surgery. Furthermore, the best result that such an intervention can attain is a rate of approximately 5%, ie, the irreducible level of postoperative atrial fibrillation caused by the intractability of the Group 1 patients. 5 Pathophysiology Multiple mechanisms have been proposed to be responsible for the pathogenesis of atrial fibrillation in the postoperative setting (13). These mechanisms include acute atrial distension or inflammation from the trauma of surgery; alteration in autonomic tone from surgery and the stress of the postoperative period; ischemic injury to atria as a result of surgery and/or inadequate protection during bypass; electrolyte and volume shifts during bypass resulting in changes in repolarization; inflammation resulting from pericarditis; and a variety of other electrophysiologic changes that may occur as a result of the bypass procedure, the cardioplegia, or the surgery itself that all may result in a lower atrial fibrillation threshold. The pathophysiology of atrial fibrillation in the nonsurgical setting has been intensively studied. One of the more widely held theories is the multiple wavelet hypothesis advanced by Moe(14). This theory proposes that atrial fibrillation is the result of multiple wavelets caused by reentry that move through the atria constantly colliding or extinguishing themselves, and reforming or combining with new wavelets. Mapping studies in animals and humans have demonstrated these multiple wavelets, whose course is dictated by atrial conduction, refractoriness, and excitability (15). The wavelets are believed to be primarily functionally determined, and a predisposition to atrial 6 reentry is caused by a combination of several factors including heterogeneity of conduction in the atria, large atrial size, alterations in electrical coupling in the atrial myocardium, and fixed anatomical obstacles. The mechanism of postoperative atrial fibrillation is less well defined. Multiple mechanisms likely play a role. Several electrophysiologic changes that may predispose to atrial fibrillation have been documented to occur in the postoperative setting. For example, Chung and colleagues have performed a series of studies before and after bypass showing suppressed sinus node function after C A B G (16,17). These investigators have also demonstrated a variety of changes in atrial refractoriness and conduction latency in patients undergoing C A B G that may predispose them to have atrial fibrillation develop (17,18). Sato et al. found prolongation of atrial conduction times during the first 2 hours after bypass in the canine heart (19). Several groups have used prolonged P wave duration measured directly from the surface E C G or with signal averaging techniques as an index of intraatrial conduction delay and shown that it correlated with an increased incidence of postoperative atrial fibrillation (20,21). A practical limitation to relying on these observations for screening patients preoperatively is the lack of standardization of P-wave measurements and the absence of commercially available P-wave signal averaging equipment. There is one recent theory from Cox et al that explained the cause of postoperative atrial fibrillation (12). In an effort to elucidate the cause of postoperative atrial fibrillation, they performed a series of experiments in the 7 1980s(22-30) and 1990s(19) in which several assumptions were made. The first assumption was that the underlying vulnerability to the development of postoperative atrial fibrillation was a preexisting electrophysiological abnormality. The second assumption was that the degree of derangement of this electrophysiological abnormality was most severe in Group 1 patients, less severe in Group 2 patients, and nonexistent in Group 3 patients. They hypothesized that in Group 1 patients, the electrophysiological abnormality was so severe that atrial fibrillation would occur after any type of surgery including noncardiac surgery. They further hypothesized that the less severe electrophysiological abnormality in Group 2 patients had to be activated by some trigger associated with cardiac surgery per se before it would lead to atrial fibrillation. This, they believed, would also explain why Group 2 patients develop postoperative atrial fibrillation if they are not prophylaxed but do not develop it if appropriate prophylactic measures are taken. Finally, this uniform theory of postoperative atrial fibrillation included the absence of postoperative atrial fibrillation in Group 3 patients because they did not have the underlying electrophysiological abnormality. The experiments mentioned identified an underlying electrophysiological abnormality that was consistent with their theory. That abnormality related to the manner in which the atrial myocardium recovered in different areas after the completion of electrical activation. The period of time between electrical activation of the atrium and complete repolarization of the atrium is called the refractory period. However, the atrial refractory period is not a singular entity but rather it varies from one part of the atrium 8 to another. By performing a complex series of stimulation tests, the local refractory periods for sites all over the atrium can be determined. There is normally an orderly progression from the relatively short refractory periods of the left atrium to the relatively long refractory periods of the right atrium. This orderly progression can be plotted to determine the so-called dispersion of refractoriness in the atria. 9 (Fig2) 110 120 130 140 150 160 Figure 2.Atria showing a composite map of the distribution of effective refractory periods (ERPs) in 14 dogs before cardiopulmonary bypass. The 10 lower panel shows the posterior view of the atria. The upper panel represents the anterior surface of the atria shown as if a sagittal section had been taken through both atria and the anterior portion of the atria was flipped up to show their surfaces. The area of shortest ERPs was in the posteroinferior left atrium below the pulmonary veins. The area of longest ERPs was in the inferior aspect of the posterior right atrium. ANT, anterior; POST, posterior; L A A , left atrial appendage; R A A , right atrial appendage; M , mitral valve; T, tricuspid valve; SVC, superior vena cava; IVC, inferior vena cava; PV, pulmonary veins, from Sato et al. The effect of augmented atrial hypothermia on atrial refractory period, conduction, and atrial flutter/fibrillation in the canine heart. JThorac Cardiovasc Surg 104: 297- 306, 1992. Under normal circumstances, there are no areas in the atrium where short and long refractory periods lie in close apposition. However, i f the dispersion of refractoriness is nonuniform, it results in areas where atrial myocardiums with a short refractory period lie adjacent to an area of atrium with a long refractory period (Fig 3A). This would appear to be the major underlying electrophysiological abnormality that causes the atria to be vulnerable to the development of postoperative atrial fibrillation (Fig 11 3B). Figure 3. (A) Distribution of the preoperative ERPs in a dog. There is some similarity between this ERP distribution map and the composite shown in Figure 2. However, the area immediately beneath the inferior pulmonary veins shows several regions where relatively long refractory periods lie in close proximity to regions of relatively short refractory periods. Despite these findings, no arrhythmias could be induced by programmed electrical stimulation in this dog preoperatively. (B) Distribution of the postoperative ERPs in the same dog. Note the greater nonuniformity (heterogeneity) of distribution of the ERPs after cardiopulmonary bypass in this animal. The asterisks mark the sites where a single prematurely paced beat induced atrial fibrillation in this animal postoperatively. The lower panel shows the posterior view; the upper panel represents the anterior surface. 1 2 ANT, anterior; POST, posterior; L A A , left atrial appendage; R A A , right atrial appendage; M , mitral valve; T, tricuspid valve; SVC, superior vena cava; IVC, inferior vena cava; PV, pulmonary veins. (From Sato et al: The effect of augmented atrial hypothermia on atrial refractory period, conduction ,and atrial flutter/fibrillation in the canine heart; J Thorac cardiovasc Surg 104:297-306,1992) Because of several clinical observations, they were strongly suspicious that the trigger mechanism necessary to activate the underlying electrophysiological mechanism was ischemia of the atrial myocardium during the period of cardioplegic arrest. Although major efforts are expended intraoperatively to maintain the temperature of the ventricular myocardium at acceptable levels of hypothermia during the period of cardioplegic arrest, little or no attention is usually paid to the level of hypothermia in the atrial myocardium. Because the atrial myocardium is also susceptible to ischemic injury, they decided to evaluate its degree of protection with cardioplegia, suspecting that it would be dismal. Indeed, they found that after an infusion of cardioplegia, the level of hypothermia attained in the atrial septum is invariably less than that in the ventricular septum and that within 2 to 3 minutes after cessation of cardioplegia infusion, the temperature of the atrial septum returns to the temperature of the systemic perfusion (Fig 4). Knowing that such inadequate hypothermia in the ventricles would likely cause ventricular failure (and perhaps ventricular fibrillation) postoperatively, it is 13 reasonable to assume that the incidence of atrial fibrillation would be increased by such blatantly, inadequate protection of the myocardium during the period of cardioplegic arrest. Once this observation was made, they felt that the likely trigger for bringing out the underlying vulnerability to atrial fibrillation in Group 2 patients was atrial myocardial ischemia (23). 14 Figure 4. Simultaneous measurement of the temperatures of the atrial septum and of the ventricular septum during the first 10 minutes of cardioplegic arrest (cardioplegia temperature = 4 C) in a patient undergoing an uncomplicated coronary artery bypass procedure. The systemic perfusion temperature was 30 C at the time the aorta was cross clamped (0.0 time). Note that the atrial septal temperature never reached the degree of hypothermia attained in the ventricular septum. In addition, within 2 to 3 minutes of cessation of cardioplegia infusion (bottom of initial downslope of each curve), the atrial septal temperature had returned to nearly the temperature of the systemic perfusate.(From Cox JL: A perspective on postoperative atrial fibrillation: Semin Thorac Cardiovasc Surg 11:299-302,1999) Since they first proposed atrial myocardial ischemia as the trigger for the development of postoperative atrial fibrillation in vulnerable patients, some doubt has been expressed regarding this theory. Nevertheless, the fact that other triggers may exist does not rule out the possibility of atrial ischemia being at least one of those triggers. Furthermore, it is irrelevant to their observation that an abnormal dispersion of refractoriness in the atria is the underlying electrophysiological abnormality that makes some patients vulnerable to the development of postoperative atrial fibrillation. In summary, it is their belief that Group 2 patients come to the operating room with an inherent electrophysiological abnormality (nonuniform 15 dispersion of refractoriness) that makes them vulnerable to the development of postoperative atrial fibrillation. Because the abnormality is of intermediate severity, some trigger mechanism (perhaps atrial ischemia) is necessary to activate that vulnerability, resulting in postoperative atrial fibrillation. In the absence of such a trigger, or i f the trigger is suppressed or overcome prophylactically, postoperative atrial fibrillation will not develop in these patients. Because Group 1 patients will always develop atrial fibrillation and Group 3 patients will never develop it, the Group 2 patients are the only ones with which we should concern ourselves as cardiac surgeons. Despite what would appear to be a reasonably clear picture of the underlying electrophysiological abnormality that makes some patients more vulnerable than others to the development of postoperative atrial fibrillation, many limitations in their knowledge remain. For example, essentially all of the electrophysiological observations described earlier were made in animal experiments and, therefore, may have limited applicability in humans. The reason that refractory period distribution maps such as those shown in Figures 2 and 3 have not been performed in humans is that the process is an extremely laborious one requiring several minutes of programmed electrical stimulation and recording at each electrode site on the atria. In the case of the animal data shown in Figures 2 and 3, there were approximately 250 electrodes on the atrial surfaces and the entire process took several hours. This is obviously not feasible in humans. Therefore, even if the theory is correct, there is no way of identifying those patients before surgery who are vulnerable to the development of postoperative atrial fibrillation. 16 Again, assuming that their theory regarding the vulnerability of atrial fibrillation is true, other questions remain regarding why the abnormal dispersion of refractoriness is present in some patients and not in others. For example, is it congenital or acquired? The increasing incidence of postoperative atrial fibrillation with increasing patient age suggests that the problem is acquired. Is it owing to a defective gene, a chemical imbalance in the atrial myocardium, an abnormality in the autonomic input to the heart, an anatomic substrate such as fibrosis, hypertrophy, or stretch of the atrium, or a maldistribution of atrial receptor sites? Until this question is answered com-pletely, the problem of postoperative atrial fibrillation is likely to persist. In the meantime, we can only attempt to prevent postoperative atrial fibrillation in the 30% of patients who are vulnerable to developing it and in whom it is preventable. Decreasing the incidence of postoperative atrial fibrillation after cardiac surgery to 5% is a worthy and attainable goal. Another mechanism that explained the cause of atrial fibrillation in patients undergoing C A B G is a significant increase in epinephrine and norepinephrine levels measuring for up to 3 days in the postoperative period (31,32). This hyperadrenergic state may contribute to increased automaticity and increased frequency of premature atrial contractions, serving as a "trigger" for episodes of atrial fibrillation. Postoperative withdrawal of beta-adrenergic blockers has also been postulated as a predisposing cause. However, investigators have not been able to demonstrate any direct 17 correlation between the elevation of catecholamines and the development of atrial fibrillation in patients. The time course of the development of atrial fibrillation parallels the development of postoperative pericarditis, which through acute inflammation may alter atrial coupling and lead to transient structural or electrophysiologic changes that predispose patients to atrial fibrillation. It has been difficult to study the relationship between pericarditis and atrial fibrillation because the diagnosis of atrial pericarditis is dependent on relatively nonspecific clinical and E C G findings. The ability of pericarditis to induce atrial flutter and atrial fibrillation is clear from animal models. The sterile pericarditis model in dogs is a well-established animal model of atrial flutter that, as the name suggests, relies on pericardial inflammation from pericardiectomy and pericardial irritation to induce atrial flutter (33). The high incidence of pericardial effusions (up to 85% in some studies), as well as the time course of pericarditis in animal models and humans, suggests that further investigation into the role of pericardial inflammation contributing to postoperative atrial fibrillation is necessary (34,35). 18 Potential Preoperative Markers for the Risk of developing Atrial Fibrillation after CABG There were several studies shown the risk factors associated with postoperative atrial fibrillation. One study from Creswell et al, reviewed their experience at the Barnes Hospital from January 1,1996 through December 31,1999(36). During that period, a total of 4,507 adult patients underwent cardiac surgeries that required the use of cardiopulmonary bypass. A univariate logistic regression analysis was performed to identify risk factors that were associated with the development of postoperative atrial arrhythmias (table 1). Independent risk factors for the development of postoperative atrial arrhythmias were analyzed in table 2. These risk factors were reduced to a relatively small set: increasing patient age, preoperative use of digoxin, history of rheumatic heart disease, history of chronic obstructive pulmonary disease, and increasing aortic cross-clamp time. In addition, some studies show a history of congestive heart failure and a history of preoperative atrial fibrillation increase the risk of developing postoperative atrial fibrillation (41,43,44). Increasing patient age has consistently been the most commonly identified risk factor for the development of postoperative atrial arrhythmias and their experience confirms the finding of other investigators (37-42). To show the effect of increasing patient age on the development of postoperative atrial arrhythmias, they used the univariate regression coefficient and 19 intercept to create a graph that might be useful for predicting the risk for an individual patient (figure 5). This curve is sigmoidal, with a low incidence of postoperative atrial arrhythmias for patients younger than 40 years of age and a steep increase in the incidence in patients between 45 and 85 years of age. (Only 3.7% in patients younger than 40 years compared with 28 % of patients 70 years) A similar graph was constructed to show the effect of increasing aortic cross-clamp time of the incidence of these arrhythmias (Figure 6). This curve is nearly linear, with a small increase in incidence for increasing aortic cross-clamp times. Although this effect is statistically significant, the effect is small and the increase in the incidence of these arrhythmias caused by increasing patient age is obviously much greater. 20 100 - i Figure 5. The slope and intercepts from a univariate logistic regression model were used to construct a graph of the predicted incidence of postoperative atrial arrhythmias according to patient age. (From Creswell L L : Hazards of postoperative atrial arrhythmias. The Annals of Thoracic Surgery 1993, vol.56, 539-549,1993). 21 100 —i Figure 6. The slope and intercepts from univariate logistic regression model were used to construct a graph of the predicted incidence of postoperative atrial arrhythmias according to the period of aortic cross clamping. (From Creswell L L : Hazards of postoperative atrial fibrillation: The Annals of Thoracic Surgery 1993, vol. 56, 539-549,1993). 22 Table 1. Risk Factors by Univariate Logistic Regression Analysis R isk Factor P- Value Patient age <.001 Race <.00l Number of myocardial infarctions <.01 Type of angina <.001 Digoxin use, preoperatively <.001 Previous cardiac surgery <.001 Chronic renal insufficiency <.01 Peripheral vascular disease <.001 Hypertension <.0l Historv of rheumatic fever <.001 Chronic obstructive pulmonary disease <.001 History of stroke <.05 History of smoking <.001 Ejection fraction <.001 Left ventricular end-diastolic pressure <.001 Cardiopulmonary bypass time <.001 Aortic cross-clamp time <.05 {The Annals of Thoracic Surgery 1993. vol.56, 539-549) 23 Table 2. Independent Risk Factors for the Development of Postoperative Atrial Arrhythmias • Increasing patient age • Preoperative use of digoxin • History of rheumatic heart disease • Chronic obstructive pulmonary disease • Increasing aortic cross-clamp (ischemic) time From Creswell LL:Postoperative atrial arrhythmias: Risk factors and associated adverse outcomes: Semin Thorac Cardiovasc Surg 11:303-307,1999 Insight into the role of atrial preservation or atrial ischemia may be gained by searching for a relationship between the various aspects of surgical technique and their relationship to the incidence of atrial fibrillation (45). One hypothesis proposes that atrial ischemia secondary to inadequate protection of atrial myocardium, or prolonged aortic cross clamp time may predispose patients to the development of postoperative atrial fibrillation. Several studies have shown an increased incidence of atrial fibrillation with increased cross-clamp or total pump time, but other studies have found no relationship (8,45). Other factors that may influence the incidence of atrial fibrillation are the type and volume of cardioplegia used to afford myocardial protection and the method of cannulation. Several small studies have examined the incidence of 24 atrial fibrillation with cold cardioplegia, crystalloid cardioplegia, blood cardioplegia, intermittent aortic cross-clamping time, and diltiazem containing cardioplegia(46-48). No consistent or only small differences in the incidence of atrial fibrillation with different types of cardioplegia were discovered in these studies. Considerable work is ongoing to further study the electrophysiologic effects of different methods of providing cardioplegia to the heart. The method of cardiac cannulation for delivery of cardioplegia will also affect atrial preservation. No clear-cut advantage has been demonstrated for single vs. bicaval cannulation on the incidence of atrial fibrillation (8,49). Other surgical variables that have been associated with a higher incidence of atrial fibrillation include bypass grafting to the right coronary artery, concomitant right coronary artery endarterectomy, use of the internal mammary artery graft, pulmonary vein venting, and postoperative atrial pacing (7,8,44). In a preliminary report from a large multicenter study, frequent preoperative premature atrial contractions (PACs) were a risk factor for post-CABG atrial fibrillation (50). The major limitation to most of these studies is the small sample size or failure to determine whether the surgical variable is independent of poor left ventricular function and age. These issues will only be clarified by analyzing the results of large, prospective multicenter registries comparing different surgical techniques in patients at high risk for having postoperative atrial fibrillation develop. 25 The role of preoperative digoxin in changing the incidence of atrial fibrillation has been reviewed in several large series. In one large recent report of 2,833 patients undergoing C A B G , the incidence of postoperative atrial fibrillation was 32% in patients not taking digoxin preoperatively and 44% in patients taking preoperative digoxin (P< 0.001)(39). In another study, preoperative use of digoxin was a univariate but not a multivariate predictor of the development of atrial fibrillation. The major limitation of these analyses is that the reason for preoperative digoxin use is often unclear. It is possible that most of these patients were taking digoxin because of a history of previous atrial fibrillation, which is also a risk factor for postoperative atrial fibrillation. Because histopathological examination of cardiac myocardium can identify degrees of cellular injury less severe than frank necrosis, A d et al felt that postoperative atrial fibrillation might be predictable on the basis of preoperative histological abnormalities in the atrial myocardium. In the ventricular myocardium, changes such as muscle fiber atrophy, myolysis (sarcomere loss), fiber disarray, cellular and/or interstitial edema, and perinuclear intracellular vacuolation can be identified when the ventricle is exposed to toxic and/or ischemic insults(51-56). Unfortunately, much less is known about morphological correlates of mild damage in the atrial myocardium. Therefore they designed the study to identify the histopathophysiological changes in atrial cardiomyocytes that might predict the development of atrial fibrillation during the postoperative period. Atrial 26 tissue from 60 patients was sampled before and after cardiopulmonary bypass. Fifteen patients(25%) developed postoperative atrial fibrillation. Histologically, there were 3 findings in the atrial myocardium that were more common in patients who developed postoperative atrial fibrillation:(l) vacuolation size (p=.017), (2) vacuolation frequency (p=.0136), and (3) lipofuscin content (p=.013)(57). In this study, they hypothesized that susceptibility to the development of postoperative atrial fibrillation might derive from preexisting metabolic deficits in the atrium and, therefore, examined the atrial myocardium for such changes. Their working hypothesis was that it might be possible to detect histopathological markers in the atrial tissue that would serve as predictors for postoperative atrial tachyarrhythmias. By identifying such markers i f present, a more selective approach to prophylaxis would then be possible. They chose vacuolation of atrial myocardium and lipofuscin accumulation in atrial myocardium as the potential markers for increased vulnerability to the development of postoperative atria fibrillation. Lipopigment storage is considered to be a part of the ubiquitous process of aging(52) and affects especially postmitotic cells such as neurons and cardiac myocytes(53) This pigment represents the end product of lysosomal degradation, and is causally associated with the long-term oxygen free radical attacks upon cellular lipids(54). However, in the present study, they did not observe any association between the subjective estimation of the lipofuscin accumulation and the chronological age of the patient. 27 Vacuolation of cardiac cells has been described in multiple conditions of mild, reversible damage to cardiac cells, both in man and experimental animals, including exposure to toxic stimuli, (55) or hypoxia and ischemia(56,5 8-60). On the other hand, the occasional finding of vacuoles in cardiac cells with no known disease led other investigators to consider this vacuolation as an insignificant aging phenomenon(59). Despite its being a potential marker of damage, vacuolation has not been previously correlated with a clinical postoperative outcome and has been studied in man only in ventricular cells and not in atrial cells. Although the findings in this study strongly suggest that vacuolation is a predictor of vulnerability to the development of postoperative atrial fibrillation, further investigation in larger numbers of patients is required to confirm this association. If confirmed in a larger series of patients, these findings may have several potential outcomes. Better predictability of the risk for developing atrial fibrillation may lead to better monitoring of vulnerable patients, and possibly to better treatment. Preventive antiarrhythmic drugs, that are not recommended for the treatment of all patients after cardiac surgery, may be indicated for those patients at higher risk for developing atrial fibrillation. The impression that the staining intensity of lipofuscin, the aging pigment, might also be associated with the risk of developing atrial fibrillation also merits attention. It should be noted that, at the narrow range of ages of patients in their study, no correlation was found between lipofuscin 28 levels and chronological age. It is possible that lipofuscin reflects aging processes in the cells better than the actual chronological age of the patient. On the other hand, it is possible that vacuolation accentuates the visibility of lipofuscin, so that the correlation between atrial fibrillation and this pigment reflects another facet of the correlation between vacuolation and atrial fibrillation. The mechanism of the initiation of postoperative atrial fibrillation is still unknown, but this study indicates that the metabolic status of the atrium, reflected in its morphology, is a major determinant in the pathogenesis of this frequent complication of cardiac surgery. Sequelae Long-term sequelae of postoperative atrial fibrillation are unusual; however, major complications may occur in a small percentage of patients. The most serious complications are thromboembolic events, especially stroke. Creswell et al(40) showed that postoperative atrial fibrillation was associated with an increased incidence of postoperative strokes compared with patients without atrial fibrillation (3.3% vs 1.4%, P<.0005). This association was independent of age. In addition, atrial fibrillation can result in hypotension or congestive heart failure, an increased incidence of ventricular arrhythmias(tachycardia or fibrillation), and an increased need for the placement of a permanent pacemaker. However, the most common complication of postoperative atrial fibrillation is an increased length and 29 cost of hospitalization (Figure7). In a single patient, atrial fibrillation is not the most expensive complication of cardiovascular surgery, but its high incidence results in a cumulative cost that exceeds all other complications. Aranki et al(8) found that the length of hospitalization in creased by 4.9 days as a direct result of atrial fibrillation (Figure 8). This translated into an additional $10,055 in hospital charges per patient. Therefore, any inter-vention that would reduce the incidence of postoperative atrial fibrillation would result in a tremendous economic benefit. 30 ICU Nursing Ward • Without Atrial Arrhythmias ^ With Atrial Arrhythmias Figure 7. (A) Patients with postoperative atrial arrhythmias experienced a longer intensive care unit (ICU) and nursing ward hospitalization. (From Creswell L L : Hazards of postoperative atrial fibrillation. The Ann Thorac Surg 56:539-549,1993) 31 • Without Atrial Arrhythmias ^ With Atrial Arrhythmias p<0.0005 V-Tach/V-Fib Pacemaker Stroke Figure 7. (B) Patients with postoperative atrial arrhythmias increased frequency of ventricular tachycardia (V-Tach) or ventricular fibrillation (V-Fib), permanent pacemacker implantation, and stroke. (From Creswell L L : Hazards of postoperative atrial arrhythmias: The Annals of Thoracic Surgery 1993, vol. 56,539-549). 32 50 5 6 7 8 9 10 >10 Length of Stay (days) Figure 8. Relationship between duration of hospitalization and development of postoperative atrial fibrillation (AFIB). (From Aranki SF, Shaw DP, Adams DH, et al: Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 94:390-397, 1996) 33 PROPHYLAXIS A variety of agents have shown to be effective in preventing the occurrence of atrial fibrillation in this setting. The most solid evidence for atrial fibrillation prophylaxis exists for the effectiveness of beta-blockers. In 1988, Lauer reported from a survey of chiefs of cardiothoracic surgery that 44% were using beta-blockers for atrial fibrillation prophylaxis in the postoperative setting (5). Hesitancy to use beta-blockers probably represents the increasing prevalence of elderly patients with poor left ventricular function and other relative contraindications to beta-blocker use among those who are now currently undergoing C A B G . A variety of beta-blockers including propanolol, timolol, metoprolol, nadolol, and acebutolol have been found effective when administered postoperatively to prevent or decrease the number of episodes of atrial fibrillation (61-63). Two meta-analyses of beta-blockers have confirmed the beneficial effects of their prophylactic administration. Andrews et al. selected 24 of 69 studies that had adequate control groups or proper randomization procedures and reported a decrease in the incidence of post-CABG atrial fibrillation from 34% to 8.7% (P < 0.0001) in 1,549 patients receiving prophylactic beta-blockers (64). Their analysis suggested beta-blocker 34 therapy was of most benefit in patients at greatest risk of hemodynamic compromise from atrial fibrillation (e.g., those patients with left ventricular dysfunction). Kowey's meta-analysis of 7 trials included 2,482 patients and showed a reduction in the incidence of supraventricular arrhythmias from 20% to 9.8% in patients taking beta-blockers (P < 0.001)(65). Various definitions of atrial fibrillation are used in different studies, with some varying from 30 seconds to several minutes in length. The effect of the time of initiation and dose of beta-blocker on the incidence of atrial fibrillation does not seem to be important. A final concern they have is the relevance of applying the results of studies done mostly during 1970-1980 to the current practice of cardiac surgery. The patients now being operated on are older, sicker, and have more severe underlying cardiac disease. Additional trials are needed to determine the safety and efficacy of beta-blocker prophylaxis in this patient population. Digoxin does not appear to have a consistent effect on the prevention of postoperative atrial fibrillation (66,67). Meta-analyses of the prophylaxis trials using digoxin showed no significant benefit of digoxin use in the prevention of atrial fibrillation. There are no placebo-controlled, double-blind trials of digoxin as a prophylactic agent for atrial fibrillation. A combination of digoxin and beta-blockers caused a greater reduction in the incidence of atrial fibrillation, suggesting a possible synergism between the two agents. Studies with oral verapamil and a meta-analysis of oral verapamil have failed to show any effect of this agent on preventing atrial fibrillation 35 (64,68,69). Oral verapamil was, however, shown to cause a lower ventricular rate, but higher rates of hypotension and pulmonary edema were also seen. In a small-randomized study of IV diltiazem vs. IV nitroglycerin, there was a lower incidence of atrial fibrillation in the patients who received IV diltiazem (70). Studies of the efficacy of magnesium in preventing post-CABG atrial fibrillation have shown variable results. Two placebo-controlled trials of IV magnesium beginning immediately in the postoperative setting failed to show any benefit (71,72). Others have found a benefit of IV magnesium when levels were increased to 2.0 mEq/L or more, but in general this difference is small. The mechanisms by which magnesium may have an effect on the incidence of atrial fibrillation are unknown. Amiodarone has also been shown to be beneficial in the prevention of postoperative atrial fibrillation. Daoud et al (73) administered oral amiodarone for at least 7 days before elective cardiac surgery. As a result, the incidence of postoperative atrial fibrillation decreased from 53% to 25% (P = .003). This was associated with a decreased length and cost of hospitalization. In addition, complication rates were similar in the 2 groups. Because many cardiac surgical patients cannot delay their surgery for 1 week to receive oral amiodarone, the Amiodarone Reduction in Coronary Heart (ARCH) Trial was performed (74). In this study, patients received intravenous amiodarone immediately after surgery. Once again, this resulted 36 in a reduction in the incidence of postoperative atrial fibrillation (47% vs. 35%), without significant morbidity or mortality. Antiarrhythmic agents such as procainamide, quinidine, and propafenone have also failed to significantly impact on the incidence of postoperative atrial fibrillation. (75-77) Nonpharmacological interventions have also been attempted because the use of beta-blockers and amiodarone may be limited by bradycardia, heart block, hypotension, and bronchospasm. As a result, atrial pacing has been studied to prevent postoperative atrial fibrillation (78-80). Gerstenfeld et al showed that continuous right atrial or biatrial pacing was safe and well tolerated. Recently, some data have suggested an additional protective effect of biatrial pacing compared with pacing the right atrium alone (81). It is common clinical practice to perform overdrive atrial pacing in the postoperative period to suppress atrial ectopy and provide optimal hemodynamics. A recent preliminary report from a randomized, controlled clinical trial of atrial overdrive pacing (AAI pacing mode) at rates greater than or equal to 10 beats/min faster than the intrinsic heart rate (i.e., approximately 90-110 beats/min) did not prevent postoperative atrial fibrillation (82). Future studies must address whether biatrial pacing has any benefit in the prevention of atrial fibrillation. However, one study showed that atrial pacing only prevented postoperative atrial fibrillation in patients who were also treated with a 37 beta-blocker. They studied the effects of atrial pacing in 123 patients undergoing coronary artery bypass graft surgery, who were also treated with propranolol (80). In this study, epicardial pacing reduced the incidence of postoperative atrial fibrillation from 31% to 13% (P = .04). In addition, the length of hospitalization was also reduced. Strategies to prevent postoperative at atrial fibrillation are most beneficial in high-risk patients. Therefore, these strategies are most important in patients with advanced age, a prior history of atrial fibrillation, or undergoing valvular surgery. Both beta-blockers and amiodarone have been shown to be beneficial, but neither has been proven superior to the other. Depite many clinical studies, there is still no consensus regarding the best prevention strategy for postoperative atrial fibrillation. Consequently, cardiac surgeons are challenged to devise strategies to prevent its occurrence. 3 8 CHAPTER 2 OBJECTIVE OF THE THESIS Everyone in the cardiac surgery team (Residents, Fellows, Nurses, Cardiac surgeons) has to deal with Postoperative Atrial Fibrillation. We found that this problem is the most common complication of postoperative coronary artery bypass grafting surgery in our hospital. Although often a benign complication, it can result in significant morbidity and prolong hospitalization with attendant increased expenditure of health care resources. The pathophysiological mechanisms responsible for atrial fibrillation after a cardiac procedure remain unclear, although several clinical studies published during the past decade have identified certain preoperative risk factors associated with postoperative atrial fibrillation, there is still no consensus regarding the best prevention strategy for this arrhythmia. We recently reviewed the literatures and discussed this problem in a group. Because of the multifactorial etiology of postoperative atrial fibriallation (for example, increased catecholamines, pericardial inflammation/effusion, rapid shifts in fluid and electrolyte status, atrial ishemia, autonomic dysfunction, local surgical trauma, abnormal electrophysiological substrate (aging, hypertension), and well known inflammatory response to cardiopulmonary bypass (83,84)) steroid might have a beneficial effect in decreasing the incidence of postoperative atrial fibrillation after coronary artery bypass grafting (CABG). Consequently, we designed the study to identify the incidence of postoperative atrial fibrillation between two groups (Steroid and Placebo) 39 Possible mechanism of inflammatory response of cardiopulmonary bypass Despite the normal convalescence of the vast majority of patients undergoing open cardiac operations, the experienced surgeon will occasionally see the patient who has an adverse reaction to the CPB experience (the "postperfusion syndrome"), with evidence of prolonged pulmonary insufficiency, excessive accumulation of extravascular water, and to a variable degree, renal and other organ dysfunction, hyperthermia, vasoconstriction, and coagulopathy. These sequelae of CPB may occur in the face of an apparently effective and complete cardiac operation with good hemodynamic performance. Such occurrences are more frequent if the surgeon operates on infants and neonates or the very elderly. Dating from the early experience with open-heart surgery, surgeons have noted the tendency for extravascular fluid accumulation in patients after CPB. Cleland and colleagues at the Mayo Clinic (85) published their observations in 1966 and related the increase in extravascular fluid to the duration of CPB. It was not until 1987, however, that Smith and colleagues (86) provided the first direct evidence for increased microvascular permeability after CPB using ultrafiltration techniques in a canine model. Using the microvascular colloid osmotic sieving ratio determined by minimal lymph-plasma protein ratios, these investigators demonstrated an increase in permeability to proteins after 2 hours of normothermic CPB in the dog. 40 It has been hypothesized that the damaging effects of CPB are related to the exposure of blood to abnormal surfaces and conditions, which then initiates a systemic inflammatory response involving both formed and unformed blood elements that normally act locally at sites of injury (87). A critical aspect of this "whole body inflammatory response" involves the humoral amplification system, which includes the coagulation cascade, the kallikrein system, the fibrinolytic system and the complement cascade. The damaging effects of CPB likely result in large part from the activation and interaction of these cascades. The organ most commonly associated with CPB induced dysfunction is the lung. During the initial phase of CPB, complement is activated primarily through the alternative pathway (88), resulting in release of the anaphylatoxins C3a and C5a. Increased pulmonary and other subsystem morbidity has been associated with higher complement C3a levels during CPB (89). Chenoweth and Hugh (90) demonstrated specific binding sites on neutrophils for the anaphylatoxin C5a. After cleavage of C5 in the complement cascade another active component, pore-forming C5b-9 complex, is known to stimulate arachidonic metabolism and further promote granulocyte activation (91). Salama and colleagues (91) have demonstrated pore-forming C5b-9 complexes on neutrophils as well as on erythrocytes during CPB. The end result is leukocyte activation and subsequent deposition in the lungs and other organs. Transpulmonary leukocyte sequestration occurs during partial bypass (88), and previous studies in patients on hemodialysis 41 demonstrated transient neutropenia with temporary pulmonary dysfunction associated with complement activation at the beginning of hemodialysis (92,93). In a sheep model, Flick and colleagues (94) showed that leukocytes are required for the increased pulmonary water seen after microembolization. These effects of CPB may in part result from oxygen free radical release (95) during pulmonary reperfusion and lysosomal enzyme release from activated neutrophils (96,97). It thus appears that leukocyte (and possibly platelet) activation and sequestration are closely linked to the changes in extrapulmonary water and to occasional pulmonary dysfunction observed after CPB. Over the past several years, the literature has been replete with studies demonstrating high circulating levels of metabolic by-products of the various cascades as well as other inflammatory by-products during CPB. Unfortunately, the vast majority of these studies simply identify the presence of various inflammatory by-products or mediators without showing some relevance to patient morbidity after CPB. Because most patients tolerate the experience of CPB extremely well, there must be a sophisticated natural process that allows neutralization, inhibition, or interruption of these pathways and the prevention of important organ damage in most patients. Steroid and inflammatory response process With the discovery of cytokines as inflammatory mediators and the ability to measure many of these molecules, many studies have demonstrated 42 the ability of glucocorticoids to blunt the cardiopulmonary bypass-related in creases in circulating levels of many of these inflammatory mediators, including IL-6, IL-8, TNF-alpha, C D l l b , leukotrieneB4, and tissue plasminogen activator (98-106). Teoh and associates (98) have shown that the peripheral vasodilatation seen after normothermic cardiopulmonary bypass from effects of cytokines can be improved by steroid administration. Jansen et al demonstrated a leukocyte inflammatory response on reperfusion of the heart and lungs, shown by an increase of TNF, LTB4, and t-PA activity, which correlates with the clinical hemodynamic condition after Cardiopulmonary bypass. They also showed that dexamethasone treatment significantly inhibits the formation of these inflammatory mediators and thus prevents the hemodynamic instability after cardiopulmonary bypass, which improves the postoperative course (99). Another study from Engelman et al showed a dramatic decrease in the level of cytokine response related to steroid administration and recommended prophylactic steroid use during routine open-heart operations (100). Although many studies showed beneficial effects of corticosteroid on open-heart operations, Mayumi et al concluded that T-cell functions are synergistically suppressed by cardiopulmonary bypass and high-dose methylpredinolone in heart operation (107). 43 Research plan With unknown mechanism of postoperative atrial fibrillation, multifactorial etiology (including pericardial inflammation/effusion from surgery, pericarditis, local surgical trauma and cannulation, postsurgical effects on previously damaged myocardial tissue, systemic inflammatory response induced by cardiopulmonary bypass, poor atrial preservation during aortic crossclamping, atrial distention, autonomic disruption from surgery, enhanced sympathetic activity, postoperative hemodynamic changes, metabolic derangements and fluid shifts, abnormal electrophysiological substrate (aging, hypertension), and the beneficial effects of steroid from the literature review, we decided to design a prospective randomized trial to determine the effects of short-term steroid administration on the incidence of postoperative atrial fibrillation after coronary artery bypass grafting surgery (CABG). Study hypothesis The purpose of this study is to investigate whether steroid (combined preoperative and postoperative in acute short term) can reduce the incidence of postoperative atrial fibrillation after C A B G , including the length of hospital stay and the adverse effects of steroid. The null and alternative hypotheses of this study are: 44 HO: Steroid (acute short term) administration pre and postoperative C A B G surgery has no effect on incidence of postoperative atrial fibrillation after C A B G . Ha: Steroid administration pre and postoperative C A B G surgery can change the incidence of postoperative atrial fibrillation after C A B G . Primary outcome In this study we plan to follow up the incidence of postoperative atrial fibrillation after C A B G compared between steroid group and placebo group. Secondary outcome In addition to the primary outcome, we plan to study the length of hospital stay between the two groups and compare the length of hospital stay between normal sinus rhythm patients and atrial fibrillation patients. Since there was one study showed that steroid administration and cardiopulmonary bypass could synergistically suppress T-cell function, we also plan to study the adverse effects (in term of complications) of steroid. Benefit Despite many clinical studies, there is still no consensus regarding the best prevention strategy for postoperative atrial fibrillation after C A B G . If we find in this study that short term steroid administration can reduce the 4 5 incidence of postoperative atrial fibrillation after C A B G , shorten the length of hospital stay with no adverse effects, prophylaxis with short term steroid in patients undergoing coronary artery bypass grating surgery would be an ideal approach. Study design This study is designed as a randomized, double blind placebo controlled clinical trial. Patients are randomized into one of the two study groups, placebo group and steroid treatment group, in blocks of 8. Material and Methods The Ethics committee for Human Experimentation of St.Paul's hospital, Vancouver, B.C. approved this study in May 2000. (Study no# p 99-0254) Sample size We reviewed the data from B.C. cardiac registration and found that the incidence of postoperative atrial fibrillation after C A B G in St.Paul's Hospital from 1993 to 1999 is 43.5%. To detect a 50 % reduction in the steroid treatment group with power of 80 % and two-sided type I error of 0.05. The require sample size for this study is 162 patients. (Placebo group 81, Steroid group 81) 46 Before we started running the study, we decided to do 50 % interim analysis and planned to stop the study if the result showed a significant decrease in the incidence of postoperative atrial fibrillation after C A B G . As a result, from August 1,2000 to February 28,2001, 88 patients were enrolled for this study, two patients were excluded from the study because the surgeon did Off-Pump coronary artery bypass grafting surgery, when we did the interim analysis we found the incidence of postoperative atrial fibrillation in the steroid group was significantly less than placebo group. PATIENT SELECTION Inclusion criteria • The patient is undergoing elective first-time coronary artery bypass grafting and was on beta-blockage. • The patient has signed a study-specific consent form agreeing to the randomization, data collection, and follow-up requirements. Exclusion criteria • The patient has history of heart block, • The patient has a permanent pacemaker. • The patient has any documented or suspected supraventricular or ventricular arrhythmias, including isolated atrial or ventricular premature depolarization noted on preoperative surface electrocardiography. 47 • The patient requires additional procedures, such as valvular surgery or left ventricular aneurysmectomy. • The patient refused to participate in this study. • The patient need radial artery to be grafted. • The patient who was steroid dependent. • The patient who was allergic to steroid. • The patient who was not on beta-blockage. Steroid administration Patients are randomly assigned to receive in a double blind fashion either • Placebo group receives maintenance fluids (5% dextrose water with 20 mEq of potassium chloride per liter) or • Steroid group receives the steroid dosage 1 gm of intravenous methylprednisolone sodiumsuccinate (Solu-Medrol; Upjohn, Kalamazoo, MI) before Cardiopulmonary bypass and 4 mg of intravenous dexamethasone (Decadron; Merck Sharp & Dohme, West Point, PA) every 6 hours for a total of four doses in the first 24 hours after operation. • A l l vials of the steroid and placebo medications were prepared and randomized by the pharmacists. 48 Operative technique A standardized anesthesia and surgical protocol was applied in all cases. A l l operations were performed using normothermic (37°c) cardiopulmonary bypass with antegrade warm blood cardioplegia. Cardiopulmonary bypass was performed using aortic and right atrial cannulation, a membrane oxygenator, and nonpulsatile flow. Standard surgical techniques were used to create the distal coronary anastomoses first, and then proximal anastomoses were followed. After weaning off cardiopulmonary bypass system, inotropic support was initiated when needed to maintain cardiac contractility or i f the cardiac index was less than 2L.min-l.m-2, or i f the mean arterial pressure was less than 70 mmHg. Electrical pacing was instituted (atrial or atrioventricular) when needed to maintain a heart rate greater than 70 beats/min. Patients were continuously monitored in the cardiothoracic intensive care unit. Patients were weaned off mechanical ventilation based on hemodynamic stability, blood gas analysis, and level of alertness. Discharge from the cardiothoracic intensive care unit was generally accomplished after extubation and the discontinuation of all vasoactive infusions. Patients receiving beta blockage, digitalis, calcium channel blockage had these medications continued until the day of operation. Standard postoperative medication will be performed. Patients received the usual postoperative cardiac care, including the use of beta blockade to prevent atrial arrhythmias as a standard protocol. 49 Hemodynamic Measurement and Monitor Patients will be continuously monitored in the cardiothoracic intensive care unit with arterial, central venous, and pulmonary artery pressure monitoring with thermodilution cardiac output determination. Cardiac rhythm will be continuously monitored in the intensive care unit with bedside monitors (MARQUETTE Hard-wire SOLAR 7000) and, after intensive care unit discharge date with Telemetry on the floor 5A/5B (HEWLETT P A C K A R D model M2360A serial no.3329A02191). Twelve lead electrocardiograms will be obtained immediately postoperatively and on the first morning after the operation. Supraventricular and ventricular arrhythmias and respective treatment interventions will be documented by the patient's nurse and supported by the inclusion of rhythm strips in the patient chart. The investigator reviewed all patients' rhythm strips on a daily basis until the patients were discharged from the hospital. For the purpose of defining end points in this study, postoperative atrial fibrillation was defined by the group as: Atrial fibrillation was defined when irregularly irregular supraventricular rhythm was present in the absence of P waves, that required treatment, which was typically sustained for more than 15 minutes. 50 Episodes of atrial fibrillation that recurred or continued into the following 24-hour period as an additional episode. Arrhythmia data were collected and recorded for the first 7 postoperative days. Using these definitions, cardiac arrhythmias will be treated under the direction of the attending surgeon. Standardized protocols for the treatment of supraventricular and ventricular arrhythmias were adhered to during the course of the study. Blood gas abnormalities will be corrected. Potassium, Magnesium, and Calcium will be administered as needed to maintain serum concentrations greater than 4 mmol/L, 1.5 mEq/L, and 8.5 mg/dL, respectively. Therapeutic approaches for treatment postoperative atrial fibrillation on the floor included: a. Drugs to control ventricular rate (digoxin or beta adrenergic blockers intravenous consider by left ventricular ejection function, heart failure, and lung disease). b. Drugs to convert to normal sinus rhythm (sotolol, propafenone, amiodarone, or any beta-blocker consider as patient status, sex, and conditions). c. Electrical cardioconversion will be attempted when atrial fibrillation results in hemodynamic instability or when clinically indicated in the setting of failure of pharmacologic conversion. Patients will be routinely anticoagulated with heparin, warfarin, or both when atrial fibrillation persisted for longer than 36 hours. Patients were followed up as routine protocol on the ward until they were discharged from the hospital. The length of hospital stay was calculated 51 from the day of surgery until the day of discharge. A l l complications were recorded in the data form. We divided complications into major and minor complication. Major complications were defined as the situations or problems that patients needed to have an operation: for example, severe sternal infection that needed debridement or rewiring. Minor complications were defined as the situations or problems that patients needed only medication for treatment: for example, superficial wound infection that needed only antibiotic for treatment. Major complications included severe strenum infection needing rewiring, acute pancreatitis, and perforated GU. Minor complications were defined as situations or problems that patients need only medication treatment. These included GI upset (gastrointestinal upset patients that need IV Fluid treatment for at least 4 days postoperative), high blood sugar (that need endocrinologist to control blood sugar postoperative), mental confusion (that need antipsychotic medication for at least 4 days postoperative), elevated creatinine postoperative, UTI (Urinary tract infection that need IV Antibiotic Treatment), sternum wound infection, IV line infection and Leg wound infection needed IV antibiotic treatment, gastritis that need Gastroenterologist consultation. 52 Statistics At the time of study termination, the treatment code was broken. Medical history, demographic data, and the clinical course were analyzed for each patient. Comparison of continuous variable across the two treatment groups was accomplished using a two-sample t test or Wilcoxon rank-sum test where appropriate. Comparison of categorical variables across the two groups was analyzed by using chi-square test or Fisher's exact test (where applicable). A logistic regression analysis was carried out to compare the two groups with possible confounders adjusted. P values of less than 0.05 are considered to be statistically significant. Statistical analysis was performed using SAS software (Cary,NC). Breaking the code-Interim analysis After 50 % of enrollment, we planned to do an Interim analysis. The benefit is that the trial might be stopped earlier if we can find a significant reduction of the incidence of postoperative atrial fibrillation after C A B G in steroid treatment group or significant detrimental effect of steroid is identified. Based on O'BRIEN-FLEMING approach, the p-value for the interim analysis is 0.005 and the p-value for the final analysis for the total patient is 0.048. 5 3 Estimated duration of study After the ethics committee accepted this study, we enrolled 88 patients as described in the inclusion criteria, followed up the patient and strips review on a daily basis and collected the data. The study was run from August 1,2000 to February 28,2001. After that the files were reviewed. The codes were broken by the pharmacists. The data were separated into two groups by the nurse and analyzed by the statisticians. The result showed significantly decreasing in postoperative atrial fibrillation in Steroid treatment group, and then we decide to stop and analyze all the data. 54 Data base form Supervisor:Dr.Samuel V.Lichtenstein, Investigator:Dr.Kriengchai Prasongsukarn No Patient name code Sex : m _ f _ DOA DOS DOC Hx of M I : Y _ N _ Hx of C H F : Y _ N _ Hx of COPD: Y _ N _ Hx of s m o k i n g : Y _ N _ Hx of Asthma: Y _ N _ Hx of HTN: Y _ N _ H x o f C R F : Y _ N _ Pre -op Med: beta-blocker Ca blocker digitalis Ejection fraction % Temp of cardioplegia cel. Xclamp time min. No. of bypass bypass time min. Pacing :A-pace Avpace Vpace Start time Stop time Pacing:A-pace Avpace Vpace Start time Stop time Pacing :A-pace Avpace Vpace Start time Stop time Pacing:A-pace Avpace Vpace Start time Stop time Pacing :A-pace Avpace Vpace Start time Stop time 5 5 Arrhythmias: Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Date Start time Stop Time Rhythm Rx Medication for control arrhythmia when D/C Complication Date Rx Complication Date Rx Complication Date Rx Complication Date Rx White blood cell count 12 hour 24 hour 56 Result This randomized, prospective clinical trial was carried out in 88 patients, and two patients were excluded from the study due to Off-pump Coronary artery bypass grafting surgery, 43 patients with steroid and 43 patients with placebo. Selected patient demographics are presented in table 9. Statistically significant differences were found for age and ejection fraction (LVEF). Other variables including sex, History of MI, asthma, COPD, Congestive heart failure, hypertension, smoking, chronic renal failure, preoperative medications, ischemic time, number of bypass grafts, pacing type were not different between two groups (table 3,5-18). There was no death in the study period. Postoperative Atrial fibrillation The percentages of incidence of postoperative atrial fibrillation patients between two groups are shown in Figure 9. The incidence of postoperative atrial fibrillation was 20.93 % (9 of 43 patients) in the short-term steroid group, as compared with 51.16 % (22 of 43 patients) in the placebo group (P=0.0035) (Table 4). The number of episode of atrial fibrillation was compared between two groups (Table 5). It is appeared that Placebo group had a higher number of episodes of postoperative atrial fibrillation than Steroid group (P=0.0164). 57 Data showed 6 patients in placebo group had three episodes of postoperative atrial fibrillation as compared with none in steroid group. Table 3 . Clinical study of Steroids Versus Placebo group Variable Steroid group Placebo group P value N 43 43 Sex F /M 10/33 10/33 1.0 Age 67.2(64.5-70) 61.7(58.6-64.8) 0.0079 History of MI 28 28 1.0 Asthma 6 1 0.1096 COPD 10 6 0.2677 CHF 9 11 0.6097 HTN 27 23 0.3819 Smoking 17 17 1.0 CRF 2 2 1.0 LVEF 3]7.8 0.0353 X clamp time 66(57-75) 71(62-80) 0.3877 A-pacing 8 13 0.2095 AV-pacing 7 1 0.0577 MI=myocardial infarction, COPD=chronic obstructive lung disease, CHF=Congestive heart failure, HTN=hypertension, CRF=chronic renal failure, LVEF=Left ventricular ejection fraction, X clamp time=Cross clamp time. 58 T a b l e o f group by a f group a f F r e q u e n c y ! Row Pet INo IVes I T o t a l S t e r o i d I 34 I 9 I 43 1 79 .07 I 20 .93 1 P l a c e b o I 21 I 22 I 43 I 48 • 84 1 51 .16 I T o t a l 55 31 86 C h i - S q u a r e : P = 0.0035 Table 4. Number of Atrial fibrillation patients in Detail Table of group by HFEpisode group AF_Episode Frequency! Row Pet I 01 11 21 31 41 51 61 S t e r o i d I 34 I 4 I 4 I 0 I 1 I 0 I 0 I I 79 . 0 7 I 9 . 3 0 I 9 . 3 0 I 0 . 0 0 I 2 . 3 3 I 0 . 0 0 I 0 . 0 0 I Placebo • 21 I 8 I 5 I 6 1 1 I 1 I 1 1 I 48 . 8 4 I 18 . 6 0 I 11 .63 I 1 3 . 9 5 1 2 . 3 3 I 2 . 3 3 I 2 . 3 3 I T o t a l 55 12 9 6 2 1 1 Fisher's Exact Test: P = 0 .0164 Table 5. Number of Episode of Atrial Fibrillation in Detail 59 Figure 9. Incidence of Postoperative Atrial Fibrillation compared between Short-Term Steroid Treatment Group and Placebo Group 60 Table of group by Sexa group Sexa Frequency! Row Pet IF IM I Total Steroid I 10 I 33 '1 43 1 23 .26 I 76 .74 I Placebo I 10 I 33 • 43 1 23 .26 I 76 .74 I Total 20 66 86 Chi-Square: P = 1.0000 Table 6. Number of sex of Patients in Detail Table of group by chf group chf Frequencyl Row Pet IHo IVes I Total Steroid 1 34 1 9 1 43 1 79 .07 1 20 .93 1 Placebo 1 32 1 11 1 43 1 74 .42 1 25 .58 I Total 66 20 86 Chi-Square: P = 0.6097 Table 7. Number of Congestive Heart Failure Patients in Detail 61 Table of group by ni group mi Frequency! Row Pet •No • Yes • Total Steroid 1 15 • 28 • 43 1 34 .88 • 65 -12 1 Placebo I 15 • 28 • 43 I 34 .88 • 65 .12 • Total 30 56 86 Chi-Square: P = 1 0000 Table 8. Number of Myocardial Infarction Patients in Detail Table of group by COPD group COPD Frequencyl Row Pet INo IVes I Total Steroid 1 33 1 10 1 43 I 76 .74 1 23 .26 1 Placebo I 37 1 6 1 43 1 86 .05 1 13 .95 I Total 70 16 86 Chi-Square: p = 0.2677 Table 9. Number of Chronic Obstructive Lung Disease Patients in Detail 62 Table of group by Asthma group Asthma Frequency! Row Pet INo IVes I Tota l S tero id I 37 I 6 I 43 I 86 .05 1 13 .95 1 Placebo • 42 • 1 • 43 • 97 .67 I 2 .33 I Tota l 79 7 86 F i s h e r ' s Exact Tes t : P = 0.1096 Table 10. Number of Asthma Patients in Detail Table of group by smoking group smoking Frequency! Row Pet INo IVes I To ta l S te ro id 1 26 1 17 1 43 1 60 .47 1 39 .53 1 Placebo 1 26 1 17 1 43 I 60 .47 I 39 .53 I To ta l 52 34 86 Chi -Square: P = 1.0000 Table 11. Number of Smoking Patients in Detail 63 Table of group by erf group erf Frequency! Row Pet INo IVes I Total Steroid I 41 1 2 1 43 I 95. 35 1 4 .65 I Placebo 1 41 1 2 1 43 • ?!>•- 35 1 4 -65 I Total 82 4 86 Fisher's Exact Test: P = 1.0000 Table 12. Number of Chronic Renal Failure Patients in Detail Table of group by HT group HT Frequency! Row Pet !No !Ves I Total Steroid 1 16 1 27 1 43 1 37 •2.1 1 62 .79 1 Placebo 1 20 1 23 1 43 1 46 .51 1 53 .49 1 Total 36 50 86 Chi-Square : P = 0.3819 Table 13. Number of Hypertension Patients in Detail 64 T a b l e o f group by a p a c e group a p a c e F r e q u e n c y l Row Pet INo IVes I T o t a l S t e r o i d I 35 1 8 1 43 1 81 .40 1 18 .60 1 P l a c e b o 1 30 1 13 1 43 1 69 .77 1 30 .23 1 T o t a l 65 21 86 C h i - S q u a r e : P = 0.2095 Table 14. Number of A-Pacing Patients in Detail T a b l e o f group by aupace group aupace F r e q u e n c y l Row Pet INo IVes I T o t a l S t e r o i d 1 36 1 7 1 43 1. 83 .72 1 16 .28 1 P l a c e b o 1 42 1 1 1 43 1 97 .67 1 2 .33 1 T o t a l 78 8 86 F i s h e r " s E x a c t T e s t : p = 0.-0577 Table 15. Number of AV-Pacing patients in Detail 65 Table of group by No_BP group No_BP Frequency! Row Pet I 11 21 31 41 51 61 71 Total S t e r o i d 1 1 I 7 I 13 1 15 I 4 I 2 I 1 I 43 I 2. 33 I 16 .28 I 30.23 1 34 .88 I 9 .30 I 4 .65 I 2 .33 • Placebo I e • 9 I 10 I 13 • 10 I 1 I 0 I 43 I 0. 00 I 20 .93 • 23.26 1 30 .23 I 23 .26 I 2 .33 I 0 .00 I Total 1 16 23 28 14 3 1 86 Fisher's Exact Test: P = 0.4803 Table 16. Number of Bypass Grafts in Patients in Detail Wilcoxon Scores (Rank Suns) for Uariable EF Classif ied by Uariable group Sum of Expected Std Deu Mean group N Scores Under HO Under HO Score Steroid 43 1625.0 1870.50 114.535648 37.790698 Placebo 43 2116.0 1870.50 114.535648 49.209302 Wilcoxon Two-Sample Test: P = 0.0353 Table 17.Left Ventricular Ejection Fraction of Patients in Each Group hr Detail. This table demonstrates that Patients in Steroid Group had lower Left Ventricular Ejection Fraction than Patients in Placebo Group (P=0.0353) 66 The TTEST Procedure S t a t i s t i c s Var iable group N Lower CL Mean Mean Upper Mean CL Lower Std Dew CL Std Dev Upper Std Deu CL Std Err Minimum Maximum age age Steroid Placebo 43 43 64.491 58.645 67.263 61.7 70.035 64.754 7.4258 8.1841 9 9. .006 9256 11.447 12.616 1 .3734 1 .5136 44 39 019 389 88.487 79.477 X_clamp_tine X^clanp_tirie Steroid Placebo 1)3 43 57.029 62.902 66.186 71.628 75.343 80.354 24.534 23.379 29 28 .755 .354 37.819 36.038 4.5376 4.324 28 29 195 136 Bypass_time Bypass_time Steroid Placebo 13 43 83.806 86.246 92.512 94.837 101.22 103.43 23.323 23.017 28 27 .286 .915 35.952 35 .48 4.3136 4.257 48 45 213 158 T-Tests Uariable t Ualue Pr > |t | age 2.72 0.0079 X_clamp_time -0.87 0.3877 Bypass_tine -0.38 0.7021 Table 18. Patients Characteristics in Age, Cross clamp time, and Bypass time. From this table, Patients in steroid group were older than patients in placebo group, the mean age was 67.2 in steroid group compared with 61.7 in placebo group, and the difference was statistically significant (P =0.0079). Other two variables (cross clamp time and bypass time) did not show any significant differences between the two groups. 6 7 Complication Data showed Steroid Group had higher complications than Placebo Group (15 Minor complications and 4 Major complications in Steroid Group, as compared with 6 Minor complications and 2 Major complications in Placebo group), but there was no statistically significant difference in the incidence of postoperative complication between two groups (P=0.0525)(Table 19,20,Figure 10). There was a significant difference in the number of White blood cell count at 12,24-hour postoperative period (Table 21,22). It was appeared that Steroid patients had higher white blood cell count at 12, 24-hours (51.2,51.2 respectively) than Placebo Group (28.5,21,7 respectively)(P<. 0001). Length of Hospital stay Normal sinus patients had a shorter length of hospital stay than Atrial fibrillation patients (median 6 days compared with 8 days, p=0.002)(Table23, Figure! 1). However, there was no statistically significant difference between the lengths of Hospital stay between two groups (median 6 days in Steroid Group as compared with 7 days in Placebo Group, p=0.3371)(Table 24,Figurel2). 68 Table 19 Complications in Each Group in Detail Variable Steroid Placebo group group GI upset 4 1 High blood sugar 4 -Mental confusion 2 2 Elevated creatinine 1 1 postop UTI 2 -Sternal wound infection 1 1 Leg wound infection 1 1 IV line infection 1 Gastritis - 1 MajonSternal dehiscence 2 2 Acute pancreatitis 1 -Perforated GU 1 GI Upset=Gastrointestinal upset, UTI=Urinary Tract Infection, Perforated GU=Perforated Gastric Ulcer. The bold prints represented Major Complications. Some patients had more than one complication. 69 T a b l e o f group by comp group comp F r e q u e n c y ! Row Pet INo Comp Imajor I m i n o r I T o t a l S t e r o i d 1 24 1 4 1 15 1 43 1 55 .81 1 9 .30 1 34 .88 1 P l a c e b o I 35 1 2 1 6 1 43 1 81 .40 1 4 .65 1 13 .95 1 T o t a l 59 6 21 86 F i s h e r ' s E x a c t T e s t : P = 0.0525 Table 20. Number of Complication patients in Detail. 34.88% • Minor Complication M Major Complication Steroid Placebo Figure 10. Percentages of Major and Minor Complications in Each Group. 70 Wilcoxon Scores (Rank Suns) For Uariable wbc12diFF ClassiFied by Uariable group Sun oF Expected Std Deu Mean group N Scores Under H0 Under H0 Score Steroid 40 2048.50 1600.0 101.975425 51.21250 Placebo 39 1111.50 1560.0 101.975425 28.50000 Wilcoxon Two-^ Sanple Test: P <-.0001 Group N Mean Median Min. Max. Steroid 40 6.80750 6.5 0.4 21.5 Placebo 39 2.96667 2.7 -1.4 9.1 Table 21. Number of White Blood Cell Count at 12-hour postoperative Period in Detail. 71 Wilcoxon Scores (Rank Suns) for Uariable wbc24diff Classi f ied by Uariable group Sun of Expected Std Deu Mean group N Scores Under HO Under HO Score Steroid 36 1846.0 1314.0 88.786895 51.277778 Placebo 36 782.0 1314.O 88.786895 21.722222 Wilcoxon Two-Sanple Test: P <.0001 Group N Mean Median Min. Max. Steroid 36 9.57222 8.45 3.2 21.7 Placebo 36 3.40000 2.50 0.2 11.1 Table 22. Number of White Blood Cell count at 24-hour postoperative period in Detail. 72 W i l c o x o n S c o r e s (Rank Suns) f o r U a r i a b l e l o s _ s u r g e r y C l a s s i f i e d by U a r i a b l e a f Sun o f E x p e c t e d S t d Deu Mean a f N S c o r e s Under H Q Under H O S c o r e NO 55 2 054 .0 2392 .50 109.318924 37 .345455 Ves 31 1687 .0 1348 .50 109.318924 54 .419355 W i l c o x o n T w o - S a n p l e T e s t : P = 0 .0020 Analysis variable length of hospital stay (by AF rhythm) AF N Mean Median Min. Max. No 55 7.52727 6 3 32 Yes 31 9.03226 8 5 24 Table 23. The Length of Hospital Stay compare between Normal Sinus Rhythm Patient and Atrial Fibrillation Patients. 73 • A F Patient • NSR Patient Figure 11.Mean score Length of Hospital Stay compare between Normal Sinus Patient and Atrial Fibrillation Patient. 7 4 Wilcoxon Scores (Rank Sums) for Uariable lossurgery Classif ied by Uariable group Sum of Expected Std Deu Mean group N Scores Under HO Under HO Score Steroid 43 1803.50 1870.50 113.841763 41.941860 Placebo 43 1937.50 1870.50 113.841763 45.058140 Wilcoxon Two-Sample Test: P = 0.5607 Analysis Variable length of hospital stay (by Group) Group N Mean Median Min. Max. Steroid 43 8.32558 6 3 32 Placebo 43 7.81395 7 4 23 Table 24. The Length of Hospital Stay Compare between Steroid Group and Placebo Group. 75 36 Steroid Placebo Figure 12. Mean score Length of Hospital Stay Compare between Steroid Group and Placebo Group. 76 Risk factors of Postoperative Atrial Fibrillation A univariate logistic regression analysis was performed to identify risk factors that were associated with the development of postoperative atrial fibrillation (Table25). Statistically significant differences were found for Steroid Group and Age. (P=0.0006,0.0047 respectively). Other variables showed no statistically significant differences (Table 26-31) Risk Factor P-Value Group 0.0006 Age 0.0047 History of MI 0.6745 History of asthma 0.6200 History ofCOPD 0.7296 History ofCITF 0.6441 Hypertension 0.2875 History of smoking 0.9106 L V EF 0.3227 Cross clamp Time 0.8323 By pass Time 0.5231 A-Pacing 0.7600 Table 25. Risk Factors by Multivariate Logistic Regression Analysis. 77 T a b l e o f a f by n i a f n i F r e q u e n c y l Row Pet •No • Ves • T o t a l No I 21 1 34 • 55 I 38 .18 I 61 .82 Ves I 9 I 22 • 31 I 29 .03 • 70 .97 • . T o t a l 30 56 86 C h i - S q u a r e : P = 0.3927 Table 26. Univariate analysis in Myocardial infarction between NSR and AF Patients. T a b l e o f a f by Chf c h f F r e q u e n c y ! Row Pet •No • V e s • T o t a l No • 43 • 12 • 55 1 78 .18 • 21 .82 I Ves • 23 • 8 1 31 • 74 -19 • 25 -81 • T o t a l 66 20 86 C h i - S q u a r e : P = 0.6742 Table 27. Univariate analysis in Congestive Heart Failure between NSR and AF patients. 78 Table of af by a p a c e af a p a c e Frequency! Row Pet INo IVes I Tota l No 1 44 1' 11 1 55 I 80.00 1 20.00 1. Ves 1 21 I 10 I 31 I 67.74 I 32.26 I Tota l 65 21 86 Chi -Square: P = 0. 2039 Table 28. Univariate analysis in A-Pacing between NSR and AF patients. Table of af by aupace af aupace Frequency! Row Pet INo IVes I Tota l No 1 50 1 5 1 55 I 90.91 1 9.09 I Ves 1 28 I 3 1 31 1 90.32 1 9.68 I Tota l 78 8 86 f i s h e r ' s Exact Tes t : P = 1. 0000 Table 29. Univariate analysis in AV-Pacing between NSR and AF patients. 79 Table of af by COPD af COPD Frequencyl Row Pet •No • Ves I Total No 1 44 1 11 I 55 I 80 .00 1 20 .00 I Ves I 26 I 5 I 31 1 83 .87 I 16 .13 1 Total 70 16 86 Chi-Square: P = 0 .6578 Table 30. Univariate analysis in Chronic Obstructive Lung Disease between NSR and AF patients. The TTEST Procedure S t a t i s t i c s Lower CL Upper CL Lower CL Upper CL Uar iab le af N Mean Mean Mean Std Deu Std Deu Std Deu Std Er r Minimum Maximum age No 55 60 098 62.771 65.443 8.3216 9.8847 12. 176 1.3329 39.389 82.957 age Ves 31 64 .177 67.516 70.856 7.2759 9.105 12 .17 1.6353 48.397 88.487 X_clamp_time Ho 55 56 .603 64.545 72.488 24.734 29.38 36. 191 3.9616 28 195 X c l a m p t i m e Ves 31 66 .696 76.645 86.595 21.676 27.125 36. 257 4.8718 29 136 Bypass_time No 55 81 .574 89.473 97.371 24.598 29.218 35. 992 3.9398 46 213 Bypass_time Ves 31 92 .231 101.13 110.03 19.386 24.259 32. 427 4.3571 45 158 T-Tests Uariable t Ualue Pr > |t | age -2.20 0.0307 Xclamptime -1.88 0.0630 Bypasstime -1.88 0.0630 Table 31. Univariate analysis in age, cross-clamp time, and bypass-time between NSR and AF patients. From this table, statistically significant difference was found in Age (P=0.0307) 80 Discussion The use of prophylactic Short-Term Steroid Administration in patients undergoing coronaray bypass grafting surgery reduced the incidence of postoperative atrial fibrillation by approximately 50 percent. Due to statistically significant difference in two patient characteristics, advancing age and low ejection fraction in steroid group (p=0.007,0.035 respectively) which are the risk factors of postoperative atrial fibrillation , the efficacy of steroid may be stronger than we expect. In our study, patients without postoperative atrial fibrillation had a shorter length of hospital stay. Overall, there was no significant difference between Steroid Group and Placebo Group with regard to the length of hospital stay. Data showed that Steroid had higher complications which may contribute to prolong hospitalization. Although there was no statistically significant difference in complication between Steroid Group and Placebo Group (P=0.0525), there was a trend toward complications in Steroid Group as P-value was close to 0.05. In our study we found 4 patients had high glucose intolerance that need to consult the endocrinologist to control blood sugar. Mayumi et al showed that glucose intolerance was worsened by the steroid during cardiopulmonary bypass (107). This might be the disadvantage of the Steroid Use. Infection is another complication that we might concern during Steroid Administration. In our study, we found infection in both group and no statistically significant difference. White blood cell count was increased significantly in Steroid Group (p<.0001) at 12,24-hour postoperative period. 81 However, we followed up white blood cell count 5 day postoperative and found that the number of white blood cell count returned back to preoperative level. This can be explained by demargination process of white blood cell which could be effect from the steroid. Many studies mentioned about the advantage of Steroid Use in Open-heart surgery. Jansen et al showed that Steroid can inhibit TNF and LTB4 release, which is the primary mediators involved in reperfusion phenomenon and sepsis. In his study, steroid improved postoperative course after Cardiopulmonary bypass (99).Teoh et al found steroid decrease cytokines release and decrease vasodilation effect (98). Engelman et al found the same result and recommended prophylactic steroid use in open heart surgery (100). We used the same dose that recommended by Engelman. This steroid doses can maintain therapeutic steroid effects for 4 days, which covers the peak incidence of postoperative atrial fibrillation. Engelman et al did not find any adverse effects of steroid use, possibly due to small sample sizes (10 steroid 19 placebo) in his study. In our study, we had an opportunity to study cytokine in some of our patient due to limited research funding. Walley KR. and Macintyre L. analysed the cytokine level in 22 of Steroid group and 86 of Placebo group. The results showed IL6 at 4,24-hour postoperative period in steroid group were statistically significant different (p=0.041,p=0.014 respectively). This showed the same result as other studies. The median of length of hospital stay of A F patient was 8 days compare with 6 days in NSR patient (p=0.002). However, the median length of hospital stay of steroid group was 6 days and in Placebo group was 7 days (p=0.337). This might be explained by increased length of hospital stay in 82 steroid group. We found that two Major complication patients in steroid group had 30 and 32 days length of hospital stay, and this was significant difference between complication and non-complication patient (p=0.0004). In our study, only advancing age has consistently been associated with an increased risk of postoperative atrial fibrillation (p=0.030). Creswell L L found Chronic obstructive lung disease and cross clamp time are the risk factors for the development of postoperative atrial fibrillation, this might be from our small sample sizes (86 compared with 4507 patients). In conclusion, with the high efficacy of steroid in decreasing the posoperative atrial fibrillation and slightly increasing in complications, we might try to adjust the steroid dose; for example give half dose of Methylprednisolone (500mg as we usually give in heart transplant patient). Or we can use prophylactic steroid for the patients who are high-risk of development of postoperative atrial fibrillation, such as old-age patients, long cross clamp time operation, low Ejection fraction patient, COPD patients, preoperative use of digoxin, valvular patients. 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