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. Or we can select to use

prophylactic steroid with patients who are not diabetes. Subsequently, we can

design other studies about prophylactic steroid administration in

postoperative atrial fibrillation ; for instance, high Vs low dose steroid use,

Steroid in high risk AF patient, Steroid combined with beta-blocker , Steroid

combined with amiodarone, Steroid with biatrial pacing. Hopefully one day

we can find the best prevention for postoperative atrial fibrillation.

83

References

1. Favaloro RG, Effler DB, Groves L K , et al: Direct myocardial

revascularization with saphenous vein autograft. Dis Chest 56:279-283,

1969.

2. Goldman L: Supraventricular tachyarrhythmias in hospitalized adults

after surgery. Chest 73:450-454, 1978.

3. Johnston K W . Multicenter prospective study of nonruptured abdominal

aortic aneurysm. J Vase Surg 9:437-447, 1989.

4. Nielsen JB, Sorensen HR, Alstrup P: Atrial fibrillation following

thoracotomy for non-cardiac diseases, in particular cancer of the lung.

Acta MedScand 193:425-429, 1973.

5. Lauer MS, Eagle K A , Buckley MJ, et al: Atrial fibrillation following

coronary artery bypass surgery. Prog Cardiovasc Dis 16:367-378,

1989.

6. Asher CR, Chung M K , Grimm RA, et al: Is the incidence of

postoperative atrial fibrillation following cardiac valve surgery reduced

by minimally invasive surgery (abstract). Circulation 94:651, 1996.

7. 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.

84

8. Matthew JP, Parks R, Savino JS, et al: Atrial fibrillation following

coronary artery bypass graft surgery: Predictors, outcomes, and

resource utilization. JAMA 276:300-306, 1996.

9. Andrew TC, Reimold SC, Berlin JA, et al: Prevention of

supraventricular arrhythmias after coronary artery bypass surgery.

Circulation 84:236-244,1991 (suppl'3)

10. Cox JL: A perspective of postoperative atrial fibrillation in cardiac

opearation. Ann Thorac Surg 56:405-409, 1993

11. Creswell L L , Schuessler RB, Rosenbloom M , et al: Hazards of

postoperative atrial fibrillation. Ann Thorac Surg 56:539-549,1993

12. Cox JL: A perspective on postoperative atrial fibrillation. Semin

Thorac cardiaovasc Surg 11:299-302,1999

13. Fuller JA, Adams GG, Buxton B: Atrial fibrillation after coronary

artery bypass grafting: Is it a disorder of the elderly? J Thorac

Cardiovasc Surg 97:821-825, 1989.

14. Moe GK: On the multiple wavelet hypothesis of atrial fibrillation. Arch

Int Pharmacodyn Ther 140:183-188, 1962.

15. Konings K , Kirchof CJJ, Smeets JRLM, et al: High density mapping of

electrically induced atrial fibrillation in humans. Circulation 89:1665-

1680, 1994.

16. Pool DP, Lee HL, Nadzam G, et al: Cardiac surgery results in changes

of atrial refractoriness that may explain vulnerability to postoperative

atrial fibrillation (abstract). J Am Coll Cordiol 27:64 65, 1995.

85

17. Chung M K , Pool DP, Leo HL, et al: Atrial conduction latency predicts

occurrence of postoperative atrial fibrillation in patients undergoing

bypass surgery (abstract). J Am Coll Cordiol 27:65A, 1995.

18. Augostini RS, Pool DP, Leo HL, et al: Sinus node function after

cardiopulmonary bypass predicts the development of postoperative

atrial fibrillation (abstract). Circulation 92:141, 1995.

19.Sato S, Yamauchi S, Schuessler RB, 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.

20. Buxton A E , Josephson M E : The role of P wave duration as a predictor

of postoperative atrial arrhythmias. Chest 80:68-73, 1981.

21. Hutchinson L A , Ehlert FA, Menchavez Tan E, et al: Towards a better

understanding of the development of atrial fibrillation after cardiac

surgery: Risk factor analysis in a large prospective study (abstract). J

Am Coll Cardiol 27:318A, 1995.

22. Cox Jl, Sabiston DC Jr: Electrophysiologic consequences of

cardioplegic preservation, Ischemia and Reperfusion, in Engelman R M :

A textbook of clinical cardioplegia. New york, Futura publishing,

1982,406-417.

23.Smith PK, Buhrman WC, Levett JM, et al: Supraventricular conduction

abnormalities following cardiac operations: A complication of

inadequate atrial preservation. J Thorac Cardiovasc Surg 85:105,1983

86

24.Smith PK, Buhrman WC, Ferguson TB Jr, et al: Conduction block after

cardioplegia arrest: Prevention by augmented atrial hypothermia.

Circulation 68:1141-1148, 1983

25. Ferguson TB Jr, Smith PK, Buhrman WC, et al: Monitoring of the

electrical status of the ventricle during cardioplegic arrest.

Circulation6S:ll27-ll33, 1983

26. Ferguson TB Jr, Smith PK, Buhrman WC, et al: Studies on the

physiology of the conduction system during hyperkalemia,

hypothermic cardioplegic arrest. Surg Forum 39:302,1983

27.Smith PK, Buhrman WC, Ferguson TB Jr et al: Relationship of atrial

hypothermia and cardioplegic solution potassium concentration to

postoperative conduction defects. Surg Forum 34:304,1983

28. Ferguson TB Jr, Damiano RJ, Smith PK, et al: The electrophysiological

effects of calcium channel blockade during standard hyperkalemic

hypothermic cardioplegic arrest. Ann Thorac Swrg 41:622-629,1986

29. Ferguson TB Jr, Smith PK, Lofland PK, et al: The effects of

cardioplegic potassium concentration and myocardial temperature on

electrical activity in the heart during elective cardioplegic arrest. J

Thorac Cardiovasc Surg 92:755-765,1986

30. Ferguson TB Jr, Smith Ls, Smith PK, et al: Electrical activity in the

heart during hyperkalemic hypothermic cardioplegic arrest: Site of

origin and relationship to specialized conduction tissue. Ann Thorac

Surg 43:373-379,1987

87

31. Kyosola A U , Mattila K, Harjula T, et al: Life threatening complications

of cardiac operations and occurrence of myocardial catecholamine

bombs. J Thorac Cardiovasc Surg 95:334-339, 1988.

32. Engelman R M , Haag,B, Lemeshow S, et al: Mechanism of plasma

catecholamine increases during coronary artery bypass and valve

procedures. J Thorac Cardiovasc Surg 86:608-615, 1983.

33. Page P, Plumb VJ , Okumura K, et al: A new model of atrial flutter. J

Am Coll Cardiol 8:872-879, 1986.

34. Angelini GD, Penny WJ, El Ghamary F, et al: The incidence and

significance of early pericardial effusion after open heart surgery. Eur J

Car diothorac Surg 1:165-168, 1987.

35. Weitzman L B , Tinker WP, Kronzon 1, et al: The incidence and natural

history of pericardial effusion after cardiac surgery: An

echocardiographic study. Circulation 69:506-511, 1984.

36. Creswell L L : Postoperative atrial arrhythmias: Risk Factors and

Associated adverse outcomes. Semin Thorac Caardiovasc Surg 11:303-

307,1999

37.0mmen SR, Odell JA, Stanton MS: Atrial arrhythmias after

cardiothoracic surgery. N Engl J Med 336:1429-1434,1997

38. Hashimoto K, Ilstrup D M , Schaff HV:Influence of clinical and

hemodynamic variables on risk of supraventricular tachycardia after

coronary artery bypass. J Thorac Cardiovasc Surg 101:56-65,1991

39. Leitch JW, Thomson D, Baird DK, et al: The importance of age as a

predictor of atrial fibrillation and flutter after coronary artery bypass

grafting. J Thorac Cardiovasc Surg 100:338-342, 1990.

88

40. Creswell L L , Schuessler RB, Rosenbloom M , et al: Hazards of

postoperative atrial arrhythmias. Ann Thorac Surg 56:539-549, 1993.

41. Frost L , Molgaard H, Christiansen EH, et al: Atrial fibrillation and

flutter after coronary artery bypass surgery: Epidemiology, risk factors

and preventive trials. Int J Cardiol 36:253-261, 1992.

42. Kannel WB, Abbott RD, Savage DD, et al: Epidemiologic features of

chronic atrial fibrillation: The Framingham Study, N Engl J Med

206:1018 1022, 1982.

43. Crosby L H , Pifalo WB, Woll KR, et al: Risk factors for atrial

fibrillation after coronary artery bypass grafting. Am J Cardiol 66:1520

1522, 1990.

44.0merod O M , McGregor CA, Stone DL, et al: Arrhythmias after

coronary bypass surgery. Br Heart J 51:618-621, 1984.

45. Dixon FE, Genton E, Vacek JL, et al: Factors predisposing to

supraventricular tachyarrhythmias after coronary artery bypass grafting.

Am J Cardiol 58:476-478, 1986.

46. Butler J, Chong JL, Rocker G M , et al: Atrial fibrillation after coronary

artery bypass grafting: A comparison of cardioplegia versus

intermittent aortic cross clamping. Eur J Cardiothorac Surg 7:23-25,

1983.

47. Pattison C, Dimitri WR, Williams BT: Dysrhythmias following

coronary artery surgery: A comparison between cold cardioplegic and

intermittent ischaemic arrest (32 C) with the effect of right coronary

artery endarterectomy. J Cardiovasc Surg 29:601-605, 1988.

89

48. Muller JC, Khan N , Weisel RD, et al: Atrial activity during

cardioplegia and postoperative arrhythmias. J Thorac Cardiovasc Surg

94:558-565, 1987.

49. Cheung EH, Arcidi JM, Jackson ER, et al: Intracavitary right heart

cooling during coronary bypass surgery, a prospective randomized

trial. Circulation 78:1735-1795, 1988.

50. Bigger JT Jr, Bloomfield D M , Rottman JN, et al: Frequent pre

operative atrial premature complexes predicts atrial fibrillation after

C A B G surgery (abstract). Circulation 94:191, 1996.

51 .Falk RH: Etiology and complications of atrial fibrillation: Insight from

pathology studies. Am J Cardiol 82:10N-17N, 1998.

52. Wolman M : Lipid pigments (chromolipids): Their origin, nature, and

significance. Pathobiol Annu 10:253-267, 1980.

53. Cotran RS, Kumar V, Collins T: Cell injury and cell death, in Robbins

Pathologic Basis of Disease (ed 6). Philadelphia, Saunders, 1999,pp 1-

29.

54. Brunk UT, Jones CB, Sohal RS: A novel hypothesis of

lipofuscinogenesis and cellular aging based on interactions between

oxidative stress and autophagocytosis. Mutat Res 275:395-403, 1992.

55.Islam M N , Kuroki H, Hongcheng B, Ogura Y , Kawaguchi N , Onishi S,

Wakasugi C: Cardiac lesions and their reversibility after long term

administration of methamphetamine. Forensic Sci Int 75:29-43, 1995.

56.Maes A, Flameng W, Nuyts J, Borgers M , Shivalkar B, Ausma J,

Bormans G, et al: Histological alterations in chronically hypoperfused

90

myocardium. Correlation with PET findings. Circulation 90:735-745,

1994.

57. A d N , Snir E, Vinde B A , et al: Potential preoperative markers for the

risk of developing atrial fibrillation after cardiac surgery. Semin Thorac

Cardiovasc Surg 11:308-313,1999.

58. Pirolo JS, Hutchins G M , Moore GW: Myocyte vacuolization in infarct

border zones is reversible. Am J Pathol 121:444-450, 1985.

59.Salerno TA, Wasan SM, Charrette EJ: Prospective analysis of heart

biopsies in coronary artery surgery. Ann Thorac Surg 28:436-439,

1979.

60. Mambo NC, Silver MD, McLaughlin PR, Huckell VF, McEwan P M ,

Britt B A , Morch JE: Malignant hyperthermia susceptibility. A light and

electron microscopic study of endomyocardial biopsy specimens from

nine patients. Hum Pathol 11:381-388, 1980.

61. Matangi MF, Neutze JM, Grahm KJ , et al: Arrhythmia prophylaxis

after aorta coronary bypass: The effect of minidose propranolol. J

Thorac Cardiovasc Surg 89:439 443, 1985.

62. Martinussen HJ, Lolk A, Szczepanski C, et al: Supraventricular

tachyarrhythmias after coronary bypass surgery: A double blind

randomized trial of prophylactic low dose propranolol. Thorac

Cardiovasc Surg 36:206 207, 1988.

63. Khuri. SF, Okike ON, Josa M , et al: Efficacy of nadolol in preventing

supraventricular tachycardia after coronary artery bypass grafting. Am J

Cardiol 60:5ID 58D, 1987.

91

64. Andrews TC, Reimold SC, Berlin JA, et al: Prevention of

supraventricular arrhythmias after coronary artery bypass surgery: A

metaanalysis of randomized control trials. Circulation 84:2365

2445,1991.

65. Kowey PR, Taylor JE, Rials SJ, et al: Meta analysis of the effectiveness

of prophylactic drug therapy in preventing supraventricular arrhythmia

early after coronary artery bypass grafting. Am J Cardiol 69:863865,

1992.

66. Johnson LW, Dickstein RA, Fruehan CT, et al: Prophylactic

digitalization for coronary artery bypass surgery. Circulation 53:819

822, 1976.

67. Tyras DH, Stothert JC, Kaiser GC, et al: Supraventricular

tachyarrhythmias after myocardial revascualrization: A randomized

trial of prophylactic digitalization. J Thorac Cardiovasc Surg 77:310

313, 1979.

68. Davison R, Hartz R, Kaplan K, et al: Prophylaxis of supraventricular

tachyarrhythmia after coronary bypass surgery with oral verapamil: A

randomized double blind trial. Ann Thorac Surg 39:336 339, 1985.

69.Smith EJ, Shore DF Monro JL, et al: Oral verapamil fails to prevent

supraventricular tachycardia following coronary artery surgery. Int J

Cardiol 9:37 44, 1985.

70.Seitelberger R, Hannes W, Gleichauf M , et al: Effects of diltiazem on

perioperative ischemia, arrhythmias, and myocardial function in

patients undergoing elective coronary bypass grafting. J Thorac

Cardiovasc Surg 107:811 821, 1994.

92

71. Fanning WJ, Thomas CS, Roach A, et al: Prophylaxis of atrial

fibrillation with magnesium sulfate after coronary artery bypass

grafting. Ann Thorac Surg 52:529 533, 1991.

72. Parikka H, Toivonen L , Pellinen T et al: The influence of intravenous

magnesium sulphate on the occurrence of atrial fibrillation after

coronary artery bypass operation. Eur Heart J 14:251 258, 1993.

73. Daoud EG, Strickberger SA, Man K C , et al: Preoperative amiodarone

as prophylaxis against atrial fibrillation after heart surgery. TV Engl J

Med?,?,!: 1785-1791, 1997.

74. Guarnieri T, Nolan S, Gottlieb SO, et al: Intravenous amiodarone for

the prevention of atrial fibrillation after open heart surgery: the

amiodarone reduction in coronary heart (ARCH) trial. J Am Coll

Cardiol 34:343-347, 1999.

75. Gold MR, O'Gara PT, Buckley MJ, et al: Efficacy and safety of

procainamide in preventing arrhythmias after coronary artery bypass

surgery. Am J Cardiol 78:975 979, 1996.

76. McCarty RJ, Jahnke EJ, Walker WJ: Ineffectiveness of quinidine in

preventing atrial fibrillation following mitral valvotomy . Circulation

34:792-794, 1996.

77. Merrick AF , Odom NJ, Keenan DJ, et al: Comparison of propafenone

to atenolol for the prophylaxis of postcardiotomy supraventricular

tachyarrhythmias: A prospective trial. Eur J Cardiothorac Surg 9:146-

149, 1995.

78.Solomon AJ , Verdino RJ, Katz NM:Dual site atrial pacing in

cardiovascular surgical patients. Circulation 94:1-677, 1996(abstr).

93

79. Gerstenfeld EP, Hil l MRS, French SN, et al: Evaluation of right atrial

and biatrial temporary pacing for the prevention of atrial fibrillation

after coronary artery bypass surgery. J Am Coll Cardiol 33:1981-1988,

1999.

80. Greenberg M D , Katz N M , Tempesta BJ, et al: Atrial pacing following

cardiovascular surgery reduces the incidence of postoperative atrial

fibrillation. Circulation 98:1-509, 1998(abstr)

81.Saksena S, Prakash A, Hil l M , et al: Prevention of recurrent atrial

fibrillation with chronic dual-site right atrial pacing. J AM Coll Cardiol

28:687-694, 1996.

82. Chung M K , Augostini RS, Asher CR, et al: A randomized controlled

study of atrial overdrive pacing for the prevention of atrial fibrillation

after coronary bypass surgery (abstract). Circulation 69:188, 1996.

83. Butler J, Rocker G M , Westaby S: Inflammatory response to

cardiopulmonary bypass. The Ann Thorac Surg 55:552-9,1993

84. Kirklin JK: Prospects for understanding and eliminating the deleterious

effects of cardiopulmonary bypass. The Ann Thorac Surg 51:529-

31,1991

85. Cleland J, Pluth JR, Tauxe WN, Kirklin JW. Blood volume and body

fluid compartment changes soon after closed and open intracardiac

surgery. J Thorac Cardiovasc Surg 1966;52:698-705.

86.Smith EEJ, Naftel DC, Blackstone EH, Kirklin JW. Microvascular

permeability after cardiopulmonary bypass. J Thorac Cardiovasc Surg

1987;94:225-33.

94

87. Kirklin JK. The postperfusion syndrome: inflammation and the

damaging effects of cardiopulmonary bypass. In: John Tinker, ed.

Cardiopulmonary bypass current concepts and controversies.

Monograph. Philadelphia: W.B. Saunders,1989:131-46.

88. Chenoweth DE, Cooper SW, Hugley TE, et al. Complement activation

during cardiopulmanory bypass: evidence for generation of C3a and

C5a anaphylatoxins. N Engl J Med 1981;304:497-503.

89. Kirklin JK, westaby S, Blackson EH, Kirklin JW, Chenoweth DE,

Pacifico A D . Complement and the damaging effects of

cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845-57.

90. Chenoweth DE, Hugh TE. Demonstration of specific C5a receptor on

intact human polymorphonuclear leukocytes Proc Natl Acad Sci USA

1978;75:3943-7.

91.Salama A, Hugo F, Heinrich D, et al. Deposition of terminal C5b-9

complement complexes on erythrocytes and leukocytes during

cardiopulmonary bypass. N Engl J Med 1988;318:408-13/

92. Craddock PR, Fehr J, Brigham K L , et al. Complement and leukocyte-

mediated pulmonary dysfunction in hemodialysis. N Engl J Med

1977;296:769-7'4.

93. Craddock PR, Fehr J, Dalmasso AP, et al. Pulmonary vascular

leukostasis resulting from complement activation by dialyzer

cellophane membranes. J Clin Invest 1977;59:879-88.

94. Flick MR, Perel A , Staub NC. Leukocytes are required for increased

lung microvascular permeability after microembolization in sheep. Circ

Res 1981;48:344.

95. Gu Y J , Wang YS, Chiang B Y , Gao X D , Ye C X , Wildevuur CRH.

Membrane oxygenator prevents lung reperfusion injury in canine

cardiopulmonary bypass. Ann Thorac Surg 1991;51:573-8.

96. Rinaldo JE, Rodgers R. Adult respiratory distress syndrome:changing

concepts of lung injury and repair. TV Engl JMed 1982;396:900-9.

97. Hammerschmidt DE, Stroncek DF, Bowers TK, et al. Complement

activation and neutropenia during cardiopulmonary bypass. J Thorac

Cardiovasc Surg 1981;81:370-7.

98. Teoh KHT, Bradley CA, Gauldie J; Steroid Inhibition of Cytokine-

Mediated Vasodilation After Warm Heart

Surgery.Circulation. 1995;92(Suppl II):II-347-II-353.)

99. Jansen NJG, Oeveren WV, Broek L V D , Inhibition by dexamethasone

of the reperfusion phenomena in cardiopulmonary bypass.J Thorac

Cardiovasc Surg 102:515-25,1991.

100. Engelman R M , Rousou JA, Flack JE; Influence of Steroids on

Complement and Cytokine Generation After Cardiopulmonary Bypass.

Ann Thorac Surg 60:801-4, 1995.

101. Lodge AJ , Chai PJ, Daggett CW; Methylprednisolone reduces the

inflammatory response to cardiopulmonary bypass in neonatal piglets../

Thorac Cardiovasc SurgMl:515-22, 1999.

102. HH1 GE, Alonso A , Spurzem JR, Stammers A H , Robbins RA.

Aprotinin and methylprednisolone equally blunt cardiopulmonary

bypass-induced inflammation in humans. J Thorac Cardiovasc

110:1658-62, 1995.

96

103. Hi l l GE, Alonso A, Thiele G M , Robbins RA. Glucocorticoids blunt

neutrophil C D l l b surface glycoprotein upregulation during

cardiopulmonary bypass in humans. Anesth Analg 79:23-7, 1994.

104. Jansen NJ, van Oeveren W, van Vliet M , Stoutenbeek CP, Eysman L,

Wildevuur CR. The role of different types of corticosteroids on the

inflammatory mediators in cardiopulmonary bypass. Eur J

Cardiothorac Surg 5:211-7, 1991.

105. Jorens PG, De Jongh R, De Backer W, Van Damme J, Van Overveld

F, Bossaert L, et al. Interleukin-8 production in patients undergoing

cardiopulmonary bypass: the influence of pretreatment with

methylprednisolone. Am Rev Respir Dis 148:890-5, 1993.

106. Kawamura T, Inada K, Okada H, Okada K, Wakusawa R.

Methylprednisolone inhibits increase of interleukin 8 and 6 during

open heart surgery. Can J Anaesth 42:399-403, 1995.

107. Mayumi H, Zhang QW, Nakashima A. Synergistic

immunosuppression caused by high-dose methylprednisolone and

cardiopulmonary bypass. Ann Thorac surg 63;129-37,1997.

97