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Ann Thorac Surg 2006;81:2121-2127
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Reduced Atrial Fibrillation in Patients Immediately Extubated After Off-Pump Coronary Artery Bypass Grafting

James R. Edgerton, MD a , b , * , Morley A. Herbert, PhD b , Syma L. Prince, RN a , Jeffrey L. Horswell, MD a , b , Luis Michelson, MD a , b , Mitchell J. Magee, MD a , b , Todd M. Dewey, MD a , b , Zachary J. Edgerton a , Michael J. Mack, MD a , b

a Cardiopulmonary Research Science and Technology Institute
b Medical City Dallas Hospital, Dallas, Texas

Accepted for publication January 3, 2006.

* Address correspondence to Dr Edgerton, CSANT, 7777 Forest Lane, Suite A-323, Dallas, TX 75230. (Email: edgertonjr{at}aol.com).

Presented at the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2–4, 2004.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 
BACKGROUND: We analyzed data from patients undergoing off-pump isolated coronary artery bypass grafting surgery (OPCABG) to determine if immediate extubation in the operating room affected the incidence of postoperative atrial fibrillation.

METHODS: The study group comprised 2,376 consecutive OPCABG patients operated on between January 1, 2000, and December 31, 2004, by 22 surgeons at 18 hospitals. The data were subjected to univariate, multivariate analysis of variance, and logistic analysis. Logistic regression of matched groups was used to eliminate the effect of some confounding variables.

RESULTS: Patients immediately extubated after surgery had a reduced incidence of atrial fibrillation (10.6% versus 18.5%; p < 0.001), shorter length of stay (4.8 ± 3.5 versus 6.3 ± 5.2 days; p < 0.001), and also reduced mortality (1.1% versus 2.4%; p = 0.04). Logistic analysis identified as significant factors for postoperative atrial fibrillation, postoperative ventilator usage (p < 0.001; odds ratio [OR] = 1.63; 95% confidence interval [CI]: 1.24 to 2.14), male sex (p = 0.002; OR = 1.51; 95% CI: 1.17 to 1.96), previous CABG (p = 0.005; OR = 0.43; 95% CI: 0.24 to 0.78). Congestive heart failure may also be a contributing factor. In patient groups matched for their risk of mortality, postoperative ventilator use (p < 0.001; OR = 1.80; 95% CI: 1.31 to 2.47), increasing age, and male sex were all statistically significant risk factors. When patient groups were matched on a combination of factors including preoperative ß-blocker usage, pulmonary disease, and smoking, postoperative ventilator use (p = 0.005; OR = 1.66; 95% CI: 1.16 to 2.38), along with increasing age, male sex, and previous CABG (reduced odds of atrial fibrillation developing) were statistically significant.

CONCLUSIONS: Immediate extubation after OPCABG appears to reduce the incidence of postoperative atrial fibrillation independent of comorbidities.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 References
 
Postoperative atrial fibrillation is the most common complication after heart surgery [1], affecting 50% of patients undergoing cardiac valve surgery [2] and 20% to 40% of coronary artery bypass grafting (CABG) patients, with a peak incidence between the second and fourth postoperative days [3–6]. Patients at increased risk for postoperative atrial fibrillation include those with a prior history of atrial fibrillation [7], those at advanced age [3], and those who have discontinued preoperative ß-blockers [8, 9]. Patients suffering this complication have more discomfort, are at increased risk of stroke [1], and have longer hospital stays [1, 10] at increased cost [3]. Indeed, we have noted that in our own practice that postoperative atrial fibrillation adds 4 days to the length of stay. The etiology and pathophysiology of atrial fibrillation after CABG remain obscure. We sought to identify factors that may influence the incidence of this complication.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 References
 
Data Set
The Cardiopulmonary Research Science and Technology Institute (CRSTI) maintains a Society of Thoracic Surgeons (STS) approved database of all patients receiving cardiac surgery for an 18-hospital, 22-surgeon practice. The database was queried for all patients who had undergone off-pump CABG between January 1, 2000, and December 31, 2004. Patients who had a postoperative ventilation time of 0 hours (not a missing value) were designated as immediately extubated. Patients were deleted who had preoperative atrial fibrillation, missing ventilation time data, were reintubated, or either died or were discharged within 1 day of surgery, a period too short to develop postoperative atrial fibrillation.

There were 2,376 patient records of off-pump procedures available for analysis. In the off-pump group (OPCABG), 800 (33.7%) of the patients were immediately extubated.

Statistics
All statistical analyses were carried out using SAS software version 9.1.3 (SAS Institute, Cary, North Carolina).

Chi-square statistics were used to test for differences in categorical variables between patient groups. When small numbers of values were observed, Fisher's exact test was utilized. Continuous variables were tested using a Student's t test (for two groups) and analysis of variance procedures when more than two groups were compared. In all cases, statistical significance required a p value of 0.05 or less.

Logistical analysis was used to test for effects of independent variables on categorical variables. Various continuous and categorical variables were tested for their effect on the development of postoperative atrial fibrillation, with calculated odds ratios (OR).

Matched Groups
To eliminate the effect of variables that were either thought to be clinically important in the development of atrial fibrillation, or were identified through the logistic analysis, we created matched groups of patients. By matching the immediately extubated to the ventilated groups on these variables, the occurrence of the matched variables (eg, ß-blocker usage) was equal in the two groups being compared. The logistic regression was then rerun on the matched groups.

Patient matching was carried out using a SAS macro. The variables to be matched and an acceptable matching "window" are supplied for the analysis. The resulting data set contains the matched patients. For most matching, an exact match was required such as sex, ß-blocker usage; for some continuous variables, a range is defined, such as age ± 3 years.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 References
 
Comparison of Immediately Extubated and Ventilated Groups
Table 1 shows a comparison of the two cohorts in the study based on whether they were immediately extubated after surgery or were ventilated for a period of 1 hour or more.


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  		Table 1. Demographic Factors
 
The ventilated group tends to include more females, to be slightly older, and to have higher rates of current smokers, lung disease, and more congestive heart disease. This is reflected in their higher STS predicted risk of mortality score.

The analysis also showed that a slightly larger fraction of the ventilated patients are on ß-blockers preoperatively whereas more of the immediately extubated group had previous CABG surgery.

As shown in Table 2, patients who were immediately extubated had reduced mortality (1.1% versus 2.4%; p = 0.04), a shorter length of stay (surgery to discharge) than the postoperatively ventilated group, 4.8 ± 3.5 days (median, 4) compared with 6.3 ± 5.2 days (median, 5; p < 0.001). The measured incidence of atrial fibrillation is 10.6% in the immediately extubated patients and 18.5% in the ventilated group. This difference is highly significant with p less than 0.001.


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  		Table 2. Selected Outcomes for Immediate Extubated and Ventilated Patients
 
Developing postoperative atrial fibrillation has a significant effect on hospital stays. Patients who had atrial fibrillation had a mean length of stay of 9.2 ± 7.7 days (median, 7) compared with 5.2 ± 3.7 days (median, 4) for patients not having atrial fibrillation (p < 0.001).

The mean number of distal anastamoses done in the immediately extubated and ventilated groups was 2.88 ± 1.15 versus 3.04 ± 1.12 (p = 0.001).

Preoperative ß-Blocker Use and Atrial Fibrillation
In the group of patients who had atrial fibrillation, preoperative ß-blockers were used by 55.9% (210 of 376) whereas in patients not having postoperative atrial fibrillation, ß-blocker usage was 55.7% (1,113 of 1,998), not a statistically significant difference.

Of patients immediately extubated, preoperative ß-blocker usage was 52.3% in those not developing atrial fibrillation and 54.1% in those who did, not a statistically significant difference. For the ventilated patients, 56.4% of the patients having atrial fibrillation used ß-blockers preoperatively, and 57.6% of the patients not having atrial fibrillation used them, again not statistically significant.

Beta-Blocker Use at Discharge
The data were analyzed for patients who were on ß-blockers both preoperatively and at discharge (Table 3). Although the database does not record how soon after surgery ß-blockers were reinstituted, it is likely that this group was placed back on ß-blockers as soon after surgery as possible. Patients in whom atrial fibrillation still developed did so despite continuing use of the drug. Thus, even when controlling for preoperative and postoperative ß-blocker usage, the immediately extubated group had significantly less atrial fibrillation (11.2% versus 16.5%; p = 0.02).


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  		Table 3. Occurrence of Atrial Fibrillation (A-Fib) in Patients Using Beta Blockers Preoperatively and Postoperatively
 
Of those patients who were on ß-blockers preoperatively but not discharged on them, 9.9% (7 of 71) of the immediate extubated group had atrial fibrillation versus 22.2% (42 of 189) of the ventilated group (p = 0.02). Thus, even in those patients who had ß-blocker withdrawal, a known predisposing factor for atrial fibrillation, there was significantly less atrial fibrillation in the immediately extubated group.

Logistic Regression for Atrial Fibrillation
Logistic regression for atrial fibrillation was run to determine factors predictive for the occurrence of atrial fibrillation in the off-pump patient population. Factors analyzed included ventilator use, preoperative ß-blocker use, patient age, chronic obstructive pulmonary disease, previous CABG, previous valve, current smoker, sex, body surface area, diabetes mellitus, renal failure, and congestive heart failure.

Statistically significant predictors are shown in Table 4. Congestive heart failure was the only other factor approaching statistical significance.


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  		Table 4. Logistic Regression for Postoperative Atrial Fibrillation
 
Matching of Patient Groups
To test whether independent variables that are significant factors in the logistic regression are actually predictors or are unevenly distributed between the ventilated and immediately extubated groups, we created matched subgroups and repeated the logistic regression analysis. Matching variables were an exact match for sex; the presence of congestive heart failure, preoperative ß-blocker usage, being a current smoker, and chronic obstructive pulmonary disease; age within ± 3 years; number of distal anastamoses, and ejection fraction ± 15%.

Since the number of anastamoses could be considered a surrogate measure for the extent of the cardiovascular disease, this was added to the matching conditions, as an exact match requirement.

After the matching, the mean age was 63.5 ± 9.9 years in the immediately extubated group and 63.4 ± 10.0 years in the ventilated group, and the ejection fraction was 52.1% ± 10.3% in the immediately extubated and 52.4% ± 11.2% in the ventilated groups. All other variables matched exactly.

A second matched group was created using the STS predicted risk of mortality (PROM) for matching, along with the number of distal anastamoses. Although this risk does not relate directly to postoperative atrial fibrillation, it consists of a large number of patient variables [11] and is a good marker for the severity of the patient's illness. To rule out that the sicker patients were in the ventilated group and atrial fibrillation was maybe more likely to develop, matching on this variable produces two groups with equivalent distributions of patient severity of illness. Again, the number of anastamoses is used as a marker of the extent of the extent of the disease, something not accounted for directly by the PROM.

Table 5 shows the results of using the matched groups for logistic regression for atrial fibrillation. In both analyses ventilator use, increasing patient age, and male sex are risk factors for postoperative atrial fibrillation. In both analyses, previous CABG is also a factor, but decreases the risk of postoperative atrial fibrillation.


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  		Table 5. Results of Logistic Regression on Matched Groups
 
Variation of Atrial Fibrillation Rate With Ventilation Time
Logistic regression was used to study the effect of the length of time of postoperative ventilation (compared with the ventilated/immediately extubated groups used previously) on the incidence of atrial fibrillation, after controlling for the previously mentioned factors. Since postoperative atrial fibrillation is observed to begin during postoperative day 2 or 3, we restricted the analysis only to patients with postoperative ventilation times of 50 hours or less.

With the unmatched data set, the postoperative ventilation time was a significant independent variable with p less than 0.001 and odds ratio of 1.033 per hour increase in ventilation time (95% confidence interval: 1.01 to 1.04). This translates to 3.3% increase per hour, or a 13.2% increase in the probability of developing atrial fibrillation for every 4-hour block of ventilation time. Using the data set matched on the individual factors (above), the increase for 4 hours was 14.1% (p < 0.001); and in the PROM matched data set, a 14.9% increase (p < 0.001).

Reintubation
From January 1, 2002, the STS database has been tracking both initial and additional (after reintubation) hours of postoperative ventilation. In our off-pump population, there are 12 patients who were immediately extubated but subsequently had to be reintubated. In this group, 7 of 12 (58.3%) went on to have atrial fibrillation after reintubation. The reasons and outcomes are shown in Table 6.


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  		Table 6. Incidence of Atrial Fibrillation in Patients Reintubated After Immediate Extubation
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 References
 
Analysis of our data has shown that immediate extubation of off-pump patients after CABG surgery reduces the incidence of postoperative atrial fibrillation to 10.6% from 18.5% in patients maintained on a ventilator. To insure that immediate extubation was not just being used with the healthiest patients who might have a lower risk of postoperative atrial fibrillation, we created various matched groups of patients and reran the analyses. Matching on selected variables that might affect the anesthesiologist's decision whether to immediately extubate, we were able to match 736 of 800 immediately extubated patients with controls who were ventilated postoperatively but otherwise matched the immediately extubated patients.

A second matching was carried out using the STS PROM as a surrogate for the severity of the patient's illness. In both of these matched groups, postoperative ventilator usage increased the risk of postoperative atrial fibrillation by either 66% (matched factors group) or 80% (matched on PROM).

Further analysis using the time (hours) of postoperative ventilation as a continuous variable in the groups matched on risk factors showed an increase in risk of 3.3% per hour of ventilation time, which translates into a 13.2% rise in the probability for a 4-hour period. Similar results were obtained when the PROM and unmatched groups were tested. Increasing length of time on the ventilator postoperative led to increasing probability of postoperative atrial fibrillation occurring.

Our findings are in contrast to some reports in the literature. Unfortunately, the design of those studies makes it difficult to assess their conclusions. Straka and coworkers [12] noted a 21% incidence in their series of immediately extubated patients, but did not have a comparison group of intubated patients. Ascione and colleagues [13] found no correlation between intubation time and development of atrial fibrillation; however, they looked only at average time on ventilator, not at early extubation specifically. Others have looked at the effects of early extubation, but none at immediate extubation. Cheng and colleagues [14] looked at extubation occurring 1 to 6 hours versus 6 to 24 hours and found no difference in rates of atrial fibrillation. However, they only tracked atrial fibrillation for 24 hours in the intensive care unit, and it is known that the peak incidence of atrial fibrillation is on postoperative day 2 [10], when most patients are out of the intensive care unit. Therefore, they likely failed to capture most episodes of this postoperative arrhythmia. Montes and coworkers [15] stated that immediate extubation did not decrease complications, but they failed to look at postoperative atrial fibrillation as a complication.

Advanced age has been shown to be associated with atrial fibrillation, with those under 60 years having a rate of 18% and those over 80 years having a rate of 52% [3]. In our matched data sets, the mean ages were the same, yet the logistic analysis showed increasing age to be a risk factor, increasing the probability of postoperative atrial fibrillation. This finding shows that the older patient is more likely to have atrial fibrillation, especially when intubated postoperatively.

We noted an increase in postoperative atrial fibrillation among patients who were on preoperative ß-blockers. This finding may be related to early ß-blocker withdrawal in the immediate postoperative period. Although it is known that ß-blockers decrease the incidence of postoperative atrial fibrillation [16, 17], the use of preoperative ß-blockers and early postoperative withdrawal has been implicated in the etiology of postoperative atrial fibrillation [18, 19]. We wonder if these patients with ß-blocker withdrawal may also have elevated catecholamine levels contributing to the pathogenesis of atrial fibrillation. We found that even among patients who were withdrawn from preoperative ß-blockers; there was significantly less atrial fibrillation if the patients were immediately extubated. It is intriguing to think that perhaps early extubation lowers circulating catecholamines and leads to less postoperative atrial fibrillation even in this high-risk group. Cheng and colleagues [14] showed similar normal postextubation catecholamine levels in patients extubated early versus late, but failed to look at catecholamine levels while the patients were intubated and ventilated. Perhaps the catechol levels were high during prolonged ventilation and only fell to normal after extubation.

This study may be limited by being a retrospective analysis of prospectively collected data. It is possible that there are subtle selection biases in patients selected for extubation that are not accounted for by the statistical methodology even though it is designed to identify the effects of each factor independently. However, when 12 patients who had immediate extubation were reintubated, they exhibited a 58.3% incidence of atrial fibrillation. This finding argues against selection bias being a significant factor, and further points to a role for intubation after surgery in the development of postoperative atrial fibrillation.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
References
 
DR ROBERT POSTON (Baltimore, MD): You excluded patients who were discharged home within the first day of surgery, but atrial fibrillation can occur within the first 2 weeks. Did you control for the length of stay as a predictor of identifying atrial fibrillation in your multivariate analysis?

DR EDGERTON: Did we look at length of stay?

DR POSTON: Patients who stayed longer in the hospital are observed for atrial fibrillation longer. So, the detection of less atrial fibrillation in patients who got extubated earlier may just be due to a shorter length of stay unless this was controlled for in your analysis.

DR EDGERTON: Thank you for that point. In the published literature, the peak incidence of the postoperative atrial fibrillation is on postoperative day no. 2, ranging usually from day 1 to day 4. All of our patients, and you saw their average length of stay, not all of them, but the average length of stay exceeded 4 days, even in the patients who were immediately extubated, and it was 6 days in those who were not immediately extubated. Therefore, I think that we captured almost all incidence of postoperative atrial fibrillation, but, no, we didn't match looking at length of stay for that factor.

DR SETH D. FORCE (Atlanta, GA): I don't have a lot of experience with heart surgery, but we know from the thoracic literature that after lung resection, esophagectomies, and lung transplants, that those are all significantly linked with a high incidence of atrial fibrillation, and really, atrial fibrillation in those patients are harbingers of other bad things going on, infections, pneumonias.

And so my first question is, how you do know that the atrial fibrillation really wasn't just a sign that the patients on the vent were just sicker or had other problems?

The second question is that clearly the point of the paper is that it is better to extubate the patients earlier, but my guess is that your intubated patients were not being extubated for other reasons, pneumonias, and so forth. Therefore, what can you do to extubate these patients earlier?

DR EDGERTON: Thank you. I think the first question was how do we know that these just weren't sicker patients, and though there may be some subtle selection bias, we have tried extensively through our statistical analyses to account for that. The logistic regression analysis we used looked at all those factors, and we track all those factors in the STS database, and I showed you the ones that emerged. So the things that you mentioned did not fall out as other causes of why these patients were intubated. Also, if you believe that the predicted risk of mortality is a marker of severity of illness, we also matched on predicted risk of mortality and still found that ventilator status was predictive of postoperative atrial fibrillation. And, I am sorry, I forgot your second question.

DR FORCE: The second question was, given that those patients required a longer time on the ventilator, clearly there were probably reasons for that, so I guess the question is, what can you really do to change incidence of atrial fibrillation in those patients?

DR EDGERTON: This is off the subject of the paper a little bit, but we found that the ability to extubate these patients really develops with intention to treat. In patients who are directed toward postoperative extubation, we have been able to extubate in one particular hospital where we particularly aim at over 90% of the patients. So I think there are things that you can do, and it starts in the operating room with the anesthetic technique.

I don't know that these patients, the vast majority of them, are intubated because of other reasons. Those would have fallen out in our statistical analyses of postoperative complications, and we didn't see that emerge in the data here. A lot of this is treatment protocols and aggressiveness of approach to extubating the patients.

DR JOHN M. KRATZ (Charleston, SC): Jim, certainly a provocative paper, but I think you are catching the sense that you haven't won us all over quite yet. A couple of possible reasons for that. If you look at your data, you also suggest that off-pump, and you know I am a favorite fan of off-pump, but nevertheless, you suggest that off-pump had a lower incidence of atrial fibrillation. There have been some fairly good randomized prospective studies that haven't shown that benefit, which maybe points out a lot of our concern about even with the best possible statistics, there are some hidden markers that we haven't tested for.

So I guess my question to you is, do you plan in the future to maybe give us a randomized prospective study that could maybe convince us remaining doubting Thomases that this really is a true effect?

DR EDGERTON: Thank you for those comments. Certainly this is a retrospective analysis that we think establishes a correlation between postoperative atrial fibrillation and length of time on ventilator. We tried to go through extensive statistical analyses to make sure that that correlation is true and report that data to the best of our scrutiny today and believe that that correlation is indeed true. However, this study was not designed in any way to look at the physiologic correlates or the etiologic mechanisms of postoperative atrial fibrillation. So why does this then lead me in the area of hypothesis?

And two things that I may hypothesize, if I wander into that area of hypothesis, are, one, perhaps there are limitations, that there are subtle biases that all of our statistical accounting don't take into account, or, two, perhaps those patients that are ventilated have increased levels of intrinsic catecholamines.

Now, it is well established in the literature that increased intrinsic levels of catecholamines are correlated with increased postoperative atrial fibrillation, but I don't know of any studies that have looked at that. Doctor Chang published one in which he looked at catecholamine levels, but he didn't draw them while the patients were on the ventilator, only after extubation. So do we want to move forward in that area?

I think that there is enough here that is intriguing to encourage further scrutiny by other investigators and perhaps by our own group, and our research group will be discussing a prospective protocol and then searching for funding for that protocol.

DR JOHN H. CALHOON (San Antonio, TX): Doctor Edgerton, a really nice paper. During the discussion one thing came out that I wondered maybe you could clarify. You have different anesthetic management at different facilities. Have you investigated the chance that some of the agents or some of the techniques used are different and could have played a role in your outcomes? Thank you.

DR EDGERTON: Thank you for that question. Two ways to look at that. We certainly have different anesthetic management and in different facilities. As you know, we are a large practice and we span multiple facilities and 18 surgeons. In one way, we could view that we are a slice of Americana, we are a look at what is going on across the board, but controlling for those factors is extremely difficult. And one of the problems is the STS database does not capture anesthetic technique by these various anesthesiologists. So, no, we couldn't account for individual techniques.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 

  1. Creswell LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postoperative atrial arrhythmias Ann Thorac Surg 1993;56:539-549.[Abstract]
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  7. Hashimoto K, Ilstrup DM, Schaff HV. Influence of clinical and hemodynamic variables on risk of supraventricular tachycardia after coronary artery bypass J Thorac Cardiovasc Surg 1991;101:56-65.[Abstract]
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  14. Cheng DC, Karski J, Peniston C, et al. Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass graftinga prospective randomized controlled trial. J Thorac Cardiovasc Surg 1996;112:755-764.[Abstract/Free Full Text]
  15. Montes FR, Sanchez SI, Giraldo JC, et al. The lack of benefit of tracheal extubation in the operating room after coronary artery bypass surgery Anesth Analg 2000;91:776-780.[Abstract/Free Full Text]
  16. Andrews TC, Reimold SC, Berlin JA, Antman EM. Prevention of supraventricular arrhythmias after coronary artery bypass surgery. A meta-analysis of randomized control trials Circulation 1991;84(Suppl 3):236-244.
  17. Kowey PR, Taylor JE, Rials SJ, Marinchak RA. Meta-analysis of the effectiveness of prophylactic drug therapy in preventing supraventricular arrhythmia early after coronary artery bypass grafting Am J Cardiol 1992;69:963-965.[Medline]
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