Örebro University School of Medicine Degree project, 15 ECTS May 2016
Does postoperative body temperature correlate with
atrial fibrillation after cardiac surgery?
Version 2
Author: Victor Gyllenflykt Supervisor: Anders Ahlsson School of health and medicine, Örebro University,
Abstract
Introduction: Atrial fibrillation is the most common arrhythmia and a common complication
after cardiac surgery. The pathogenesis of postoperative atrial fibrillation (POAF) remains unclear. Studies indicate that postoperative inflammation may be a part of the pathogenesis.
Objective: The primary aim of this study was to investigate the correlation between a
postoperative rise in body temperature, as a marker of inflammation, and the development of POAF.
Material and Methods: Body temperature postoperative day 1 through 5 was retrospectively
collected from 80 consecutive patients who had undergone isolated coronary artery bypass grafting surgery between May and November 2015. A temperature deviation from normal (36.7° C) was calculated and added to a total temperature deviation day 1 through 5. The difference in mean total temperature deviation between those with and without POAF was evaluated with statistical analysis.
Results: Of the 80 patients, 75 were included in the analysis. The incidence of POAF was 29
of the 75 patients (38.7%). The patients with and without POAF had a mean total temperature deviation of 1.84° C and 1.54° C, respectively. The difference was not statistically significant (p-value = 0.481).
Conclusion: The study shows no correlation between a postoperative rise in body
temperature and POAF. The study is limited by a small sample size, its methods and its retrospective design. Therefore, a larger study with different methods and design should be made to further investigate the correlation.
Abbreviations
ACE – angiotensin-converting enzyme AF – atrial fibrillation
BMI – body mass index
CABG – coronary artery bypass grafting CK-MB – creatinine kinase-myocardial band COPD – chronic obstructive pulmonary disease CPB – cardiopulmonary bypass
CRP – C-reactive protein EF – ejection fraction
EuroSCORE – European system for cardiac operation risk evaluation IL – interleukin
MI – myocardial infarction
NSAID – non-steroidal anti-inflammatory drug POAF – postoperative atrial fibrillation
Q-Q plot - quantile-quantile plot S-Creatinine – serum-Creatinine TIA – transient ischemic attack
Contents
1. Introduction ... 5
1.1 Atrial fibrillation ... 5
1.2 Postoperative atrial fibrillation ... 5
1.3 Inflammation and POAF ... 7
2. Objective ... 8
3. Material and Methods ... 8
3.1 Cohort ... 8
3.2 Data collection and definitions ... 8
3.3 Perioperative management ... 9 3.4 Statistics ... 9 3.5 Ethics ... 10 4. Results ... 10 5. Discussion ... 12 6. Conclusion ... 14 7. Acknowledgements ... 14 8. References ... 15
1. Introduction
1.1 Atrial fibrillation
Atrial fibrillation (AF) is a tachyarrhythmia in which the cardiac impulses in the atrium are uncoordinated and disoriented, resulting in loss of atrial pump function [1].
AF is the most common arrhythmia with an estimated overall prevalence of 0.4% - 1.0%. The prevalence is higher in men than in women and is increasing with age. The incidence is in the range of <0.1% to approximately 2.0% annually, also depending on age and sex. These numbers are increasing over time due to various reasons, such as an ageing population [1].
The electrophysiological mechanisms of AF in the general population are not completely understood. The literature mentions trigger events for initiation of AF and separate mechanisms for maintenance. The most common trigger event is spontaneous impulses arising from the pulmonary veins [2-3]. AF is then thought to be maintained by a reentry phenomenon, in which multiple depolarization waves continuously travel through non-refractory areas in the atrium [2-4]. Normally, excitation of the atrial muscle causes a refractory state throughout the whole atrium, which makes the impulse stop [4]. In contrast, electrical and structural changes in the atrium could make it possible for non-refractory areas to appear before the impulse stops, which in turn may cause the reentry phenomenon
previously mentioned. Electrical changes may be alterations in ionic properties that shortens the refractory period and make the conduction velocity slower, whereas structural changes include, for example, myocyte loss, fibrosis, and dilation of the atrium, which also make the refractory period shorter or the conduction velocity slower, or make the impulse pathway longer [2-4].
1.2 Postoperative atrial fibrillation
Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery. The incidence varies in the literature and is in the range of approximately 20% to 40%, depending on, for example, the definition of POAF, type of cardiac surgery, and the age of the study population [5-14]. Day of onset is typically postoperative day 2 or 3 [5-6, 11]. POAF, in turn, is associated with a higher complication rate (e.g. stroke, respiratory failure, infection), longer hospital stays, and higher short-term and long-term mortality [15].
To reduce the incidence of POAF with prophylactic treatment, researchers have tried to find risk factors for POAF. Higher age has consistently been the strongest risk factor in these studies [6-7, 11-13]. Other mentioned factors associated with a higher incidence are the following: a history of AF or other arrhythmia [7, 11], chronic obstructive pulmonary disease (COPD), postoperative withdrawal of treatment with beta-blockers or angiotensin-converting enzyme (ACE) inhibitors [11], valve surgery (compared to coronary artery bypass grafting (CABG)), combined CABG with other types of cardiac surgery (compared to isolated CABG) [6, 11-12], heart failure [7, 12-13], preoperative serum-Creatinine (S-Creatinine) ≥ 150
micromole/l, male gender, current smoking, previous myocardial infarction (MI), absence of hyperlipidemia [13], pre – and postoperative kidney failure, CABG with cardiopulmonary bypass (CPB) (compared to no CPB (“off-pump” surgery)), postoperative pulmonary congestion and respiratory failure, postoperative treatment with catecholamines [7], some postoperative complications (stroke, infection, unstable hemodynamics), non-use of beta-blockers preoperatively [6], hypertension, race (higher incidence in Caucasians), and
intraoperative use of cardioplegia and intraaortic balloon pump [12]. It should be pointed out that these factors are not as consistent in the studies. The problem with inconsistency could come from the study design, since all of these are observational studies. In general, it seems hard to find risk factors for POAF and thus hard to find effective prophylactic treatments [11-13].
Some treatments have been evaluated for its prophylactic effect against POAF. As already mentioned there are evidence indicating that both postoperative withdrawal of beta-blockers or ACE-inhibitors and non-use of beta-blockers preoperatively increase the incidence of POAF [6, 11]. In contrast, pre - and/or postoperative treatment with beta-blockers, ACE-inhibitors, potassium supplement, or non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease it [7, 11], although other studies have not been able to demonstrate such an effect [12]. In fact, recent meta-analyses of randomized clinical trials do confirm a prophylactic effect with beta-blockers given before, during or after surgery [16-17], even though there are limitations to those meta-analyses. Other pre – and/or postoperative treatments shown to reduce the incidence of POAF are amiodarone, sotalol, steroids,
colchicine, statins, N-Acetylcysteine, vitamin C, and cardiac pacing (i.e. controlling the pace of the patient’s heart with electrical pulses delivered through the chest) [18].
The pathogenesis of POAF is not completely understood. Researchers state that the same reentry phenomenon and some of the same structural and electrical changes involved in AF in the general population may be involved in the pathogenesis of POAF as well. These changes can be long-term, for example, age-related, come from structural heart disease, or come from a history of AF, which all create an atrium that predisposes to both AF in general and POAF. The changes can also be acute, caused by surgery-related factors such as inflammation, sympathetic overload, and oxidative stress, which may work as triggers for POAF in a predisposed atrium [19-21].
1.3 Inflammation and POAF
It is well established that cardiac surgery induces a systemic inflammation, evident by an increase in serum inflammatory markers, together with a local cardiac inflammatory reaction (i.e. from surgical trauma) [22-25]. The inflammation is particularly prominent in surgery using CPB compared to off-pump surgery [22, 26-27]. It is also evident that the inflammatory response may cause some of the symptoms sometimes seen after surgery, for example,
hemodynamic instability (e.g. tachycardia and increase in white blood cell count) and fever [24, 28]. The fever is most possibly due to the effect of inflammatory cytokines promoting prostaglandin biosynthesis. Prostaglandins, in turn, act on hypothalamus, the central regulator of body temperature, to increase the body temperature [29].
There is evidence of a link between the postoperative inflammation and POAF. First of all, increase in some of the inflammatory markers can predict the occurrence of POAF. For instance, research has indicated that postoperative white blood cell count correlates with POAF [8, 10]. Increase in other inflammatory markers such as C-reactive protein (CRP) and interleukin (IL)-6 have been correlated with POAF in some studies, while other studies have failed to show such a correlation [5, 14]. In a recent systematic review Jacob et al. confirmed that white blood cell count is the only inflammatory marker that can predict POAF, whereas inconsistency remains for CRP, IL-6, and other markers [30]. Furthermore, animal studies have discovered that inflammation has an effect on cardiac function. More specifically, these studies have demonstrated that a local atrial inflammation causes an electrical remodeling in the atrium and may therefore have a role in the genesis of POAF [31-32]. Moreover, genetic polymorphism complicates the inflammatory component in the development of POAF with studies that have shown that polymorphism in the promotor of the IL-6 gene influences the
IL-6 level after CABG surgery [33]. This may, in turn, alter the postoperative inflammatory response and consequently the incidence of POAF [9]. Additionally, a meta-analysis of randomized trials have shown a decreased incidence in off-pump surgery vs. surgery with CPB [34]. Since off-pump surgery is known to reduce the postoperative inflammation, this further supports the evidence of an inflammatory component in the genesis of POAF. Lastly, some of the treatments that have been shown to reduce the incidence of POAF are anti-inflammatory, for example, NSAID, steroids, colchicine, and statins. All the these facts strongly indicate a link between POAF and inflammation, although the exact role of systemic and local inflammation in the pathogenesis is still not known [35].
2. Objective
The objective of this study is to further investigate the development of POAF, because this will take us further towards effective prophylactic treatments and thereby reduce the burden of POAF. With the main focus on the inflammatory component, the primary aim of this study is to investigate if there is a correlation between a postoperative rise in body temperature, as a marker of inflammation, and the occurrence POAF. No research has studied this before. The secondary aim is to study the association between POAF and other variables, such as patient characteristics and a few perioperative variables. Many of these have been studied before with varying results.
3. Material and Methods
3.1 Cohort
Eighty consecutive patients who underwent isolated CABG at the Department of Thoracic and Cardiovascular Surgery, Örebro University Hospital, between May and November 2015, were included in the study. Of these, four patients with a history of atrial fibrillation and one patient who died before postoperative day 5 were excluded. Thus, the total number of participants was 75 (n = 75).
3.2 Data collection and definitions
Data were retrospectively collected from patient journals. Preoperative data included age, weight, height, body mass index (BMI), hypertension (yes/no), diabetes (yes/no), smoking (yes/no), previous stroke/transient ischemic attack (TIA) (yes/no), previous MI (yes/no), previous AF (yes/no), ejection fraction (EF), preoperative S-Creatinine, and EuroSCORE
(European System for Cardiac Operative Risk Evaluation). Postoperative data included POAF (yes/no), day of POAF onset, body temperature day 1 through 5 (day 1=the day after surgery), CRP day 3, creatinine kinase-myocardial band (CK-MB) day 1, Troponin-I day 3, and length of hospital stay.
Both current smoking and a history of smoking were defined as “yes”. EF was classified based on echocardiography results as “normal”, “slightly reduced”, “moderately reduced”, or “markedly reduced”. For detection of POAF, all patients were monitored with five-lead telemetry until postoperative day 4. From day 5, pulse was checked daily and telemetry was reinstituted in signs of symptoms of arrhythmia. POAF was defined as AF registered on telemetry in 30 seconds or more. Body temperature was measured in ear daily with Braun ThermoScan® Pro 4000 (Welch Allyn, Skaneateles Falls, NY, USA). The first measured temperature of the day was collected day 1 through 5. From the collected temperature a temperature deviation from normal was calculated. Normal body temperature was defined as 36.7° C, which is the average core temperature [4]. If no temperature was registered, the deviation was set to 0.0° C. Temperature deviation day 1 through 5 were added to a total temperature deviation which was the variable used to study the correlation. Length of hospital stay was counted from the day of registration through the day of discharge.
3.3 Perioperative management
Preoperative medication was continued until the day of surgery, except warfarin which was discontinued 3 days before surgery. All patients received similar anesthetic management. Beta-blockers were routinely given all patients postoperatively. In the occurrence of POAF, the patients received a beta-blocker, amiodarone, digoxin, verapamil, or a combination of these. POAF medication was maintained for at least 4 weeks. In addition, all patients received paracetamol postoperatively.
3.4 Statistics
A Student’s T test for independent samples was used to compare means for continuous variables in the two groups (i.e. those with and without POAF). Continuous variables not approximately normally distributed (preoperative S-Creatinine, CK-MB and Troponin-I) were transformed to logarithms before using the T test. Normality was approximated with quantile-quantile (Q-Q) plots (plots not included). To compare means for data on an ordinal scale (i.e.
was used for categorical variables. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS, version 24 (IBM Corp., Armonk, NY, USA).
3.5 Ethics
This study required access to patient journals and, consequently, the confidentiality was violated. Since this study is a part of the quality assurance project “Hjärtkirurgi och komplikationer” (eng. “Cardiac surgery and complications”), no approval from the ethics review board was needed. However, full considerations were given to patient integrity and confidentiality. All personal data were kept at the clinic’s computers and data was collected de-identified and anonymously, where the patients’ social security numbers and names were exchanged by numbers.
4. Results
Among the 75 participants, 13 were females and 62 were males (17.3% and 82.7%, respectively). Twenty-nine patients (38.7%) developed POAF, where most of the cases occurred in postoperative day 2 or 3 (Fig. 1). Table 1 summarizes the baseline characteristics of the two groups (i.e. POAF or no POAF). The observed proportion females in the POAF group was higher compared to the no POAF group, although not statistically significant. The two groups did not differ significantly in respect to age, height, body weight, BMI,
hypertension, diabetes, smoking, previous stroke/TIA/MI, and EuroSCORE. Peri – and postoperative data are shown in Table 2. Length of hospital stay was significantly longer in the POAF group (p-value = 0.028). There was no significant difference between the groups in aspect of preoperative S-Creatinine, CK-MB, CRP, or Troponin-I. The mean total
temperature deviation for patients with and without POAF was 1.84° C and 1.54° C, respectively. The difference was not statistically significant.
Fig. 1. Day of postoperative atrial fibrillation (POAF) onset. Day 1=the day after surgery.
Table 1. Baseline characteristics for patients with and without POAF
No POAF (n=46) POAF (n=29) p-value Femalea Malea Age (years)b Height (cm)b Weight (kg)b BMI (kg/m2)b Hypertensiona Diabetesa Smokinga Previous stroke/TIAa Previous MIa EFa Normal Slightly reduced Moderately reduced Severely reduced EuroSCOREd 5 / 10.9% 41 / 89.1% 67.7 ± 9.3 173.0 ± 7.1 84.2 ± 14.8 28.0 ± 3.8 38 / 82.6% 19 / 41.3% 26 / 56.5% 5 / 10.9% 12 / 26.1% 31 / 67.4% 9 / 19.6% 4 / 8.7% 2 / 4.3% 4e 8 / 27.6% 21 / 72.4% 69.2 ± 7.6 171.4 ± 10.0 83.7 ± 17.7 28.6 ± 5.7 24 / 82.8% 13 / 44.8% 15 / 53.6%c 4 / 13.8% 7 / 24.1% 21 / 72.4% 6 / 20.7% 2 / 6.9% 0 / 0.0% 5f 0.063 0.063 0.441 0.457 0.902 0.579 0.987 0.764 0.804 0.704 0.850 0.339
a count / % within group b mean ± 1 SD c n=28
d median e n=44 f n=27
Table 2. Peri – and postoperative data for patients with and without POAF
No POAF (n=46) POAF (n=29) p-value Pre-op S-Creatinine (mg/L)
CK-MB day 1 (µg/L) CRP day 3 (mg/L) Troponin-I day 3 (ng/L) Tot. temp. deviation (°C) Length of stay (days)
93.5 ± 41.2 29.1 ± 71.0 204.3 ± 86.4 4239.7 ± 17973.7 1.54 ± 1.68 7.7 ± 2.7 108.3 ± 128.3 17.4 ± 13.4 214.1 ± 86.0 1097.0 ± 1830.8a 1.84 ± 1.98 9.8 ± 5.2 0.920 0.650 0.632 0.661 0.481 0.028 All data presented as mean ± 1 SD a n = 27
5. Discussion
The incidence of POAF in this study was 29 of 75 patients (38.7%) and this confirms that POAF remains a common complication after cardiac surgery. The day of onset peaked at postoperative day 2 and 3, which agrees with other studies [5-6, 11].
The primary aim of this study was to investigate if there is a correlation between a
postoperative rise in body temperature and the occurrence of POAF. In this study cohort, a higher mean total temperature deviation was found in the POAF group. Since this result is not statistically significant, one cannot conclude that higher postoperative body temperature is a predictor for POAF. An explanation to the lack of significance may be a small sample size leading to a type II error.
The secondary aim was to study the association between other variables, such as patient characteristics and a few perioperative variables, and POAF. The results show a significantly longer hospital stay for those who developed POAF, which is consistent with other studies [15]. This should be interpreted with caution, since there were two outliers in the POAF group who stayed 30 and 20 days, respectively, which is far from the mean value. They may
therefore have distorted the result. The study fails to show a significant association between higher age and POAF, which does not agree with other studies [6-7, 11-13]. Neither of the other results are statistically significant, but as already mentioned these factors have not always been associated with POAF in the studies that have been made earlier.
There are several limitations to this study. One of the main limitations is the small sample size (n=75). There was also a clear male predominance and only isolated CABG patients were included in the study, which make it harder to generalize to all patients undergoing cardiac surgery.
There are also limitations regarding the temperature data. First, with a retrospective study design one cannot guarantee that the same measurement methods are used during the whole study period. In this case, this fact gave rise to random errors. For example, there were some missing temperature data. Thirty-seven patients (49.3%) had missing temperature data on at least one of the five postoperative days. Furthermore, the goal was to register the first measured temperature each day, but some patients did not have a registered morning
temperature. Thus, we could not consistently use the morning temperature for all patients. This created random errors because body temperature follows a circadian rhythm, with the lowest temperature in the morning [36]. Another random error could have come from using the total temperature deviation from 5 postoperative days as a method for calculating the correlation to POAF. Let us say we had two patients, where one of them had a normal temperature (i.e. for that patient) just above average all postoperative days, while the other had high fever one day and normal (i.e. average) the other days. These patients may have had the same total temperature deviation, but only one of them had a postoperative rise in
temperature. Random errors, like these ones, cannot be neglected with a small study
population because the number of errors could differ between the groups that are compared. What is interesting is that there were significantly more patients in the no POAF group who had missing temperature on at least one of the days (p-value = 0.041). This means that this may, in fact, have been a systematic error rather than a random error. Lastly, there is a limitation in that all patients received paracetamol, which is an antipyretic, postoperatively. Since paracetamol is thought to reduce fever by blocking the cytokine induced biosynthesis of prostaglandin [37], the antipyretic effect would be absent in patients without a postoperative increase in body temperature. Since the observed mean total temperature deviation in the POAF group was higher than in the no POAF group, it is possible that they, as a group, had a greater antipyretic effect. Therefore, without the effect of paracetamol, the difference in mean total temperature deviation between the groups could have been bigger than observed.
Since the POAF monitoring from day 5 through discharge was based on symptoms and pulse control, rather than telemetry, it is possible that episodes of POAF could have been missed. There may also have been missed cases of POAF after discharge. Therefore, one cannot exclude the possibility that some patients had one or more undetected episodes of fibrillation. Moreover, in this study all patients with a history of atrial fibrillation were excluded, and it is possible that some of the included patients may have had undetected episodes of AF before.
Lastly, there is a limitation in the study design itself. As with all observational studies, there is a risk of confounding factors. That is, factors not included in the study may have had an influence on measured variables and consequently affected the correlation with POAF.
6. Conclusion
POAF remains a common complication after cardiac surgery. Consistent with other studies, this study found a significantly longer hospital stay for those who developed POAF, although this finding has limitations. The study shows no correlation between a postoperative rise in body temperature and POAF, but this result is also limited. The limitations are concerning sample size, methods, and study design. Because of these limitations, a larger study with different methods and design should be made to further investigate the correlation.
7. Acknowledgements
I would like to show appreciation to my supervisor, Anders Ahlsson, for his availability to answer questions at any time. Also, for letting me work and learn independently with guidance when needed.
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