Association of Neutrophil to Lymphocyte Ratio as a Predictor of New Onset of Atrial Fibrillation After Off Pump Coronary Artery Bypass Grafting
Dr. Bijay Kumar Sah *1, Professor Dr. Md. Aslam Hossain 4, Dr. Md. Alauddin 3,
1. MBBS, MS (CV & TS), Bangabandhu Sheikh Mujib Medical University, Dhaka Bangladesh.
2. MBBS, MS (CV & TS), FACS (USA) Professor, Cardiac Surgery Bangabandhu Sheikh Mujib Medical University
3. MBBS, MS (CV&TS), Bangabandhu Sheikh Mujib Medical University.
Corresponding Author: Dr. Bijay Kumar Sah, MBBS, MS (CV & TS), Bangabandhu Sheikh Mujib Medical University, Dhaka Bangladesh.
Copy Right: © 2023, Dr. Bijay Kumar Sah, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received Date: April 25, 2023
Published Date: May 01, 2023
DOI:https://doi.org/10.5281/zenodo.15544022
Abstract
Background: Atrial fibrillation is frequently seen in patients underwent off pump coronary artery bypass graft. Neutrophilia and lymphopenia may be strongly associated with developing atrial fibrillation by both electrical and structural remodeling of the atrium due to atrial fibrosis and oxidative stress also plays an important pathological role. The aim of this study is to investigate the association of neutrophil to lymphocyte ratio with postoperative atrial fibrillation in the patients who underwent off pump coronary artery bypass grafting.
Methods: This comparative cross sectional study was carried out in department of cardiac surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka. Total 70 patients were selected for this study, divided into two groups. Among them, 35 patients with preoperative neutrophil to lymphocyte ratio level ≥ 2.63 were in group A and 35 patients with preoperative neutrophil to lymphocyte ratio level < 2.63 were in group B. The data was collected by semi structured questionnaire and reviewing medical records. The continuous data was evaluated by independent t-test and categorical data by chi-square test, where quantitative as mean & SD and qualitative as frequency & percentage. Prediction was reviewed using logistic regression analysis. P value ≤ 0.05 was significant for data analysis which was summarized in tables & charts. Ethical approval was taken from the institutional review board of Bangabandhu Sheikh Mujib Medical University.
Results: The Mean ± SD age was 52.71±11.49 in group A and 51.91±10.04 in group B. There were 28 (80%) male in group A and 34 (97.1%) male in group B and also 31 (88.6%) patients in group A had hypertension where as 24 (68.6%) patients in group B had hypertension which was statistically significant. Postoperative atrial fibrillation occurred in 28 (80%) of patients in group A whereas only 2 (5.7%) patients in group B which was statistically significant. In the logistic regression model, Neutrophil to lymphocyte ratio was found to be an independent predictor for new onset of postoperative atrial fibrillation development with 70% sensitivity, 87.5% specificity, OR 5.649, 95% CI 2.353 – 13.562, p=0.001S.
Conclusion: This study showed that there is association between the preoperative neutrophil to lymphocyte ratio as a predictor of new onset of postoperative atrial fibrillation after off-pump coronary artery bypass graft.
Abbreviation
ABG = Arterial Blood Gas
AF = Atrial Fibrillation
AHA = American Heart Association
AKI = Acute Kidney Injury
ASA = American Society of Anaesthesiologist
AUC = Area Under the Curve
BMI = Body Mass Index
BP = Blood Pressure
BSMMU = Bangabandhu Sheikh Mujib Medical University
CABG = Coronary Artery Bypass Graft
CAD = Coronary Artery Disease
CAG = Coronary Artery Angiogram
CI = Confidence Interval
CKD = Chronic Kidney Disease
CMV = Controlled Mandatory Ventilation
COPD = Chronic Obstructive Pulmonary Disease
CPB = Cardio Pulmonary Bypass
CRP = C - Reactive Protein
CVTS = Cardiovascular and Thoracic Surgery
DALYs = Disability – Adjusted Life Years
DM = Diabetes Mellitus
DVD = Double Vessels Diseases
ECG = Electrocardiogram
EDTA = Ethylenediamine Tetraacetic Acid
GBD = Global Burden of Cardiovascular disease
GSV = Great Saphenous Vein
HDU = High Dependency Unit
ICU = Intensive Care Unit
IHD = Ischemic Heart Disease
IRB = Institutional Review Board
LA = Left Atrium
LAD = Left Anterior Descending
LCX = Left Circumflex
LIMA = Left Internal Mammary Artery
LMD = Left Main Disease
LVEF = Left Ventricular Ejection Fraction
MI = Myocardial Infraction
MPO = Myeloperoxidase
NADPH= Nicotinamide Adenine Dinucleotide Phosphate
NLR = Neutrophil to Lymphocyte Ratio
NYHA = Newyork Heart Association
OPCAB= Off-Pump Coronary Artery Bypass Graft
OR = Odds Ratio
PLR = Platelet Lymphocyte Ratio
PoAF = Post-Operative Atrial Fibrillation
POD = Postoperative Day
SD = Standard Deviation
SVD = Single Vessel Disease
TVD = Triple Vessels Disease
WBC = White Blood Cell
Introduction
Coronary artery bypass graft surgery is the definite surgical procedure for the treatment of ischemic heart diseases. CABG resolves symptoms and improves the survival of the patients suffering from severe coronary artery diseases (Roger et al. 2012). Conventional CABG is performed on cardiopulmonary bypass (CBP) which have some serious complications like stroke, kidney or liver failure, decrease in higher mental function and bleeding (Shekar P et al. 2006). Off-pump coronary artery bypass graft (OPCABG) operation possibly avoid the risk of extracorporeal circulation although there are some possible risks which include infection, bleeding, atrial fibrillation, blood clots leading to stroke or heart attack, kidney failure and complications from anesthesia among which postoperative atrial fibrillations is greater distress for the cardiac surgeons. Therefore, it is very much necessary to rule out patients at risk and take effective prophylaxis and management on due time to reduce the associated risks of adverse outcome.
Neutrophil to lymphocyte ratio (NLR) has emerged as a novel systemic inflammatory marker and also as a prognostic indicator of adverse cardiovascular complications (Papa A et al. 2008). Neutrophil are activated non-specific inflammatory cell which are attracted to the myocardium during & after cardioplegia and CPB by a diffuse failure of endothelial cells, later resulting from ischemia and reperfusion injury (Jacob KA et al. 2014). Lymphopenia is a marker of physiological stress. Both raised neutrophil and lymphopenia are indicators of inflammation and inflammation can alter conduction, facilitating re-entry thus predispose the development of postoperative atrial fibrillation (Echahidi N et al. 2008). NLR seems significantly higher in the CPB group compared with the OPCAB group (Aldemir M et al. 2015).
Neutrophilia represent activated non-specific inflammation and lymphopenia is a marker of poor general health and physiological stress. NLR shows the balance between the neutrophil and lymphocyte levels and integrates these two important and opposite immune pathways which serve as a measures of both systemic inflammation and stress response (Shao Q et al. 2015). Leukocytes were identified in atrial tissue of AF patient’s even without an underlying structural heart disease (Frustaci A et al. 1997). Inflammation appears to be a critical confounder for structural remodeling of the atria and thus for genesis of atrial fibrillation (Spodick DH, 1997).
Neutrophils are major constituents of the innate immune system. Local endothelium release local cytokines and expression adhesion molecule that attracts neutrophils due to expression of integrins (CD11b/ CD18) on the leukocytes outer membrane which is the principal pre requisite for the leukocytes subsequent extravasations. Neutrophils release myeloperoxidase (MPO) and matrix metalloproteinase (MMP) stored in primary granules of neutrophils, to endothelial cells via -a direct CD11b/ CD18 –integrins mediated intercellular link. These enzymes known to accelerate tissue remodeling and atrial fibrosis by increasing deposition of interstitial matrix such as collagen I & II and fibronectine which impairs atrial conduction, allowing for an increased electrical ectopic and re-entry. Thus atrial fibrosis plays a major role in the pathogenesis of atrial fibrillation (Friedrichs K et al. 2014).
Postoperative atrial fibrillation is the commonest arrhythmia observed in 18-40% of patients after isolated coronary artery bypass surgery (El-Chami 2010; Ozturk 2019), 35-40% after isolated valvular surgeries and even higher from 35% to greater than 60% after combined coronary artery bypass graft (CABG) and valve surgery (Greenberg J et al. 2017) which may leads to hemodynamic disturbances associated with increased risk of embolism, heart failure, prolong hospital stay and increase cost.
Postoperative atrial fibrillation onset follows nonlinear trend and usually highest on 2nd postoperative day. Onset depends on risk factors and can be divided into two phases of risk. First phase of risk occurs immediately after surgery and declines sharply during first 18 hrs depending upon factors like elderly age, prolong cross clamp time and mitral valve surgery. The second phase increase to a peak from hour zero to 36-48 hrs depending upon the risk factors like advanced age, greater weight, Caucasian race and mitral valve surgery (Greenberg J et al. 2017).
Postoperative atrial fibrillation was found as a major morbid event (Almassi et al. 2007), which is associated with thromboembolism and stroke (Fuller et al. 2007), ventricular dysrhythmias, hemodynamic instability (Aranki et al. 2006), and iatrogenic complication associated with therapeutic interventions. AF results ineffective irregular contraction and incomplete ejection of blood, especially within the left atrial appendage which is the main source of thrombus formation in patients with AF (Safavi-Naeini et al. 2020). There is about 3-fold greater risk of perioperative stroke for the patients with postoperative atrial fibrillation. About 3,855 patients went cardiac surgery among which hospital mortality and 6-month mortality were significantly more in patient with postoperative atrial fibrillation (Almassi et al. 2007).
The etiology of postoperative atrial fibrillation after OPCABG are most likely multifactorial which include metabolic abnormalities (hyperuricemia, hypoxia, hypothyroidism, diabetes), advanced age, male sex, hypertension, withdrawal of β-blockers, impaired cardiac function, chronic renal failure, myocardial ischemia and reperfusion, myocardial infarction, right coronary artery disease, excessive catecholamine, electrolyte imbalance, particularly hypomagnesemia, (Kohno et al. 2005) as well as inflammatory and oxidative changes which closely linked to initiation of atrial fibrosis and AF. The inflammatory mediators contribute to postoperative atrial fibrillation has been suggested by evidence of high C-reactive protein (CRP) and white blood cell (WBC) count within 3 days after cardiac surgery (Walsh J et al. 2017).
For these reasons, inflammatory parameters have been the subject of research to rule out the results after cardiac surgery, just as in many areas of medicine, and exert various effects on cardiovascular diseases. It also has been reported that preoperative calculated NLR may be associated with postoperative atrial fibrillation (Gibson PH et al. 2007).
In BSMMU, no study has yet been carried out for the prediction of postoperative atrial fibrillation by using NLR. Therefore in this study we aim to investigate whether NLR can be used preoperatively as an early predictor of postoperative atrial fibrillation after off – pump coronary artery bypass graft.
Rationale of the Study
Postoperative atrial fibrillation is a common complication after off-pump coronary artery bypass graft which leads to thromboembolism, stroke, ventricular dysrhythmia, hemodynamic compromise and many more, and directly linked to inflammatory process which leads to atrial fibrosis. Complete blood counts routinely done for all the patients as preoperative investigations during optimization of the patients. Neutrophil to lymphocyte ratio, a novel and inexpensive biomarker, is reported to physicians in clinical practice as part of the automated complete blood count. However, Neutrophil to lymphocyte ratio is usually overlooked while studying simple complete blood count report.
Previous meta-analysis and prospective studies have shown that higher Neutrophil to lymphocyte ratio is associated with postoperative atrial fibrillation in patients undergoing isolated off-pump coronary artery bypass graft. Although there are many risks assessment methods which are used to assess risk but even have some limitations. The risk assessment tools need improvement to know which patients should be closely monitored for atrial fibrillation after surgery. So, new tool need to be established which ought to be simple enough for clinical use and cost-effectiveness. Hence, Neutrophil to lymphocyte ratio can be utilized to upgrade risk models which further benefit the surgical patients without extra financial burden.
Recently, some studies have shown the predictive role of Neutrophil to lymphocyte ratio in postoperative atrial fibrillation. However, previously, no studies have been carried out in Bangladesh to see the predictive role of Neutrophil to lymphocyte ratio for postoperative atrial fibrillation after off-pump coronary artery bypass graft. The study was attempted to establish the predictive role of Neutrophil to lymphocyte ratio for atrial fibrillation after off-pump coronary artery bypass graft that would helpful for further management of patients.
Research Hypothesis
Preoperative neutrophil to lymphocyte ratio has an association as a predictor of new onset of atrial fibrillation in the patient following off-pump coronary artery bypass graft.
Objectives of the Study
General Objective
Specific Objectives
List of Variables:
Dependent Variable:
New onset of atrial fibrillation
Independent Variable:
Confounding Variables:
Variables related to demographic and anthropometric characteristic:
Variables related to risk factors:
Variables related to preoperative laboratory findings:
Variables related to per operative attributes:
Variables related to postoperative attributes:
Operational Definitions
Arrhythmia:
A cardiac arrhythmia is a disturbance of the electrical rhythm of the heart. Arrhythmias are often a manifestation of structural heart disease but may also occur because of abnormal conduction or depolarization in an otherwise healthy heart (Davidson, 2014. pp.562).
Atrial Fibrillation:
AF is a complex arrhythmia characterized by both abnormal automatic firing and the presence of multiple interacting re-entry circuits looping around the atria. Episodes of atrial fibrillation are initiated by rapid bursts of ectopic beats arising from conducting tissue in the pulmonary veins or from diseased atrial tissue. AF becomes sustained because of re-entrant conduction within the atria or sometimes because of continuous ectopic firing (Davidson, 2014. pp. 564).
New onset AF:
A patient with new symptom attributable to AF or an asymptomatic patient with irregularly irregular and rapid impulse is known as new onset AF.
Neutrophil to lymphocyte ratio:
The NLR is simply the number of neutrophils divided by the number of lymphocytes. Under physiologic stress and inflammation, the number of neutrophils increases, while the number of lymphocytes decreases. The NLR combines both of these changes, making it more sensitive than either alone.
Interpretation: depends on clinical context. However, to provide some idea of how to interpret this:
Body mass index:
It was calculated by the following method:
BMI =(weight in kg)/(height in meter)2
Ejection fraction:
Left Ventricular Ejection fraction is a measurement percentage of blood the left ventricle pumps out with each cardiac cycle. It is calculated as the difference between LV end-diastolic volume (EDV) and end-systolic volume (ESV) divided by LV end-diastolic volume (EDV).
LVEF = stroke volume (EDV - ESV) ÷ EDV It remains the most commonly used method for assessing systolic function.
Acidosis:
Increase H+concentration with decrease pH below 7.35 (Ralston, 2018, p. 363).
Alkalosis:
Decrease H+ concentration with increase pH above 7.45 (Ralston, 2018, p. 363).
Normal renal function:
Those patients who had serum creatinine level < 1.4mg/dl (Shilpak, et al. 2002).
NYHA:
The Newyork Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity; the limitations/symptoms are in regards to normal breathing and varying degrees in shortness of breath and/or angina pain.
Methods
Study design:
This study was a Comparative Cross- Sectional study.
Study Population:
Patients admitted to the department of cardiac surgery, BSMMU who underwent off pump coronary artery bypass grafting surgery.
Place of study:
The study was conducted at Department of Cardiac Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbagh, Dhaka - 1000, Bangladesh which is a 60 bedded well equipped tertiary level hospital with thoracic and vascular wings providing multidisciplinary support and advanced technologies for surgical care of cardiac patients.
Period of study:
The study was conducted within the period of 24 months commencing from September 2020 to August 2022. During this time, protocol development, protocol submission, literature review, research instrument development, data collection, data entry, processing and analysis was done.
Grouping of patients:
Cut off value for NLR was 2.63 (Gibson PH, et al., 2010).
Sample Size:
Formula to calculate sample size
We hypothesized the NLR at cutoff point 2.63 should detect the patients with atrial fibrillation after off pump CABG with a specificity of 80% or greater. The sample size will be calculated for a power level of greater than 80%, an α error of 0.05, and an expected specificity of 68% or greater based on previous reports (Gibson PH, et al., 2010).
Solution:
It is assumed that both the diagnostic test and the criterion standard are dichotomous tests. That is, a subject either tests positive or negative; a subject either has the expected outcome (≥ 2.63 cutoff point) or no expected outcome (no or <2.63).
Sample size calculation based on specificity (Buderer’s formula):
Sample size (n) based on specificity = The ingredients for the sample size calculation are as follows:
n = required sample size Sp= anticipated sensitivity
α= size of the critical region (1-α is the confidence level)
Z1-α/2= standard normal deviate corresponding to the specified size of the critical region (α)
L= absolute precision desired on either side (half-width of the confidence interval) of specificity P= the estimated prevalence of disease in the target population (patients who have clinically Suspected coronary artery disease) Sp=80%
α = 5%
Z1-α/2 = 1.96
L = 10%
Prevalence = 5% (in our hospital setting 5% patients could have coronary artery disease)
So, n =
= 64.67
According to the formula mentioned above, my sample size will be 70 which will be divided in two group each having 35 number of patients.
Sampling method:
Convenience sampling method was applied for this study.
Selection criteria of patients:
Participants enrolled in this study that underwent OPCAB with fulfilling inclusion and exclusion criteria.
Inclusion criteria:
Exclusion criteria:
Study procedure:
All relevant data was collected from each respondent by use of interview schedule, measured parameters and investigations in a predesigned format.
Group A: NLR level ≥ 2.63
Group B: NLR level < 2.63
Monitoring of:
The impact of different variables on either group was evaluated accordingly.
Data collection form was filled and collected throughout my study period and was accumulated at the end of the study period.
Anaesthesia & Surgical technique
All patients received a standard general anesthesia protocol for surgery through a standard median sternotomy approach. OPCAB performed by using left internal mammary artery and reversed saphenous vein graft as a conduit.
Postoperative evaluation
At the end of the surgery, the patients were transferred to the Intensive Care Unit (ICU). Initially, they will be ventilated with controlled mandatory ventilation (CMV) followed by synchronized intermittent mandatory ventilation. Extubation was performed when the patient fulfilling extubation criteria, hemodynamically stable, alert and proper ventilation maintained and blood gas values are within safety levels. Antibiotic and analgesics were used as the standard protocol of the institution follow. Postoperatively patients were evaluated in ICU on 0, 1st, 2nd, 3rd & 4th postoperative days for the incidence of any form of atrial arrhythmia.
Data collection Technique:
Data collection Instrument:
A semi structured questionnaire was developed in English, followed by conversion to Bangle. The questionnaire was developed using the selected variables according to the specific objectives and it contained questions related to socio-demographic characteristics, preoperative, per operative and postoperative outcomes.
Data collection tools were developed by reviewing the related literature and seeking an opinion from the subject experts, research advisors, seniors, and colleagues.
Pretesting:
The preformed structured questionnaire and checklist was pre-tested on 5 patients in department of cardiac surgery, BSMMU. It was finalized after necessary modification based on pre-testing with the help of supervisor.
Quality control checks:
Data were checked immediately after completing interview and review of necessary investigation reports. Again, before data processing, collected information was checked for completeness and internal consistency considering the norms of missing data.
Statistical analysis:
Ethical considerations:
Results
Distribution of patients by Age between two groups
Among study population, most of the patients were within 41-60 years age group i.e., 20 (57.1%) and 21 (60.0%) in group A and B respectively. Mean age was found 52.71 ± 11.49 years in Group A and 51.91 ± 10.04 years in Group B. There was no statistically significant difference of age distribution between two groups.
n = Total number of subjects NS = Not significant
SD = Standard Deviation
Data were presented as mean ±SD
Statistical analysis was done by independent t-test p value ≤0.05 was considered as significant.
Distribution of patients by Sex between two groups
Table- 2 shows the distribution of patients by sex between two Groups. In Group A 80.0% of the patients were male 20.0% were female, where in group B 97.1% of the patients were male and 2.9% were female. Statistical significant difference present between two Groups in distribution of patients by sex.
n = Total number of subjects S = significant (p < 0.05)
Data were expressed as frequency (f) and percentage.
Chi-square test was done to measure the level of significance. p value ≤0.05 was considered as significant.
Distribution of patients according to Body Mass Index between two groups
The following table-3 shows BMI class in group A and group B. 6 patients in group A and 7 patients in group B were normal and 18 patients in group A and 19 patients in group B were overweight. 11 patients in group A and 9 patients in group B were obese. Among the study population most of the patients are overweight in both group. Mean BMI was found 28.02 ± 3.30 and 27.68 ± 2.87 in group A and group B respectively. There is no significant difference in BMI between two groups.
n = Total number of subjects NS = Not significant
SD = Standard Deviation
Data were presented as frequency (f) and mean ±SD. Figures in the parentheses denote corresponding %. Statistical analysis was done by independent t-test.
p value ≤0.05 was considered as significant.
Comparison of preoperative risk factor between two groups
Table 4 shows the distribution of data obtained by evaluating risk factors. The comparison of history of smoking, hyperlipidemia and diabetes mellitus in group A and B patients were statistically not significant (p>0.05) but hypertension is found statistically significant (p<0.05) between the groups.
n = Total number of subjects S = significant (p < 0.05)
NS = Not significant (>0.05)
Data were expressed as frequency (f) and percentage.
Chi-square test was done to measure the level of significance between two groups.
p value ≤0.05 was considered as significant.
Distribution of patients according to preoperative routine investigations between two groups
Table 5 shows preoperative NLR was 3.70 ± 1.13 in group A and 1.90 ± 0.60 in group B and there are statistically significant differences between the groups. Mean serum creatinine was 1.07 ±
0.19 in group A and 1.07 ± 0.18 in group B. Mean Na+ and K+ level of group A was 139.47 ±
2.78 and 3.79 ± 0.17 and of group B was 138.25 ± 2.67 and 3.76 &pl