Effects of Cardiovascular Autonomic Neuropathy (CAN) on Acute Kidney Injury and Clinical Outcomes in Patients Undergoing Isolated Coronary Artery Bypass Surgery
Conditions: Acute Kidney Injury (AKI), Coronary Artery Bypass Graft (CABG), Cardiovascular Autonomic Neuropathy (CAN), Postoperative Outcomes
Sponsor: Akdeniz University

 Study Document Cover Page 
 
Official Title: : The Effects of Cardiovascular Autonomic Neuropathy (CAN) on Acute Kidney Injury 
and Outcome Parameters in Patients Undergoing Isolated Coronary Artery Bypass Grafting (CABG) 
 
NCT Number: 
NCT ID not yet assigned 
Document Type: 
Study Protocol with Statistical Analysis Plan and Informed Consent Form 
 
Document Date: 
October 1, 2020 
 
Sponsor / Institution: 
Akdeniz University Faculty of Medicine, Department of Anesthesiology and Reanimation 
 
Principal Investigator: 
Emel Gündüz, MD 
 
Contact Information: 
emelgunduz@akdeniz.edu.tr 

Study Protocol 
 
Title: The Effects of Cardiovascular Autonomic Neuropathy (CAN) on Acute Kidney Injury and 
Outcome Parameters in Patients Undergoing Isolated Coronary Artery Bypass Grafting (CABG) 
Document Date: October 1, 2020 
Institution: Akdeniz University Faculty of Medicine, Department of Anesthesiology and Reanimation 
Principal Investigator: Emel Gündüz, MD 
1. Study Objective 
This study aims to analyze the effects of cardiovascular autonomic neuropathy (CAN) on primary 
outcome of acute kidney injury (AKI) and secondary outcome parameters in patients undergoing 
coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC). 
Specifically, the study will investigate: 
The incidence of CAN in patients scheduled for isolated CABG 
The effect of CAN on AKI 
The impact of CAN on outcome parameters (mortality and morbidity) 
The relationship between changes in regional cerebral oxygen saturation (rSO₂) and CAN 
CAN Diagnosis: 
1. Valsalva maneuver 
2. Sitting-to-standing test 
3. Temperature sensitivity test 
 
2. Materials and Methods 
This is a prospective multicenter study including all patients scheduled for CABG requiring ECC. 
Preoperative CAN diagnosis will be performed 1 day before surgery using Valsalva maneuver, sitting-
to-standing test, and temperature sensitivity test. A positive result in at least two tests will confirm 
CAN. 
Preoperative data to be recorded: 
Demographics and comorbidities (hypertension, diabetes, COPD, recent MI, atrial fibrillation, 
dyslipidemia) 
Kidney function (BUN, creatinine, GFR) 
Hemodynamic parameters before anesthesia induction 
Baseline rSO₂ (monitoring will be blinded for clinical purposes) 
Intraoperative data: 
Hemodynamics, urine output, blood gases 

 
Total cardiopulmonary bypass time, aortic cross-clamp time 
Number of coronary artery anastomoses 
Postoperative data: 
rSO₂ at 1st and 4th hours, and 60 minutes after extubation 
Intubation duration, prolonged mechanical ventilation, inotropic agent use 
Renal function (BUN, creatinine, GFR) and urine output at 24, 48 hours, and 7th day per KDIGO 
criteria 
Postoperative complications (reoperation, mediastinitis, perioperative MI, neurological 
complications) 
Transfusion volume, IABP use, drainage volume 
ICU and hospital length of stay, mortality 
 
3. Acute Kidney Injury (KDIGO Criteria) 
Stage 
Serum Creatinine 
Urine Output 
1 
1.5–1.9× baseline or >0.3 
mg/dL increase 
<0.5 mL/kg/hr for 6 hrs 
2 
2.0–2.9× baseline 
<0.5 mL/kg/hr for 2 
consecutive 6-hr periods 
3 
≥3× baseline or >4 mg/dL or 
RRT initiation 
<0.3 mL/kg/hr for ≥24 hrs or 
anuria ≥12 hrs 
 
 
4. Intraoperative Management 
IV crystalloid infusion ≥100 mL/h from anesthesia induction 
Mean arterial pressure maintained between 60–100 mmHg 
If MAP <60 mmHg → 5 mg ephedrine 
Inotropic agents per standard clinical practice 
Transfusion if Hct <27% 
Hourly urine output monitoring 
ECC pump flow >1.8 L/m²/min 
Body temperature during ECC ≥28°C 
 
 

6. Outcomes 
Intubation duration 
Prolonged mechanical ventilation 
Inotropic agent use 
Renal failure (KDIGO criteria) 
Neurological injury (stroke, confusion, agitation, memory loss, seizure, neurocognitive dysfunction) 
Reoperation 
Mediastinitis 
Transfusion requirement 
IABP use 
Postoperative drainage 
Perioperative MI 
ICU and hospital length of stay 
Mortality 
7. Inclusion and Exclusion Criteria 
Inclusion: 
All patients >18 years old scheduled for CABG requiring ECC 
Exclusion: 
Emergency or revision surgeries 
Orthopedic issues preventing standing test 
Chronic respiratory diseases (bronchitis, asthma, COPD) affecting Valsalva reliability 
Uncontrolled hypertension 
Use of antiarrhythmic drugs affecting heart rate-based tests 
Chronic kidney failure 

Statistical Analysis Categorical variables will be presented as counts and percentages. Between-group 
comparisons for categorical variables will be performed using the chi-square test. The distribution of 
continuous variables will be evaluated using skewness and kurtosis. Variables with distribution 
between -1.5 and +1.5 will be considered normally distributed (parametric), otherwise non-
parametric. Parametric continuous variables will be expressed as mean ± SD. Between-group 
comparisons will be performed using the independent Student’s t-test, and within-group temporal 
comparisons using the paired Student’s t-test. Non-parametric continuous variables will be presented 
as median and interquartile range (IQR). Between-group comparisons for non-parametric variables will 
be performed using the Mann-Whitney U test, and within-group temporal comparisons using the 
Wilcoxon signed-rank test. Correlation analysis will be conducted using Pearson (parametric) or 
Spearman (non-parametric) correlation coefficients. Factors affecting AKI and neurological 
complications will be evaluated using multiple regression analysis. 
 
Sample Size Calculation The primary objective of this study is to compare the incidence of AKI between 
CAN-positive and CAN-negative patients undergoing coronary artery bypass grafting (CABG). Based on 
previous studies using heart rate variability (HRV) for CAN diagnosis, the prevalence of CAN after 
myocardial infarction (MI) is approximately 60%. In the CABG population, approximately 30% of 
patients have diabetes and/or MI. Therefore, we anticipate a CAN prevalence of at least 20%. 
Postoperative AKI incidence ranges from 12–36% in the literature. Assuming that at least 20% of our 
patients will be CAN-positive and that AKI incidence in CAN-positive patients will be at least 10% higher 
than in CAN-negative patients, with α = 0.05 and β = 0.2, a minimum of 884 patients will be required. 

INFORMED CONSENT AND VOLUNTEER INFORMATION FORM 
 
(Physician’s Explanation) 
 
Dear Patient / Patient’s Relative, 
This study aims to investigate the effects of cardiovascular autonomic neuropathy (CAN) on acute 
kidney injury and outcome parameters in patients undergoing isolated coronary artery bypass surgery 
(CABG). 
We recommend your participation in this study. However, it is entirely your choice whether or not to 
participate. Participation is voluntary. Before making your decision, we would like to inform you about 
the study. After reading and understanding this information, if you wish to participate, please sign this 
form. 
Your participation in this study, which will be conducted at the Department of Anesthesiology and 
Reanimation at ……………………… Hospital, is important for the success of the research.  
If you agree to participate, Dr. ………………….. will review the data recorded after your surgery, and the 
findings will be documented. This research is not experimental, and its procedures do not pose any 
risk to you. You will not be charged any fees for participating in this study. No additional payment or 
insurance will be provided. Your medical information will be kept confidential. 
You may refuse to participate. Participation is completely voluntary, and refusal will not affect your 
treatment in any way. 
(Participant Declaration) 
Dear Dr. ………………………, I have been informed about the medical research to be conducted at 
……………………… Hospital, and the above information has been explained to me. After this explanation, 
I have been invited to participate in this study as a volunteer. 
If I participate, I understand that my personal information will be handled with strict confidentiality 
throughout the study. I trust that my data will be protected during the educational and scientific use 
of the study results. I will not bear any financial responsibility for the study procedures, nor will I 
receive any payment. 
I understand that if any health problems arise, directly or indirectly, as a result of participating in this 
study, I will receive appropriate medical care without financial burden. 
I understand that in case of a health issue during the study, I can contact Dr. ………………… at ……………… 
(work) or ……………… (mobile) at any time, or reach the Department of Anesthesiology and Reanimation 
at ……………………… Hospital. 
I understand that participation is voluntary and that I have not been pressured to join. Refusal to 
participate will not affect my medical care or my relationship with my physician. 
I have fully understood all explanations. After careful consideration, I voluntarily accept the invitation 
to participate as a study subject. 
A copy of this signed form will be provided to me. 

 
Participant 
Name, Surname: 
Address: 
Phone: 
Signature: 
 
Witness of the Discussion 
Name, Surname: 
Address: 
Phone: 
Signature: 
 
Physician Who Discussed the Study 
Name, Surname, Title: 
Address: 
Phone: 
Signature: