Can It Be the Crystal Ball of Cardiac Anesthesia?

ACA_9_18R2

AQ2 Originial Article: Janak Mehta Award 1 1 2 2 3 ANSiscope™: Can it be the Crystal Ball of Cardiac Anesthesia? 3 4 4 5 5 Abstract Rohini Mayur Balaji, 6 6 Background: Autonomic dysfunction (AD) is infrequently evaluated preoperatively despite having 7 Nagaraja PS, 7 profound perioperative implications. The ANSiscope™ is a monitoring device that quantifies Naveen G Singh, AQ12 8 AD. This study aims to determine the potential of the device to predict hypotension following 8 9 anesthetic induction, occurrence of arrhythmias, and inotrope requirement for patients undergoing Prabhakar V, 9 10 off‑pump coronary artery bypass surgery (OPCAB). Study Design: Prospective observational Manjunatha N 10 11 double‑blinded study. Materials and Methodology: Seventy‑five patients undergoing OPCAB had Department of Cardiac 11 12 their autonomic function assessed by ANSiscope™. They were classified into four groups based on Anaesthesiology, Sri Jayadeva 12 Institute of Cardiovascular 13 their AD and compared to perioperative adverse events. Results: Patients with diabetes had a higher 13 ANSindex (P = 0.0263). They had a greater decrease in systolic blood pressure (P = 0.001) and mean Sciences and Research, 14 Bengaluru, Karnataka, India 14 arterial pressure (P = 0.004) postinduction, had an increased incidence of arrhythmias (P = 0.009), 15 required higher inotropic support immediately (P = 0.010) and at 24 h after surgery (P = 0.018), 15 16 and longer duration of postoperative ventilation (P < 0.001). They also had a higher incidence of 16 17 emergency conversion of OPCAB to on‑pump surgery (P = 0.009). Conclusions: An increased 17 18 association between AD as quantified by the ANSiscope™ and perioperative adverse outcomes was 18 19 observed. An increased rate of emergency conversion of OPCAB to on‑pump surgery with higher 19 20 dysfunction was noted. The authors opine that the threshold for conversion must be lower in patients 20 21 deemed to be at a higher risk. Proper evaluation of the autonomic nervous system empowers the 21 22 anesthesiologist to anticipate and adequately prepare for complications. 22 23 Keywords: Autonomic dysfunction, ANSiscope™, arrhythmia, cardiac surgery, conversion, 23 24 postoperative ventilation 24 25 25 26 26 27 Introduction pressure variation with postural change, and 27 sustained handgrip, have been in use since 28 Autonomic nervous system (ANS), 28 the 1970s to diagnose impaired HRV.[3] 29 which includes the sympathetic and 29 However, these tests are time‑consuming 30 parasympathetic divisions, is a key 30 and require active patient participation, and 31 regulator of the cardiovascular system. Both 31 instantaneous objective quantification of 32 the divisions work in tandem to maintain 32 autonomic dysfunction (AD) is difficult. 33 homeostasis. Various clinical conditions 33 34 such as diabetes, myocardial ischemia, ANSiscope™ (Dyansys Inc., 34 35 and familial dysautonomia can lead to an California, USA) is a noninvasive device that 35 36 imbalance in the system. This results in overcomes the shortcomings of the clinical 36 37 37 an increased incidence of perioperative tests by quantifying AD. It gives a real‑time Address for correspondence: 38 complications such as postanesthetic graphical representation of the interaction Dr. Naveen G Singh, 38 39 hypotension, arrhythmias, coronary artery between sympathetic and parasympathetic Department of Cardiac 39 40 spasm, stroke, and sudden cardiac death. systems. It uses the principle of scale Anaesthesiology, Sri Jayadeva 40 41 Institute of Cardiovascular 41 Despite this, the ANS is not routinely covariance obtained from the analysis of Sciences and Research, 42 evaluated in the preoperative period.[1,2] 572 successive R‑R interval recordings Bengaluru - 560 069, 42 43 of the electrocardiography (ECG). The Karnataka, India. 43 Heart rate variability (HRV), reflecting 44 absence of coupling between these two E-mail: naveengsingh@hotmail. 44 sympathovagal balance, has been used com 45 systems is extrapolated to quantify the 45 as a prognostic factor in assessing 46 percentage of AD (ANSindex). Higher 46 cardiovascular autonomic neuropathy. 47 percentage translates to greater sympathetic 47 Ewing’s battery of clinical tests, which Access this article online 48 predominance.[4,5] 48 49 include heart rate response to Valsalva Website: www.annals.in 49 50 maneuver and deep breathing, blood The aim of the researchers was to DOI: 10.4103/aca.ACA_9_18 50 51 determine the relationship between the Quick Response Code: 51 This is an open access journal, and articles are AD, as quantified by the ANSiscope™, 52 distributed under the terms of the Creative Commons 52 53 Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows 53 54 others to remix, tweak, and build upon the work non‑commercially, How to cite this article: Balaji RM, Nagaraja PS, 54 as long as appropriate credit is given and the new creations are Singh NG, Prabhakar V, Jeyabalan S, Manjunatha N. 55 licensed under the identical terms. ANSiscope™: Can it be the Crystal Ball of Cardiac 55 56 For reprints contact: [email protected] Anesthesia? Ann Card Anaesth 2018;XX:XX-XX. 56

1 and postanesthesia hypotension, arrhythmias, and inotrope • Group 2 (Late dysfunction) – 24%–50% 1 2 requirement following cardiac revascularization surgery. • Group 3 (Advanced dysfunction) – >51%. 2 3 3 Anesthetic induction 4 Materials and Methodology 4 5 Study design The anesthesiologist assigned to the patient had a minimum 5 6 experience of 5 years in managing OPCAB cases. A large 6 7 This study design was a prospective double‑blinded bore peripheral intravenous access and radial arterial line 7 8 observational clinical study. were secured under local anesthesia. The baseline systolic 8 9 Criteria blood pressure (SBP), diastolic blood pressure (DBP), 9 10 and mean arterial pressure (MAP) were recorded. All 10 11 After obtaining Institutional Ethical Committee clearance, patients received standardized titrated doses of induction 11 12 all patients scheduled to undergo elective off‑pump agents – midazolam 0.05 mg/kg, fentanyl 5 µg/kg, 12 13 coronary artery bypass grafting (OPCAB) at a tertiary vecuronium – 0.1 mg/kg, lidocaine – 1.5 mg/kg, and 13 14 cardiac care center were included in the study. propofol titrated to effect. A second reading of SBP, DBP, 14 15 15 The exclusion criteria were patient refusal, combined and MAP was obtained 3 min postinduction and before 16 16 valve and CABG procedures, elective on‑pump intubation. Patients were intubated with appropriate sized 17 17 CABG (ONCAB), and emergency and redo procedures; endotracheal tube and anesthesia was maintained with 18 18 patients with preoperative arrhythmias and in cardiac 50:50 oxygen and air. Sevoflurane was the inhalational 19 19 failure; and patients on preoperative intra‑aortic balloon agent of choice. Revascularization was performed by 20 20 pump and/or inotropic support. professors of cardiac surgery with a minimum of 8 years of 21 experience in the same. 21 22 Study protocol 22 23 Data collection 23 Informed and written consent was obtained from all 24 A person blinded to the ANSindex obtained performed data 24 25 the patients who enrolled for the study. Demographic 25 collection. In addition to the blood pressure readings, the 26 data, comorbid conditions, medications, and relevant 26 occurrence and nature of arrhythmias up to 48 h, conversion 27 preoperative investigation reports were noted. All patients 27 to on‑pump surgery, and inotrope score immediately, at 28 received appropriate preanesthetic instructions, which 28 24 h and at 48 h postsurgery were noted. The duration of 29 included anxiolytic premedication and continuation of 29 postoperative ventilation and the development of any other 30 beta‑blockers on the morning of the surgery, if any. 30 complications were recorded. 31 Autonomic dysfunction quantification 31 32 Statistical analysis 32 ™ 33 ANSiscope was used to determine the percentage of AD 33 Statistical analysis was performed using IBM SPSS 34 before anesthetic induction. ECG electrodes were attached 34 Statistics for Windows, version 22.0 (IBM Corp., Armonk, 35 to the palmar aspects of both the wrists and above the 35 N. Y., USA). Categorical variables were analyzed using 36 medial malleolus of both the lower limbs, with the patient 36 37 lying supine and undisturbed, and the leads were connected Chi‑square test and continuous variables were analyzed 37 38 to the device. Based on the ANSindex obtained after serial with ANOVA test. Continuous variables were expressed 38 39 R‑R interval analysis [Figure 1a and b], patients were as mean ± standard deviation. Student’s t‑test was used to 39 40 classified into different groups as described below:[4] compare mean values. P < 0.05 was considered statistically 40 41 • Group 0 (Healthy) – <13.5% significant. 41 42 • Group 1 (Early dysfunction) – 13.5%–23% 42 Results 43 43 44 Seventy‑five patients (16 female and 59 male) satisfied 44 45 the inclusion criteria and consented to participate in the 45 46 study. Demographic data [Table 1a and Figure 2a] were 46 47 comparable. Of the 75 patients, 49 (65%) had AD. 47 48 48 Of a total of 49 patients with dysfunction, 30 (61.22%) 49 49 50 were diabetic. There was a significant association between 50 51 diabetes and AD (71.42% of diabetics had AD as compared 51 52 to 57.5% in nondiabetics, P = 0.0263). 52 53 a b Since beta‑blockers can influence HRV, their effect on AD 53 54 Figure 1: (a) ANSiscope™ monitor in the process of recording serial R‑R was considered. The degree of AD was found to be higher 54 55 intervals. (b) Graphical representation of sympathovagal interaction with 55 ANSindex displayed at the end of analysis. (Orange ‑ Sympathetic system, in patients not on beta‑blockers (36% mean AD in those 56 Blue ‑ parasympathetic system) not on beta blockers vs. 27% in those on beta‑blockers). 56

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1 Comparing the preinduction SBP, DBP, and MAP, used (1* dopamine in µg/kg, 1* dobutamine µg/kg, 100* 1 2 the difference in the percentage fall in blood pressure adrenaline in µg/kg, and 100* noradrenaline in µg/kg). 2 3 postinduction was analyzed between the groups. Patients with Patients with and without AD were compared for inotrope 3 4 AD had a significantly greater percentage fall in SBP and requirement. Those with dysfunction had a significantly 4 5 MAP [Table 1b]. The greatest difference was seen in the group higher inotropic score immediate postsurgery (P = 0.01) 5 6 with late dysfunction when compared to normal patients. and at 24 h postsurgery (P = 0.023). However, at 48 h, 6 7 there was no difference in the score in between the 7 The incidental finding during interpretation of 8 groups [Table 2a and b]. 8 9 intraoperative data was a higher rate of conversion of 9 10 OPCAB to ONCAB with greater dysfunction (P = 0.009). The authors also noted the occurrence and nature of 10 11 The overall conversion rate was 25.3%, and 22.6% arrhythmias during the intra‑ and postoperative period. 11 12 cases were emergency conversions. Eighty‑nine percent A total of 19 (25.3%) patients had arrhythmias. Nearly 95% 12 13 of the patients, who had to be converted, had AD of the patients who had arrhythmias had AD (P = 0.009, 13 14 [Table 1c and Figure 2b] Table 3a). Ventricular arrhythmias were more frequent than 14 15 atrial arrhythmias (68.42% vs. 31.57%). 15 The inotrope requirement at immediate, 24 h, and 48 h 16 16 postsurgery was analyzed. Vasoactive inotropic score was Patients with greater degree of AD required significantly 17 longer duration of postoperative ventilation (P < 0.001, 17 18 Table 3b). 18 19 19 20 Discussion 20 21 21 Despite having a profound influence on the cardiovascular 22 22 system, the ANS is rarely evaluated in preoperative 23 [1] 23 24 patients. Literature review has shown that AD can result 24 25 in sympathetic predominance, causing increased workload 25 26 on the heart, endothelial dysfunction, arrhythmias, stroke, 26 [2] 27 and sudden death. The frequency of these complications 27 is highest in the early hours of the morning and on 28 a 28 29 Monday in employed patients, which concurs with time of 29 [2,6,7] 30 sympathetic predominance. 30 31 The major causative factors for AD in cardiac surgical 31 32 patients are diabetes and myocardial ischemia.[8‑10] In the 32 33 present study, thirty patients were found to have type 2 33 34 diabetes, of whom 71.42% were found to have AD. 34 35 However, Ziegler et al., in their study of 1171 patients, 35 36 reported a much lower incidence of dysautonomia (22.1%) 36 37 in type 2 diabetics.[8] Diabetes has known to cause CAN 37 38 by inducing oxidative and nitrosative stress in the fibers 38 39 innervating the heart. Persistent hyperglycemia leads to 39 40 accumulation of sorbitol and alters the NAD: NADH ratio, 40 41 b resulting in direct injury to the nerves.[9] 41 42 42 Figure 2: (a) Percentage‑wise distribution of patients in each group. 43 (b) Conversion to elective on‑pump coronary artery bypass grafting in Hypotension during anesthesia has been associated with 43 [10,11] 44 patients with autonomic dysfunction worse postoperative patient outcome. One of the 44 45 45 46 Table 1a: Demographic characteristics 46 47 AD classification (mean±SD) P 47 48 Group 0, (n=26) Group 1, (n=10) Group 2, (n=25) Group 3, (n=14) 48 49 Age (years) 59.38±7.574 58.50±9.192 60.04±7.197 56.36±7.292 0.526 49 50 Height (cm) 160.50±7.855 161.3±9.154 160.92±10.866 159.79±7.485 0.976 50 51 Weight (kg) 63.69±8.930 60.90±7.534 67.32±10.832 65.86±7.502 0.251 51 52 BMI 24.7±3.14 23.35±1.408 26.05±3.874 25.79±2.519 0.104 52 53 Sex 53 54 Female 2 3 6 5 0.182 54 55 Male 24 7 19 9 55 56 SD: Standard deviation, BMI: Body mass index, AD: Autonomic dysfunction 56

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1 objectives of the researchers was to assess the ability of study also demonstrates a greater degree of AD in patients 1 2 the ANSiscope to predict hypotension after induction of not on beta‑blockers (mean AD of 36%) when compared to 2 3 general anesthesia. Patients with late dysfunction (Group 2) those on beta blockers (mean AD of 27%) although it was 3 4 had a greater percentage fall in SBP, DBP, and MAP not statistically significant (P = 0.086). 4 5 when compared to normal patients (Group 0). The fall in 5 A serendipitous outcome encountered by the researchers 6 SBP (P = 0.001) and MAP (P = 0.004) was statistically 6 was a significant increased rate of conversion of OPCAB 7 significant. This finding concurs with Latson et al.[12] and 7 to ONCAB in patients with AD (P = 0.009). The most 8 Hanss et al.,[13] who demonstrated a greater incidence of 8 common indication was severe hypotension during obtuse 9 hypotension after general anesthesia administration in 9 marginal grafting. Edgerton et al.[16] in their study found 10 patients with AD, using clinical tests and HRV to detect 10 that the patients who underwent an urgent–emergent 11 AD. ANSindex was used as a tool to predict postspinal 11 conversion (in comparison with elective conversion) had 12 hypotension in parturients undergoing elective lower 12 [4] a higher rate of postoperative cardiac arrest, MI, and 13 segment cesarean section by Prashanth et al. in their study [17] 13 14 comprising 108 patients. The area under receptor operator multisystem organ failure. Lim et al. have described the 14 15 characteristic curve for ANSindex as a solitary predictor 5‑year survival rate to be 83.5% in the off‑pump group 15 16 for hypotesion was 0.737. The use of anesthetic drugs and 73.9% in the conversion group. The CORONARY 16 17 decreases the capacity to release residual catecholamines in trial (Coronary artery bypass grafting Off or On Pump 17 18 patients with dysautonomia.[14] Revascularization Study), which studied 4718 patients 18 19 undergoing CABG, also found a higher incidence of stroke, 19 A total of 19 patients developed perioperative arrhythmias, 20 MI, renal failure, and death in emergent conversions, 20 of whom 18 (94.7%) had AD (P = 0.009). Although 21 whereas the elective conversions were comparable with 21 arrhythmias of atrial origin are most common after cardiac [18] 22 off‑pump surgeries. In the current study, 89% of the 22 surgery,[15] we found a higher incidence of ventricular 23 patients who had to be converted were found to have AD. 23 arrhythmias (31.57% vs. 68.42%). Chen et al. have 24 The overall conversion rate was 25.3%, with 22.6% of 24 documented an increased association between arrhythmias 25 them being emergency conversions. Various studies have 25 and sudden cardiac death due to abnormal patterns of 26 investigated the risk factors favoring conversion, ranging 26 sympathetic reinnervation.[6] 27 from advanced age, absence of beta blocker therapy, low 27 28 The Autonomic Tone and Reflexes After Myocardial ejection fraction, prior MI, cardiac failure, etc. However, 28 29 Infarction investigators opine that recognizing the there is limited literature implicating AD as a potential risk 29 30 inadequacy of vagal tone empowers the treating physician factor for conversion. 30 [7] 31 to target the loss of antifibrillatory effects. The present The ANSindex was used to compare the requirement 31 32 of inotropes immediately, at 24, and 48 h after surgery. 32 33 Table 1b: Comparison between the mean percentage There was a significant higher inotrope score at 33 34 changes from baseline in systolic blood pressure, immediate (P = 0.010) and at 24 h postsurgery (P = 0.018) 34 35 diastolic blood pressure, mean arterial pressure between in patients with AD, whereas there was no difference 35 36 the groups between the groups at 48 h. 36 37 AD classification P 37 38 Prolonged postoperative ventilation contributes to 38 Group 0, Group 1, Group 2, Group 3, significant morbidity.[18] Of the 75 patients studied, 39 (n=26) (n=10) (n=25) (n=14) 39 2 patients had a requirement for ventilation for >48 h. 40 Mean SBP 26.33 29.18 37.29 30.17 0.001 40 41 percentage decrease Both had advanced AD (Group 3). Five patients required 41 42 Mean DBP 23.12 24.16 30.21 22.82 0.07 ventilation ranging from 20 to 48 h. All of them had 42 43 percentage decrease either late or advanced dysfunction (Group 2/3). There 43 44 Mean MAP 24.91 26.71 33.71 26.30 0.004 was a significant prolongation of duration of ventilation in 44 45 percentage decrease patients with AD (P < 0.001). Positive pressure ventilation 45 46 SBP: Systolic blood pressure, DBP: Diastolic blood pressure, decreases the venous return and cardiac output.[19] Patients 46 47 MAP: Mean arterial pressure, AD: Autonomic dysfunction with AD who already have a maximally activated 47 48 48 49 Table 1c: Conversion to on‑pump CABG compared between the groups 49 50 AD classification Total χ2 P 50 51 Group 0 (n= 26) Group 1 (n=10) Group 2 (n= 25) Group 3 (n=14) 51 52 Conversion to ONCAB 52 53 No 24 (42.9) 9 (16.1) 16 (28.6) 7 (12.5) 56 (74.6) 11.528 0.009 53 54 Yes 2 (10.5) 1 (5.3) 9 (47.4) 7 (36.8) 19 (25.3) 54 55 Total 26 (34.6) 10 (13.3) 25 (33.3) 14 (18.6) 75 (100) 55 56 ONCAB: On‑pump CABG, AD: Autonomic dysfunction 56

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1 sympathetic system may be incapable of increasing their aldose reductase inhibitors (epalrestat and fidarestat), 1 2 reserves to counteract the effects of positive pressure ACE inhibitors, prostaglandin analogs, and alpha‑lipoic 2 3 ventilation.[20] This can account for the increased inotrope acid, apart from specific medication for symptoms such as 3 4 requirement and increased duration of ventilation. erectile dysfunction and loss of bladder control.[22] 4 5 5 Increasing age has been associated with declining 6 Limitations 6 autonomic functions.[21] 7 The quantification of dysfunction as provided by the 7 8 The current therapy for AD aims at early diagnosis, regular 8 ANSiscope™ was not compared with any other method to 9 screening and follow‑up, exercise regimens, adequate 9 assess AD. The device cannot be used in the presence of 10 glycemic control, and management of cardiovascular risk 10 arrhythmias. 11 factors. Medical therapy available includes beta blockers, 11 12 12 Conclusions 13 13 Table 2a: Inotrope score‑immediate postsurgery 14 AD is commonly encountered in the perioperative cardiac 14 AD Total χ2 P 15 15 No, n (%z) Yes, n (%) setting and contributes to significant morbidity. Despite 16 16 Inotrope score having a profound influence on the cardiovascular 17 (immediate) system, the ANS is rarely evaluated on a routine basis 17 18 A 8 (66.7) 4 (33.3) 12 11.402 0.010 preoperatively. ANSiscope™ is a time efficient, easy to 18 19 19 B 15 (41.7) 21 (58.3) 36 use, noninvasive device to quantify AD. The researchers 20 20 C 3 (23.1) 10 (76.9) 13 noticed an increased association between dysfunction 21 D 1 (7.1) 13 (92.9) 14 21 22 and diabetes, occurrence of arrhythmias, postoperative 22 Total 27 (36) 48 (64) 75 duration of ventilation, and inotrope requirement. One of 23 A: No inotrope, B: 1‑5 score, C: 6‑10 score, D: >11 score. 23 the significant findings was the increased rate of emergency 24 AD: Autonomic dysfunction 24 25 conversion of OPCAB to ONCAB with higher degree of 25 26 dysfunction, which is again proven to be associated with 26 27 Table 2b: Inotrope score‑24 h postsurgery higher morbidity and mortality. The authors opine that the 27 AD Total χ2 P 28 threshold for conversion must be lower in patients deemed 28 29 No, n (%) Yes, n (%) 29 Inotrope score (24 h) to be at risk. Adequate evaluation of the ANS empowers 30 the anesthesiologist to anticipate and formulate tailor‑made 30 31 A 20 (54.05) 17 (45.9) 37 11.892 0.018 31 B 5 (26.3) 14 (73.68) 19 plans for patients as required. 32 32 C 2 (16.66) 10 (83.33) 12 33 Acknowledgments 33 D 0 5 (100) 5 34 34 Total 27 (36) 48 (64) 73 We thank the clinical support team of Dyansys Inc., India, for 35 35 providing the ANSiscope™ to conduct the research without any 36 A: No inotrope, B: 1‑5 score, C: 6‑10 score, D: >11 score. 36 AD: Autonomic dysfunction additional cost to the patient. 37 37 38 38 39 Table 3a: Incidence of arrhythmias and autonomic dysfunction 39 40 AD classification Total χ2 P 40 41 Group 0, n (%) Group 1, n (%) Group 2, n (%) Group 3, n (%) 41 42 Arrhythmia 42 43 No 25 (44.6) 8 (14.3) 15 (26.8) 8 (14.3) 56 (74.6) 11.612 0.009 43 44 Yes 1 (5.3) 2 (10.5) 10 (52.6) 6 (31.6) 19 (25.3) 44 45 Total 26 (34.6) 10 (13.3) 25 (33.3) 14 (18.6) 75 (100) 45 46 AD: Autonomic dysfunction 46 47 47 48 Table 3b: Ventilator hours and autonomic dysfunction 48 49 AD classification Total χ2 P 49 50 Group 0, n (%) Group 1, n (%) Group 2, n (%) Group 3, n (%) 50 51 Ventilator hours 51 52 A 17 (58.6) 7 (24.1) 2 (6.9) 3 (10.3) 29 (39.7) 35.696 0.000 52 53 B 9 (20.9) 1 (2.3) 21 (50.0) 11 (25.6) 42 (57.5) 53 54 C 0 1 (50.0) 1 (50.0) 0 2 (2.7) 54 55 Total 26 (35.1) 9 (12.2) 24 (32.8) 14 (18.9) 73 (100) 55 56 A: <6 h, B: 7‑24 h, C: >24 h. AD: Autonomic dysfunction 56

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1 Financial support and sponsorship Analg 2005;101:622‑8. 1 2 11. Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and 2 Nil. 3 one‑year mortality after non‑cardiac surgery. Anesthesia and Analgesia 3 2005;100:4‑10. 4 Conflicts of interest 4 12. Latson TW, Ashmore TH, Reinhart DJ, Klein KW, Giesecke AH. 5 5 There are no conflicts of interest. Autonomic reflex dysfunction in patients presenting for elective surgery 6 is associated with hypotension after anesthesia induction. Anesthesiology 6 7 References 1994;80:326‑37. 7 8 13. Hanss R, Renner J, Ilies C, Moikow L, Buell O, Steinfath M, et al. Does 8 9 1. Deschamps A, Denault A, Rochon A, Cogan J, Pagé P, D’Antono B, heart rate variability predict hypotension and bradycardia after induction 9 et al. Evaluation of autonomic reserves in cardiac surgery patients. of general anaesthesia in high risk cardiovascular patients? Anaesthesia 10 J Cardiothorac Vasc Anesth 2013;27:485‑93. 10 11 2008;63:129‑35. 11 2. Curtis BM, O’Keefe JH Jr. Autonomic tone as a cardiovascular risk factor: 14. Mustafa HI, Fessel JP, Barwise J, Shannon JR, Raj SR, Diedrich A, 12 12 The dangers of chronic fight or flight. Mayo Clin Proc 2002;77:45‑54. et al. Dysautonomia: Perioperative implications. Anesthesiology 13 3. Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic 2012;116:205‑15. 13 14 neuropathy. Br Med J (Clin Res Ed) 1982;285:916‑8. 15. Peretto G, Durante A, Limite LR, Cianflone D. Postoperative arrhythmias 14 15 4. Prashanth A, Chakravarthy M, George A, Mayur R, Hosur R, after cardiac surgery: Incidence, risk factors, and therapeutic management. 15 16 Pargaonkar S, et al. Sympatho‑vagal balance, as quantified by ANSindex, Cardiol Res Pract 2014;2014:615987. 16 17 predicts post spinal hypotension and vasopressor requirement in 16. Edgerton JR, Dewey TM, Magee MJ, Herbert MA, Prince SL, Jones KK, 17 parturients undergoing lower segmental cesarean section: A single blinded 18 et al. Conversion in off‑pump coronary artery bypass grafting: An 18 prospective observational study. J Clin Monit Comput 2017;31:805‑11. 19 analysis of predictors and outcomes. Ann Thorac Surg 2003;76:1138‑42. 19 5. Lafitte MJ, Fevre‑Genoulaz M, Burger AJ. Mathematical assessment of 17. Lim J, Lee WY, Ra YJ, Jeong JH, Ko HH. Analysis of risk factors for 20 20 diabetic autonomic neuropathy. Diabetes 2005;54:2307. conversion from off‑pump to on‑pump coronary artery bypass graft. 21 6. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian HS, Fishbein MC, Korean J Thorac Cardiovasc Surg 2017;50:14‑21. 21 22 et al. Sympathetic nerve sprouting, electrical remodeling and the 18. Stevens LM, Noiseux N, Avezum A, Ayapati DR, Chen X, Lucchese FA, 22 23 mechanisms of sudden cardiac death. Cardiovasc Res 2001;50:409‑16. et al. Conversion after off‑pump coronary artery bypass grafting: The 23 24 7. La Rovere MT, Bigger JT Jr., Marcus FI, Mortara A, Schwartz PJ. CORONARY trial experience. Eur J Cardiothorac Surg 2017;51:539‑46. 24 25 Baroreflex sensitivity and heart‑rate variability in prediction of total 19. Trouillet JL, Combes A, Vaissier E, Luyt CE, Ouattara A, Pavie A, et al. 25 26 cardiac mortality after myocardial infarction. ATRAMI (Autonomic Prolonged mechanical ventilation after cardiac surgery: Outcome and 26 tone and reflexes after myocardial infarction) investigators. Lancet 27 predictors. J Thorac Cardiovasc Surg 2009;138:948‑53. 27 1998;351:478‑84. 20. Neukirchen M, Kienbaum P. Sympathetic nervous system: Evaluation 28 28 8. Ziegler D, Gries FA, Spüler M, Lessmann F. The epidemiology of and importance for clinical general anesthesia. Anesthesiology 29 diabetic neuropathy. Diabetic cardiovascular autonomic neuropathy 2008;109:1113‑31. 29 30 multicenter study group. J Diabetes Complications 1992;6:49‑57. 21. Parashar R, Amir M, Pakhare A, Rathi P, Chaudhary L. Age related 30 31 9. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic changes in autonomic functions. J Clin Diagn Res 2016;10:11‑5. 31 32 neuropathy. Diabetes Care 2003;26:1553‑79. 22. Balcıoğlu AS, Müderrisoğlu H. Diabetes and cardiac autonomic 32 33 10. Reich DL, Hossain S, Krol M, Baez B, Patel P, Bernstein A, et al. neuropathy: Clinical manifestations, cardiovascular consequences, 33 34 Predictors of hypotension after induction of general anesthesia. Anesth diagnosis and treatment. World J Diabetes 2015;6:80‑91. 34 35 35 36 36 37 37 38 38 39 39 40 40 41 Author Queries??? 41 42 AQ2: Kindly check the article type provide in JOW “Janak Mehta Award,” kindly confirm anyone article type. 42 43 AQ12: Please upload updated copyright form. 43 44 44 45 45 46 46 47 47 48 48 49 49 50 50 51 51 52 52 53 53 54 54 55 55 56 56

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