AJA Asian Journal of Anesthesiology

Advancing, Capability, Improving lives

Research Paper
Volume 58, Issue 1, Pages 35-44
Reza Jouybar 1 , Mahtab Setoodeh 2 , Zeinabsadat Fattahi Saravi 3 , Sedigheh Ahmadi 4 , Ali Karami 1 , Saeed Khademi 5 , Ahad Izadpanah 2 , Mansour Jannati 6 , Masih Shafa 6 , Elham Asadpour 7 , Farzaneh Masih 8 , Mahyar Malekzadeh 9
24563 Views


Abstract

Objective: Cardiopulmonary bypass has been recognized as one of the main causes of systemic inflammatory response syndrome, leading to post-operative complications. The aim of this study was to investigate the effect of melatonin on the serum levels of interleukin 6 (IL-6) and IL-9 in patients undergoing coronary artery bypass grafting surgery.

Methods: Forty-four patients undergoing elective coronary artery bypass surgery were randomly allocated into two study groups of melatonin (n = 23) and placebo (n = 21). Patients in the melatonin group received two melatonin tablet, 5 mg daily for 3 days before surgery, 10 mg tablet (two doses of 5 mg) 1 h before induction of anesthesia and finally, 10 mg melatonin tablet in the intensive care unit, placebo group patients received placebo at the same time periods. Serum levels of IL-9 and IL-6 were measured as baseline (T1), before induction of anesthesia (T2), 6 and 24 h after off pump (T3, T4). Data were analyzed using SPSS 23 software (IBM Corp., Armonk, NY, USA).

Results: The mean serum level of IL-6 was significantly lower in the melatonin group at T3 and T4 (p < 0.05). Also, in both groups, serum levels of IL-6 in T3 showed a significant increase compared to T1. Serum levels of IL-9 had no significant difference between the two groups at T1, T2, T3, and T4.

Conclusion: The results of this study showed that pre-operative melatonin administration could modify inflammatory cytokines secretion such as IL-6 while it has no significant effect on the serum levels of IL-9. Neither of the changes was clinically significant.

Keywords

coronary artery bypass graft, interleukin 6, interleukin 9, melatonin


Introduction

Coronary artery bypass grafting (CABG) is one of the most commonly performed major surgical procedures worldwide, and improves the life expectancy and quality in ischemic heart disease.1

Cardiopulmonary bypass (CPB) has been recognized as one of the main causes of systemic inflammatory response syndrome, which may lead to post-operative complications and even multiple organ dysfunction syndrome.1,2

Anesthesia, surgical trauma, blood contact with non-physiologic surfaces within extracorporeal circulation, hemodilution, body temperature changes, and blood transfusions lead to activation of astrocytes, resulting in the release of inflammatory mediators.3

CABG surgery results in physiological stress response as well as ischemic reperfusion injury that involves activation of metabolic, endocrine, inflammatory and immunological mediators.4

Different inflammatory mediators are released during or after CABG surgery. Furthermore, a decrease of endogenous secretion of melatonin after surgeries has a negative effect on oxidative state.4 Therefore, finding an effective way to reduce this physiological stress and improve the oxidant response leads to better survival in the patients.

The pro-inflammatory cytokine, interleukin 6 (IL-6) is known as inflammatory mediator that is secreted from T helper, B lymphocytes, macrophages, endothelial cells and astrocyte, and stimulates the immune responses in tissue damages during surgery, infection, trauma, and burn. The target receptor of IL-6 is CD130/IL6RB, CD126/IL6RΔ.5 IL-6 has a fundamental role in the systemic inflammatory induced by cardiac surgery and CPB and raised by the cardiac cell in cardiac ischemia and heart failure. IL-6 is considered as marker of cardiac dysfunction, inflammation, and the rate of ailment severity before surgery.6

The IL-9 gene, another inflammatory mediator, located on chromosome 5. IL-9 was firstly illustrated as a growth factor which is secreted by Th2 cells.7 Th17, regulatory T cells (Tregs), TGF-b, and IL-4 also increase IL-9 secretion.8 It can do various functions in immune and inflammatory responses, its function is through a γC-family receptor on target cells.7 It also acts as a regulator of the hematopoietic stem cells. This cytokine stimulates cell differentiation and prevents apoptosis.8,9 IL-9 can act as positive and negative regulators on immune responses. In other words, IL-9 has different effects on the disease progression.8,9 Melatonin is a chemical substance of N-acetyl-5-methoxy-tryptamine, a hormone which is secreted by tryptophan from pineal gland into the bloodstream and cerebrospinal fluid.10 Melatonin plays an important role in regulating the biological clock in humans and has a wide range of antioxidant properties.7 Melatonin antioxidant mechanisms are directly (through free radical scavenging) or indirectly (by regulating the activity of antioxidant enzymes) involved.11 Melatonin reduces oxidative damage associated with surgery and ischemia reperfusion injury.4

Previous studies have shown that melatonin is more effective than classical antioxidants and its efficacy and safety in usual doses for short term usage makes it drug of interest for anesthesia and different surgical procedures.12,13

The aim of this study was to investigate the effect of melatonin on inflammatory response in patients undergoing CABG.

Methods

Study Population

This double blinded placebo control study was conducted from April 2017 for a 10-month period, after approval of ethics committee of Shiraz University of Medical Sciences. This study was registered in the Iranian registry of clinical trials (IRCT20141009019470N72). Written informed consent was obtained from each eligible participant.

All patients in the operating theater of Nemazee hospital affiliated to Shiraz University of Medical Sciences, undergoing elective CABG surgery were the target population, and 140 patients entered the study. The patients were randomly allocated in either the case group or the placebo group based on a computer-generated chart with fixed size block of 4.

The exclusion criteria included patients who express unwillingness to participate in the study, allergy to melatonin, American Society of Anesthesiologists physical status > III, emergent or urgent surgery with no adequate time to take melatonin or placebo for 3 days before CABG, redo CABG patients, patients with ejection fraction (EF) < 35%, patients who underwent CABG surgery with other simultaneous cardiac operation, history of depression, (duration of on pump less than 30 min or more than 90 min), a past history of cancer, history of chemotherapy, radiotherapy or immunosuppressive therapy, autoimmune disease, history of surgery within past 6 months, local or systemic infection, pregnancy, breastfeeding, non-sinus rhythm, recent myocardial infarction, patients who were receiving warfarin, evening schedule, sever pulmonary disease, patients who reported adverse effects of melatonin, corticosteroid therapy, unstable hemodynamic and smoking.

The serum level of IL-6 and IL-9, pump time, the number of grafts, the intensive care unit (ICU) stay length, the mean duration of post-operative hospital stay, hemoglobin, platelets, blood glucose, blood urea nitrogen (BUN), creatinine and hepatic enzymes (alanine amiotransferase [ALT], aspartate aminotransferase [AST]) were compared in both groups of melatonin and placebo.

Study Design

A sample size of 44 (group melatonin = 23, group placebo = 21) was calculated based on large effect size, alpha error probability (α = 0.05), power (1-β err p = 0.80) and allocation ratio (N2 / N1 = 1), according to similar to other study.13

The patients in the melatonin group (n = 23) received 10 mg (two doses of 5 mg tablet) melatonin tablet (Nature Made®) for 3 days before surgery, 10 mg (two doses of 5 mg tablet) of melatonin tablet 1 h before induction of anesthesia and finally, 10 mg (two doses of 5 mg tablet) melatonin tablet in the ICU (second night after surgery), placebo group patients (n = 21) received placebo at the same time periods. Dose and treatment period of melatonin were determined.13

Anesthesia

After the patients’ entry into the operating theater, all the patients received standard monitoring which included pulse-oximetry, thermometry, non-invasive blood pressure (BP), invasive radial artery BP measurement, continuous electrocardiographic leads, central venous pressure, capnometry, and urine output. Patients were anesthetized using opioid based general techniques with midazolam 0.10 mg/kg, suefentanil 0.60–0.70 mg/kg, propofol 0.50–1.50 mg/kg, pancuronium 0.15 mg/kg and morphine 0.12–0.15 mg/kg. All patients received an intra-operative infusion of propofol.

Surgical Procedures and Extracorporeal Circulation

After skin preparation and sterilization, surgery began with median sternotomy approach and 400 IV/kg heparinization, extra-corporal circulation (CPB) was started with injecting priming solution of ringer in advance by non-pulsatile flow between 2.4–2.8 lit/min/m2 at moderate hypothermia 32–34°C. The cardiopulmonary cannula was applied to the root of the aorta. Though, myocardial protection was obtained by anterograde cold blood cardiopelegia during aortic cross clamping.

All the patients in the present study underwent the same technique of on pump which was performed with the same surgical team and also the same cardiac medication regimen maintaining systolic BP 60–70 mmHg, hematocrit 20–30%, arterial oxygen pressure at about 250 mmHg.

During the operation, inotropes (ephedrine and epinephrine) and vasopressor (norepinephrine and phenylephrine) or vasodilators (nitroglycerine or sodium nitroprusside) were used to maintain hemodynamics stability. After cross-clamp opening, heparin was reversed with protamine sulfate with control of activated clotting time and patients were transferred to the ICU, postoperatively.

Sample Collection

Blood sample of 5 mL was taken at four different time points from all patients in both groups, before onset of the melatonin or placebo (T1) administration, before anesthesia induction (T2), 6 h after CPB (T3), 48 h after CPB (T4).

Blood samples were placed in a test tube, then centrifuged at 3,000 rpm for 15 min. Serum was obtained and stored in a deep freeze (at -70°C) for measurement of serum levels of biochemical markers. Finally, a human Th cytokine panel (13-plex) (BioLegend®, San Diego, CA, USA) was used with flow cytometry multiplex bead-based assay method to measure serum levels of IL-6 and IL-9.

Other laboratory findings, including hemoglobin, platelet, creatinine, BUN, and liver enzymes, were assessed before administration of the melatonin or placebo and 48 h after surgery in the ICU.

Statistical Analysis

Statistical analysis was performed using SPSS (version 23; IBM Corp., Armonk, NY, USA). Descriptive statistic data were reported as frequency (percentage) for qualitative variables, and mean ± standard deviation and median & range for quantitative variables. Independent sample t-test and chi-square were used for comparison between variables of two groups with normal distribution. Due to the abnormal distribution of data, we used Friedman (α = 0.05) and Wilcoxon with bonferroni correction (α / 6 = 0.008).

Results

A total of 140 patients who had elective CABG surgery were eligible for inclusion in this study. Patients were randomly divided into two groups: melatonin (n = 23) and placebo (n = 21) (Figure 1).

Figure 1.
Download full-size image
Figure 1. Consort Diagram of Patient
Abbreviation: ICU, intensive care unit.

Among 44 patients included, 28 were male (63.6%) and 16 were female (36.3%). The average age of patients was 62.28. The demographic and baseline characteristics of the patients were similar in two groups and there was no significant difference in age, sex, body mass index, EF, and preoperative tests (Table 1).

Table 1. Demographic and Base Line Characteristic Factors for the Participants of Each Group
Table 1.
Download full-size image

The duration of surgery, pump time, number and type of grafting, length of ICU stay and overall hospital length of stay were also evaluated and there was no significant difference between the two groups. Hemoglobin, platelet, creatinine levels, BUN, ALT, AST, and blood sugar in both melatonin and placebo groups did not show any significant difference after surgery (Table 2).

Table 2. Variables Comparison Between Groups and Pre and Post Intervention
Table 2.
Download full-size image

The two groups did not differ significantly in the serum levels of IL-6 at T1 and T2, while, changes in serum levels of IL-6 were significant in the melatonin and placebo groups over time (p < 0.05), and increased in both groups, apparently reaching its peak at 6 h after the pump at T3. The serum levels of IL-6 in both melatonin and placebo groups at T3 showed a significant difference (p < 0.05). Despite the decrease of serum levels of IL-6 at T4 in comparison with T3, the serum levels of IL-6 was higher than pre-operative serum levels in both groups (Table 3).

Table 3. The Serum Levels of IL-6 and IL-9 Over Time
Table 3.
Download full-size image

The comparison of two groups showed that the serum levels of IL-6 in the melatonin group was significantly different between T2 and T4 (p < 0.008) while in the placebo group there was significant difference between T2–T3, T2–T4, and T3–T4 (p < 0.008) (Table 4).

The serum levels of IL-9 was similar in both groups over time, there was no significant difference between melatonin and placebo group at serum level of IL-9 at T1. At T2, the serum levels of IL-9 in the melatonin group slightly decreased compared to the placebo group at T3, the serum levels of IL-9 increased in both melatonin and placebo group and reached its peak at T3, the serum levels of IL-9 declined at T4, but none of these changes were statistically significant (Table 3).

Meanwhile, in independent comparisons at different times, there was no significant difference in IL-9 between the two groups (Table 4) (p > 0.008).

Table 4. The Paired Comparison of Times in IL-6 and IL-9
Table 4.
Download full-size image

Discussion

Regardless of improvements in anesthesia techniques and surgical procedures, CABG leads to activation of inflammatory responses and oxidative stress. Inflammatory factors could pass the blood through extracorporeal blood circuit and non-physiological endothelial surface which are associated with myocardial ischemia reperfusion.14

The myocardium is a major source of IL-6 synthesis.15 It is shown that the increased IL-6 after surgery is associated with post-operative complications.16

On the other hand, IL-9 is a pleiotropic cytokine that is associated with allergic inflammation and immunity to extracellular parasites. Besides, the IL-6 or IL-9–responsive cell roles in Th1/Th17-mediated inflammation are not well-defined in the procedures such as CABG.8

Melatonin acts mutually as a hormone and an antioxidant with or without the melatonin receptors in practically all tissues of mammals.17

It has been demonstrated that the beneficial effects of melatonin in ischemia-reperfusion injuries is correlated to activation of Nrf2 pathway. Nrf2 is a transcription factor inserting its antioxidant effect throughout binding with DNA antioxidant response element (ARE) and Nrf2-ARE pathway has a significant protecting role in ischemia-reperfusion injury.18 Furthermore, Nrf2 which is up regulated by melatonin, inhibits IL-6 secretion. Reduced IL-6, downregulate the STAT3 and its downstream genes associated with inflammation.19 Therefore, melatonin indirectly through inhibition of IL-6 can also insert its cardioprotective effects (Figure 2).

Figure 2.
Download full-size image
Figure 2. The cardioprotection pathaway of melatonin
Abbreviations: ARE, antioxidant responsive element; IL-6, interleukin 6; STAT3, signal transducer and activator of transcription 3.

Some data showed that both IL-9 and IL-6 activate the Gp130/JAK/STAT pathaway which induce negative effects on heart function. Sometime when medications with anti-inflammatory effects, reduce IL-6 level, IL-9 is overexpressed in escape manner from IL-6 suppression aimed at maintaining the Gp130/JAK/STAT pathway activated which might lead to negative effects on heart in long term. Hence, it is worth to measure IL-9 in cardiovascular diseases.20

Moreover, plasma melatonin secretion reduces in coronary heart disease.21,22 Consequently, administration of melatonin could be beneficial against clinically critical problems due to direct and indirect free radical scavenger activity of the melatonin.

In our study, the serum levels of IL-6 and IL-9 did not show any significant difference in baseline. Six hours after the CPB, IL-6 showed a significant increase and reached the maximum plasma levels in the melatonin and placebo groups, but the increase in the melatonin group was lower than placebo group. None of these changes were clinically significant. IL-9 also increased in both melatonin and placebo groups at the same time, and serum level of IL-9 in the melatonin group was lower than the placebo group; however, it was not statistically and clinically significant.

Notably, 48 h after the completion of the cardiopulmonary pump (T4), the level of IL-6 decreased in both melatonin and placebo groups but remained higher than the baseline level (T1), and this reduction was significantly in favor of the antioxidant effect of melatonin. At the same time, the serum level of IL-9 decreased in each melatonin and placebo group, and this reduction also reaches the baseline level before surgery. The melatonin group showed further decrease than placebo group that was not statistically significant.

Dwaich et al. compared the two different doses of melatonin (10 and 20 mg) with placebo group. The plasma levels of cardiac troponin-I, IL-1β, and inducible nitric oxide synthase were significantly reduced by melatonin prophylaxis 5 days before the CABG.13

Shafiei et al. demonstrated that during myocardial ischemia and reperfusion in CABG, the level of malondialdehyde (MDA) compared to baseline is elevated and remains high at the recovery room and preoperative melatonin prophylaxis decreased heart tissue MDA levels, which shows that preoperative treatment with melatonin can be an advantageous method for restraining the oxidative stress mediated reperfusion injury.23 In the study by Haghjooy Javanmard et al., the cellular level of Nrf2 in CABG patients was investigated after administration of melatonin and they concluded that oral administration of the melatonin 1 month before surgery may associated with increase in plasma levels of Nrf2 concentration and melatonin.18

These results suggested that melatonin may be beneficial in preventing reperfusion injury after CABG. It was shown that melatonin protected the heart against ischemia-reperfusion injury by antioxidant effects throughout down regulating inflammatory cytokines like tumor necrosis factor-α, reducing lipid peroxidation product like MDA, up regulating the anti-oxidant enzymes like superoxide dismutase and catalase, stabilizes cell membrane, and improvement the activity of mitochondrial electron transport chain.24,25

In 2012, Ai et al. showed that the level of oxidative stress after cardiac surgery was associated with the hospital length of stay.26 Ziabakhsh-Tabari found that postoperative oxidative stress was associated with cardiac complications, including arterial fibrillation.27 Melatonin with inhibition of apoptosis and enhance cellular survival can protect cardiac cell from damaging.24

Besides, there are some other pathways which are claimed for melatonin cardioprotective effects such as interfering in activating extracellular signal-regulated protein kinases 1 and 2 (ERK1/2),2 reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways,2 Silent information regulator 1,25,28 and reducing PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury via RISK and SAFE pathways interaction.2

In our study, hemoglobin levels, platelet count, serum creatinine, ALT, BUN, and AST levels in both melatonin and placebo groups did not show any significant difference before and after surgery.

Strengths and Limitations

The major limitation of this clinical trial: there was no follow-up including EKG, recorded hemodynamics, EF, heart functions, and it was single center randomized clinical trial.

Conclusion

This study showed that administration of oral melatonin tablet before and after CABG surgery could prevent inflammatory cytokines secretions such as IL-6 and this would make melatonin an attractive choice for cardiologists and anesthetists.

According to the results, melatonin had no significant effect on the serum level of IL-9 and melatonin may have no significant effect on the improvement of clinical or laboratory outcomes.

Acknowledgments

This study was supported by Shiraz University of Medical Sciences. The authors would like to thank the patients who participated in this trial.

Author Contributions

Reza Jouybar participated in the study conception, proposal writing, data analysis and the article draft and manuscript revision. Mahtab Setoodeh was contributed in proposal preparation, data collection and the primary draft. Zeinabsadat Fattahi Saravi, Ali Karami, Saeed Khademi were contributed in the study conception, proposal writing and final draft. Sedigheh Ahmadi, Ahad Izadpanah, Mansour Jannati, Masih Shafa were contributed in the proposal writing, data collection and article draft. Elham Asadpour participated in data analysis, manuscript preparation, article writing and editing and final draft. Farzaneh Masih, Mahyar Malekzadeh participated in study design and data analysis.

Comment

Oral administration of melatonin can be offered as a pre-hospital treatment to reduce myocardial ischemia/reperfusion injury due to induced oxidative stress, inflammation responses after CABG, these effects may be dose- dependent.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

The present article was extracted from the thesis written by Dr. Mahtab Setoodeh. This article was financially supported by Shiraz University of Medical Sciences grants No 12367. The author declared that they have no other relevant financial interest.


References

1
Shinde S, Kumar P, Neela P.
Systemic inflammatory changes after off-pump and on-pump coronary artery bypass surgery.
Indian J Thorac Cardiovasc Surg. 2006;22(1):10–14.
2
Wan S, LeClerc JL, Vincent JL.
Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies.
Chest. 1997;112(3):676–692.
3
Elahi MM, Yii M, Matata BM.
Significance of oxidants and inflammatory mediators in blood of patients undergoing cardiac surgery.
J Cardiothorac Vasc Anesth. 2008;22(3):455–467.
4
Kücükakin B, Gögenur I, Reiter RJ, Rosenberg J.
Oxidative stress in relation to surgery: is there a role for the antioxidant melatonin?
J Surg Res. 2009;152(2):338–347.
5
Kelberman D, Fife M, Rockman MV, Brull DJ, Woo P, Humphries SE.
Analysis of common IL-6 promoter SNP variants and the AnTn tract in humans and primates and effects on plasma IL-6 levels following coronary artery bypass graft surgery.
Biochim Biophys Acta. 2004;1688(2):160–167.
6
Greenberg JH, Whitlock R, Zhang WR, et al.
Interleukin-6 and interleukin-10 as acute kidney injury biomarkers in pediatric cardiac surgery.
Pediatr Nephrol. 2015;30(9):1519–1527.
7
Beyer CE, Steketee JD, Saphier D.
Antioxidant properties of melatonin—an emerging mystery.
Biochem Pharmacol.. 998;56(10):1265–1272.
8
Goswami R, Kaplan MH.
A brief history of IL-9.
J Immunol. 2011;186(6):3283–3288.
9
Kelleher K, Bean K, Clark SC, et al.
Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells.
Blood. 1991;77(7):1436–1441.
10
Dianatkhah M, Ghaeli P, Talasaz AH, et al.
Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder.
J Tehran Heart Cent. 2015;10(3):122–128.
11
Maldonado MD, Murillo-Cabezas F, Calvo JR, et al.
Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury–related lymphocytopenia and oxidative damage.
Crit Care Med. 2007;35(4):1177–1185.
12
Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B.
Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas.
Cell Mol Life Sci. 2017;74(21):3863–3881.
13
Dwaich KH, Al-Amran FGY, Al-Sheibani BIM, Al-Aubaidy HA.
Melatonin effects on myocardial ischemia–reperfusion injury: impact on the outcome in patients undergoing coronary artery bypass grafting surgery.
Int J Cardiol. 2016;221:977–986.
14
Iqbal J, Ghaffar A, Shahbaz A, Sami W, Khan JS.
Postoperative arrhythmias after coronary artery bypass grafting a comparison between ‘off pump’ and ‘on pump’ CABG.
J Ayub Med Coll Abbottabad. 2010;22(3):48–53.
15
Dreyer WJ, Phillips SC, Lindsey ML, et al.
Interleukin 6 induction in the canine myocardium after cardiopulmonary bypass.
J Thorac Cardiovasc Surg. 2000;120(2):256–263.
16
Rettig TC, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EM, Noordzij PG.
Postoperative interleukin-6 level and early detection of complications after elective major abdominal surgery.
Ann Surg. 2016;263(6):1207–1212.
17
Reiter RJ, Robinson J.
Melatonin: Your Body’s Natural Wonder Drug.
New York, NY: Bantam. 1995.
18
Haghjooy Javanmard S, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M.
The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery.
Oxid Med Cell Longev. 2013;2013:676829.
19
Chen D, Li Z, Bao P, et al.
Nrf2 deficiency aggravates angiotensin II-induced cardiac injury by increasing hypertrophy and enhancing IL-6/STAT3-dependent inflammation.
Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1253–1264.
20
Marra AM, Arcopinto M, Salzano A, et al.
Detectable interleukin-9 plasma levels are associated with impaired cardiopulmonary functional capacity and all-cause mortality in patients with chronic heart failure.
Int J Cardiol. 2016;209:114–117.
21
Kilic U, Kilic E, Tuzcu Z, et al.
Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway.
Nutr Metab (Lond). 2013;10(1):7.
22
Wang Z, Ma C, Meng CJ, et al.
Melatonin activates the Nrf2‐ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model.
J Pineal Res. 2012;53(2):129–137.
23
Shafiei E, Bahtoei M, Raj P, et al.
Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: a randomized, open-labeled, placebo-controlled trial.
Medicine (Baltimore. 2018;97(30):e11383.
24
An R, Zhao L, Xi C, et al.
Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism.
Basic Res Cardiol. 2016;111(1):8.
25
Yu L, Liang H, Dong X, et al.
Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin.
J Pineal Res. 2015;59(3):376–390.
26
Ai AL, Hall D, Bolling SF.
Interleukin-6 and hospital length of stay after open-heart surgery.
Biol Psychiatry Psychopharmacol. 2012;14(2):79–82.
27
Ziabakhsh-Tabari S.
Can perioperative C-reactive protein and interleukin-6 levels predict atrial fibrillation after coronary artery bypass surgery?
Saudi Med J. 2008;29(10):1429–1431.
28
Yu L, Liang H, Lu Z, et al.
Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies.
J Pineal Res. 2015;59(4):420–433.

References

Close