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Melatonin, Delirium, Thoracic surgery, What&,rsquo s Known Patients undergoing cardiac surgery are particularly prone to delirium due to the complexity of the operation, cardiopulmonary bypass, macro- and microemboli, reperfusion, and postoperative complications. The prevalence of delirium after open-heart surgery is about 50% to 67%, while it is between 10% and 46% in noncardiac surgery. What&,rsquo s New Melatonin may be effective in reducing the severity of delirium after cardiac surgery. The effect of melatonin as a delirium prevention agent should be considered in patients admitted to the cardiovascular intensive care unit. IntroductionDelirium is characterized by a disturbance in the level of consciousness and cognitive or perceptual function that lasts for hours and days and fluctuates over time. 1,, 2, Delirium is an acute disturbance of consciousness and cognition, which develops over a short time in the context of an acute medical condition. 3, Advances in surgical techniques have made it possible to perform cardiac surgery even in the elderly. 4,- 6, Old age can be effective in increasing postoperative delirium. 4, The occurrence rate of delirium ranges from 11% to 33% on admission, and its frequency during hospitalization is between 3% and 56% among aging patients in emergency units or medical and surgical wards in general hospitals. 4, With the rise in the number of aged people, further increases in delirium appear likely. Delirium occurs after major surgeries within the first three days. 7, Contrary to popular belief about delirium, only 4% of the patients with delirium were fully recovered at discharge and 80% had remaining defects for up to six months postoperatively in a previous investigation. 8, Therefore, delirium is not always transient and, in some cases, may be associated with structural brain damage, resulting in persistent cognitive impairment. 8, Delirium can lead to increased morbidity and mortality, the need for longer mechanical ventilation, risk of injury to patients or staff, the risk of falling out of bed, unwanted extubation, and increasdlength of intensive care unit (ICU) stay, contributing to increased treatment costs. 9, Delirium may be affected by several etiological factors such as age type of surgery and anesthesia hypoxia and hypercapnia severe pain opioid use long-term lack of sleep previous trauma to the head a history of impaired cognitive status before surgery alcohol consumption diabetes systemic infection and sodium, potassium, or glucose disturbances before surgery. 9, Patients undergoing cardiac surgery are particularly prone to delirium due to the complexity of the operation, cardiopulmonary bypass, macro- and microemboli, reperfusion, and postoperative complications. 9,, 10, The prevalence of delirium after open-heart surgery is about 50% to 67%, whereas it ranges between 10% and 46% in noncardiac surgery. 4, One of the main mechanisms of delirium is the disruption of melatonin levels following heart surgery. 10, A serotonin-produced hormone in the pineal gland, melatonin (N-Acetyl-5-methoxytryptamine) is secreted with the circadian rhythm into the circulatory and cerebrospinal fluid and adjusts the cycle of sleep and awakening. 11,- 13, Delirium and perioperative sleep disorders are possibly linked, either as predisposing factors or as symptoms of one another. 11, To our knowledge, there is a dearth of data on the role of exogenous melatonin in the inhibition of delirium after heart surgery. Hence, we conducted the present study to evaluate the effect of melatonin administration on the inhibition of delirium following on-pump coronary artery bypass graft (CABG).Patients and MethodsThis randomized double-blind clinical trial was conducted from September 2018 to March 2019 in Golestan Hospital, Ahwaz, Iran. A convenience sample of 60 patients were assessed by dividing them in to two groups of intervention and control. The Ethics Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, approved all the procedures of this study (IR.AJUMS.REC.1398.199 and the RCT code was IRCTID, IRCT20180909040979N3).Written informed consent for participation in the study was obtained from all the patients after they received clear explanations about the objective and potential risks and benefits of the study. During the study period, 120 patients undergoing elective on-pump CABG were eligible to participate in the trial. After the initial screening, 90 patients agreed to participate and provided informed consent. Among them, 30 patients did not meet the inclusion criteria, five patients had an ejection fraction below 30%, 10 underwent off-pump CABG, five had allergies, five were on antipsychotic drugs, and five suffered from renal disease. Ultimately, 60 patients were enrolled in the study and were assigned to two groups of melatonin and placebo, 30 patients in each group (figure 1,).Figure 1. The figure illustrates the CONSORT flowchart diagram. The inclusion criteria consisted of being at least 30 years of age, being a candidate for elective on-pump CABG, being in anesthesia class II&,ndash III anesthetic risk, having a minimum ejection fraction of 30%, and being admitted to Golestan Hospital (September 2018&,ndash October 2019). The exclusion criteria constituted the presence of melatonin contraindications, allergy to the drug or its compounds, the chronic or recent use of melatonin or hypnotic drugs, receiving barbiturates or antipsychotics, a history of liver or kidney disease or chronic pulmonary disease, a history of neurological or psychological diseases, alcohol consumption, inability to communicate verbally, and the occurrence of serious and life-threatening events during or after.RandomizationThe participants were randomized 1,1 to receive either melatonin or a placebo. To ensure that both the patients and the investigators were blind to the treatment group before the study begins, we utilized a computer-generated allocation-concealment process before recruiting the patients. The eligibility criteria were electronically confirmed in a web-based case-report form and subsequently randomization was performed. Then, randomization was performed centrally without stratification. The sequence was generated with the aid of using an unbiased statistician, and the use of a random range generator with a 1,1 allocation the use of random block sizes of two. InterventionThe patients in the melatonin group received 3 mg of melatonin (prolonged-release tablets Webber Naturals&,reg , Canada) the evening before the operation and 3 mg on the morning of surgery. The treatment was continued until second postoperative day with 3 mg of melatonin. In the control group, the patients received a placebo. The placebo capsules were filled with cornstarch powder (Beijing, China). A reliable intravenous line was inserted to allow the hydration of the patients using Ringer&,rsquo s lactate solution (Iran Injection and Pharmaceutical Products Company, Iran), 10 mL/kg. Next, necessary monitoring, including pulse oximetry, invasive and noninvasive blood pressure control, electrocardiography, and capnometry was established and the patients underwent general anesthesia with the same drugs, 0.1&,ndash 0.2 mg/kg of midazolam (Caspian Tamin, Iran), 0.5&,ndash 1 &,micro g/kg of sufentanil (Aburaihan, Iran), 1 mg/kg of ketamine (Rotexmedica, Germany), and 0.5 mg/kg of cisatracurium (Rosamed, Iran). Additionally, isoflurane 1% (Piramal Critical Care, USA) in 50% oxygen, 0.1 &,micro g/kg/h of sufentanil, 0.1 mg/kg/h of midazolam, and 0.1 mg/kg/h of cisatracurium were used to maintain general anesthesia. After the induction of anesthesia, a central venous catheter (Arrow, USA) was inserted. For the initiation of cardiopulmonary bypass, 400 u/kg of heparin (Alborz Darou, Iran) was injected to all the patients. The heparin dosage was adjusted based on the target activated clotting time (ACT) of 450 to 480 seconds. 14, After the bypass was cut off, protamine (Exir Darou, Iran) was administered to reverse heparin. Cardiac surgery and postoperative management were standardized. After surgery, all the patients were admitted to the cardiovascular ICU, where a standard protocol was implemented for sedation, analgesia, and mechanical ventilation management. The patients were extubated if they were responsive and cooperative, had PO2 levels of 80 to 100, had an oxygenation index (PO2/FiO2) of greater than 300, and were hemodynamically stable. The patients were sedated in the ICU with propofol (B.BRAUN, Germany 0.5 mg/kg/h) until extubation. Analgesia was provided with an intravenous morphine infusion (Darou Pakhsh, Iran) at 2 mg/h and 0.3 &,micro g/kg/h of dexmedetomidine (Pfizer, USA).Primary and Secondary OutcomesDelirium occurrence was assessed based on the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), and delirium intensity was assessed based on the Memorial Delirium Assessment Scale (MDAS) for up to 48 hours after extubation every 12 hours. For the monitoring of delirium in both ventilated and extubated patients, The CAM-ICU was used. This is a tool according to the Diagnostic and Statistical Manual of Mental Disorders criteria and includes a four-step algorithm. 15, Patients are adjudged delirious (CAM-positive) if they manifest the standard features of delirium. 15, All the cardiovascular ICU nurses were educated and well-qualified in the application of the CAM-ICU and MDAS in both ventilated and non-ventilated patients.16, The mechanical ventilation time and the ICU length of stay comprised the secondary outcomes.Statistical AnalysisThe statistical analyses were performed using SPSS Software, version 22.0, (SPSS, Inc, Chicago, IL, USA). The quantitative variables were described as mean&,plusmn SD and the qualitative variables as frequencies and percentages. The continuous variables were compared using the unpaired t test or a nonparametric equivalent (Mann&,ndash Whitney U test). Group comparisons were performed using the t test and the Chi-square tests. Statistical significance was defined as a P value of less than 0.05. ResultsDuring the study period, from September 2018 to March 2019, a total of 120 patients undergoing elective on-pump CABG surgery were eligible to participate in the trial. After the initial screening, 90 patients agreed to participate and provided informed consent. Among them, 30 patients did not fulfill the inclusion criteria. Ultimately, 60 patients were enrolled in the study and were assigned to two groups of melatonin and placebo (n=30 per group). As is shown in table 1,, there were no statistically significant differences between the two groups in terms of demographic characteristics (P&,gt 0.05).VariableMelatonin Group (n=30)Control Group (n=30)P valueAge (y), mean&,plusmn SD 60.26&,plusmn 9.5062.9&,plusmn 8.080.251*,&,lt 50 n (%)4 (13.3%)3 (10%)0.626**,50&,ndash 70 n (%)21 (70%)19 (63.3%)&,gt 70 n (%)5 (16.6%)8 (26.6%)SexMale20 (66.6)22 (73.3)0.58**,Female10 (33.3)8 (26.6)EuroSCORE (%), mean&,plusmn SD 2.63&,plusmn 2.652.86&,plusmn 2.830.48*,Diabetes n (%)12 (40)13 (43)0.79**,Hypertension n (%)26 (86.6)29 (96.6)0.16**,Hyperlipidemia n (%)21 (70)26 (86.6)0.56**,Smoking n (%)10 (33.3)12 (40)0.59**,Alcohol consumption n (%)0 (0)0 (0)0.07**,Opium addiction n (%)4 (13.3)6 (20)0.49**,Aortic cross-clamp time (min) (mean&,plusmn SD)55.11&,plusmn 38.6149.47&,plusmn 30.730.53*,&,le 60 min n (%)25 (83.3%)23 (76.6%)0.52**,&,gt 60 min n (%)5 (16.6%)7 (23.3%)Cardiopulmonary bypass time (min) (mean&,plusmn SD)79.50&,plusmn 5.377.43&,plusmn 6.80.32*,&,le 120 min n (%)25 (83.3%)23 (76.6%)0.52**,&,gt 120 n (%)5 (16.6%)7 (23.3%)*Group comparisons were performed using the t test, **Group comparisons were performed using the Chi-square test |