ANAESTHESIOLOGY AND INTENSIVE CARE
Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients

Introduction

Post-cardiac surgery delirium is a severe complication which can develop in any patient during the early postoperative period and is characterized by altered consciousness and global cognitive disturbances. The delirium has been reported to occur in 10% to 60% of surgical patients [1]. Moreover, in intensive care unit (ICU), up to 81% of patients manifest delirium [2].
Melatonin is a neurohormone that is synthesized from tryptophan and secreted by the pineal gland and is released directly into the bloodstream in a circadian pattern governed by the light and dark cycle. It produces hypnotic effects by accelerating sleep initiation and improving sleep maintenance and efficiency. This circadian rhythm of melatonin secretion has been shown to be altered postoperatively, and this may lead to changes in sleeping patterns [3]. Moreover, its plasma levels are decreased after surgery and in hospitalized patients [4].
Delirium and perioperative sleep disturbance are potentially linked, either as predisposing factors or as symptoms of one another.

Aim

Thus it was hypothesized that restoring normal sleeping patterns with a substance that is capable of resynchronizing circadian rhythm such as exogenous administration of melatonin may possibly reduce the incidence of postoperative delirium. Moreover, synthetic melatonin supplements proved successful when used as a premedication to reduce anxiety and sedate patients preoperatively, with an excellent cognitive profile [5].
The aim of this prospective observational study was to study the effect of melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients.

Material and methods

In this prospective single center observational non-randomized study the patients were divided into two consecutive groups. The study took place in a tertiary level care facility from September 2012 to July 2013. The first group (group A), which was the control group, included 250 consecutive patients who had various types of cardiac surgery in our institution and were operated on in an elective (n = 183) or urgent (n = 67) regime. The second group (group B) also included 250 consecutive patients who received prophylactic perioperative melatonin treatment and had various types of cardiac surgery in our institution and were also operated on in an elective (n = 178) or urgent (n = 72) setting (frequency and representation of the types of operations are presented in Table I). The patients received 5 mg of melatonin (Circadin, Neurim Pharmaceuticals EEC Limited, UK; prolonged-release tablets) the evening before the operation, and the treatment was continued until postoperative day 3. Patients treated on an emergency basis were excluded from the study in both groups (group B – emergent patients could not receive the evening before surgery prophylactic melatonin treatment; group A – the need for a comparable homogeneous group). Of the patients who participated in both groups, medical history and preoperative characteristics (concomitant diseases or risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, smoking, alcoholism, previous psychiatric disease), perioperative details (type of operation, duration of cardiopulmonary bypass and aortic cross-clamp, doses of opiates and benzodiazepines administered during the operation) and postoperative details (duration of mechanical ventilation > 24 hours, ICU and hospital stay) were recorded.
Also the EuroSCORE II value was calculated for all patients in both groups, and they were accordingly categorized into three groups as high, moderate and low risk (low risk < 1.6%, moderate risk 1.6%-6.7%, high risk > 6.7%).
Cardiac surgery, the anesthetic regimen and the postoperative management were standardized.

Ethics

Ethical approval for this study was provided by the local Ethical Committee on 26/8/2012.
All the study participants provided written informed consent.

Anesthetic technique

All patients in both groups received premedication of 10 mg oxazepam the evening before surgery and 7.5 mg of midazolam 1 to 2 h before surgery. Anesthesia was induced by 2.5-5 mg, midazolam, 2-2.5 mg/kg propofol, sufentanil 0.01-0.025 mg and sevoflurane 1-2%. Tracheal intubation was facilitated by 0.6-1 mg/kg atracurium. Anesthesia was maintained with sufentanil infusion 0.0005 mg/kg/h and sevoflurane 1-2%, while neuromuscular blockade was maintained with the administration of atracurium 50 mg every 40 minutes. No propofol was administered during anesthesia maintenance.

Surgical procedure of cardiopulmonary bypass

All surgical procedures were performed through median sternotomy. For patients undergoing off-pump surgery, distal anastomoses were performed using a tissue vacuum stabilizer (ACROBAT V, MAQUET Holding GmbH). The no-touch aorta technique was used in off-pump surgery. Nasopharyngeal temperature was maintained above 35°C and systolic blood pressure was kept at 80 mmHg or higher throughout the procedure.
For patients undergoing on-pump surgery, anticoagulation was achieved with heparin to maintain an activated clotting time above 480 s, and the cardiopulmonary bypass circuit was primed with 1 l of Ringer’s Lactate and 250 ml of 20% mannitol. Mild hypothermia of 34-35°C was induced during cardiopulmonary bypass; the pump flow rate was 2.4-2.8 l/min/m², and the mean perfusion pressure was within 70-75 mmHg. Hematocrit was maintained within 25-35%. Myocardial protection was achieved with intermittent blood-enriched cold cardioplegic solution (St. Thomas cardioplegic solution at 3-6°C) using a blood to crystalloid ratio of 5 : 1. Fractional concentration of inspired oxygen was adjusted to keep oxygen partial pressure within 150-250 mmHg, and gas flow was adjusted to maintain arterial carbon dioxide tension within 35-40 mmHg without temperature correction (α-stat).
After all distal anastomoses were completed, the aortic cross-clamp was removed and proximal anastomoses were then performed by means of a single side-clamp on the aorta.

Postoperative management

After surgery, all the patients were admitted to the cardiovascular ICU, where a standard protocol was implemented for sedation, analgesia and management of mechanical ventilation. Patients were extubated according to the following criteria: responsive and cooperative, pO2 of 10-11 kPa and oxygenation index of pO2/FiO2 > 300. In the ICU patients were sedated with propofol until extubation. Analgesia was provided with intravenous morphine infusion at 2 mg/h, Algifen (metamizole, pitofenone, fenpiverinium, Zentiva Group a.s. Czech Rep.) 2.5 γ every 8 hours and intravenous tramadol 100 mg every 8 hours.

Delirium assessment

Delirium was assessed with the CAM-ICU (Confusion Assessment Method for the Intensive Care Unit) every 12 h postoperatively. The CAM-ICU allows the monitoring of delirium in both ventilated and extubated patients. It is based on the Diagnostic and Statistical Manual of Mental Disorders criteria and includes a 4-step algorithm. The patient is determined to be delirious (CAM-positive) if he or she manifests standard features for delirium.
All cardiovascular ICU nurses were educated and well trained in the application of the CAM-ICU in both ventilated and non-ventilated patients.
The level of sedation (level of arousal) was assessed by means of the Richmond Agitation Sedation Scale (RASS).

Statistical analysis

Data are given as mean value ± standard deviation (SD) and standard error of the mean (SEM). Categorical variables are presented as numbers of patients (percentage). A univariate analysis was performed to identify perioperative risk factors in both groups associated with delirium using chi-square analyses or Fisher’s exact test. Different cut-off points for continuous variables were examined to determine the best association with delirium. Odds ratios (OR) were calculated to indicate the effect size of perioperative risk factors on delirium. Variables associated with outcome with a p value <0.05 in the univariate analyses and variables considered clinically significant were entered into a multiple logistic regression model for delirium in order to identify independent risk factors. This was performed using the stepwise logistic regression technique. Finally, groups A and B were statistically matched, analyzed and compared.
For statistical analysis the SPSS software version 22 (SPSS Inc., Chicago, IL, USA) was used.

Results

The study included two groups, each with 250 eligible patients. Delirium developed in 52 (20.8%) patients from group A and 21 (8.4%) patients from group B, with the difference in incidence of delirium between the groups being statistically significant (p = 0.001). The patients developed only hyperactive delirium. No hypoactive or mixed types of delirium were observed.
The preoperative and perioperative clinical patients’ characteristics of the two groups and the comparison of groups are shown in Table I.
Patients with postoperative delirium in both groups had a longer stay in the ICU (p < 0.0001, p = 0.001 respectively) and longer total duration of hospitalization (p < 0.0001, p = 0.002). However, the ICU stay is not a predictor of postoperative delirium (p = 0.534) in the control group.
Univariate analysis of the variables of group A confirmed that older age (p < 0.0001), a higher EuroSCORE II value (p < 0.0001), longer cardio-pulmonary bypass (CPB) time (p < 0.0001), longer aortic cross-clamping (ACC) time (p < 0.0001), and sufentanil dose (p = 0.010) were strongly independently associated with postoperative delirium.
In multivariate analysis of the variables of group A, age (p < 0.001), EuroSCORE II value (p < 0.001), CPB and ACC time (p < 0.05), sufentanil dose (p < 0.001) and the coronary artery bypass graft surgery (CABG) type of operation (p < 0.001) are all predictors of postoperative delirium development.
Univariate analysis of the variables of group B confirmed that only older age (p = 0.001) and a higher EuroSCORE II value (p = 0.001) were strongly associated with the development of delirium. Concerning CPB time > 120 min, it was shown to be a weak predictor for developing postoperative delirium (p = 0.097). The results showed that the administration of melatonin reduced the predictive effect of CPB, ACC time and sufentanil dose in the development of postoperative delirium.
In group A, patients who had a CPB time more than 120 min had a 15 times higher risk for developing postoperative delirium. Also, the longer the ACC time, the higher was the risk for developing postoperative delirium. Finally, the higher the sufentanil dose (the patients were receiving a fixed dose per kg per minute), the higher was the risk for developing postoperative delirium. From this analysis we can see that certain variables such as CPB and ACC time and sufentanil dose are linked to a common parameter, time; so we can infer that the longer the operation lasts, the higher is the risk for developing postoperative delirium.
In group B, administration of melatonin in the univariate analysis eliminated the parameter of time in the development of postoperative delirium.
Concerning benzodiazepine administration, it was shown in group A to be an intermediate predictor for developing postoperative delirium (p = 0.055) in univariate analysis, whereas in group B it was shown not to be a predictor for the development of postoperative delirium (p = 0.809).
Concerning the type of surgery only in group A, CABG was shown to be associated with the incidence of postoperative delirium (p = 0.010).
In group B, in multivariate analysis age and EuroSCORE II were shown to be predictors of postoperative delirium development (p = 0.014).
Table II shows the univariate analysis of the variables in group A, Table III shows the univariate analysis of the variables in group B, and Table IV shows the multivariate analysis of both groups.
After matching, the two groups were found to be comparable. The only variable that could not be match was consumption of alcohol, but the number of patients was low so it could not have any effect on the results. The comparison of the two groups is shown in Table I.
After comparison of the two groups, older age (p = 0.001), higher EuroSCORE II (p = 0.001), CABG type of operation (p = 0.003) and CABG and combined valve operations (p = 0.018, p = 0.010 respectively) were all confirmed to be associated with an increased risk for the development of postoperative delirium. Perioperative predictors connected with the operative time, such as CPB time (p = 0.001), ACC time (p = 0.008), and sufentanil dose > 0.15 mg (p = 0.001), were also associated with an increased risk for the development of postoperative delirium. Moreover, increased ventilation time (p = 0.033) was also associated with postoperative delirium. Finally, patients who suffered from delirium had a prolonged ICU stay (p = 0.001) and hospitalization time (p = 0.001).
The statistical comparison analysis of the variables of both groups based on the incidence of postoperative delirium is shown in Table V.
The hospital mortality in each group of patients was 1.6%.

Discussion

In our study the reduction in the incidence of postoperative delirium between the two compared groups was statistically significant. Other authors have published similar results. Sultan SS [6] found in his study of three hundred patients scheduled for hip arthroplasty that only preoperative melatonin administration succeeded significantly in decreasing the incidence of postoperative delirium to 9.43%. Recently, a study concluded that low-dose melatonin in elderly medical patients admitted to the emergency department decreases the risk of delirium [7].
In the melatonin group only older age and a higher EuroSCORE II value were shown to be strongly associated with the development of delirium. The results showed that the administration of melatonin reduced the predictive effects of CPB, ACC time and the sufentanil dose in the development of postoperative delirium.
After matching, the two groups were found to be comparable. After comparison of the two groups, older age, higher EuroSCORE II, CABG type of operation and CABG combined with valve operations were all confirmed to be associated with an increased risk for the development of postoperative delirium. Perioperative predictors connected with the operative time, such as CPB time, ACC time, and sufentanil dose > 0.15 mg, were also associated with an increased risk for the development of postoperative delirium.
Age has consistently been reported as a predictor of postoperative delirium [8]. Moreover, concerning the EuroSCORE value, Osse et al. [9] found that a EuroSCORE value greater than 6 was associated with the occurrence of postoperative delirium.
Another two intraoperative predictors found in our study to be associated with postoperative delirium are longer CPB and ACC times. Other reports published in the literature have similar results. Andrejaitiene et al. [10] found that ACC time > 68 min is associated with the development of delirium. Similar results are reported by other authors, finding that increased CPB times are associated with the development of postoperative delirium [11].
Furthermore, it was shown that the higher the sufentanil dose (the patients in our study were receiving a fixed dose per kg per minute), the higher is the risk for developing postoperative delirium. The sufentanil dose is linked with time, so the longer the duration of the operation, the higher is the sufentanil dose, and the higher is the risk for developing postoperative delirium. This association has also been investigated by other authors. Burkart et al. [12] found that an increasing dose of fentanyl administered intraoperatively appeared to be a risk factor for postoperative delirium.
Concerning the benzodiazepine dose, it was also found in the control group to be an intermediate predictor for developing postoperative delirium, whereas in the melatonin group it was not a predictor of postoperative delirium. Pandharipande et al. [13] also reported that exposure to benzodiazepines is one of the strongest modifiable risk factors for postoperative delirium development. In our study the patients developed only the hyperactive type of delirium. McPherson et al. [14] found that patients who received benzodiazepines and were restrained after heart surgery had the hypoactive type of delirium. Avoiding chemical restraint via the use of benzodiazepines or the use of physical restraint via the use of benzodiazepines or the use of physical restraint devices and as much as possible early mobilization could be an effective preventive strategy to decrease the development of postoperative delirium. In our department patients with an uncomplicated postoperative course were usually mobilized on the 1st or 2nd postoperative day.
Concerning the type of the operation, in our study only CABG and CABG combined with valve operation were associated with the development of postoperative delirium. Other authors have also reported a higher incidence of delirium in patients undergoing valve replacement and combined surgery with valve replacement and CABG compared with patients undergoing isolated coronary artery bypass graft surgery [15]. The reason for this according to the authors may be the embolization of air which is trapped within the cardiac chambers during the valve replacement surgery. Concerning our study, the relatively small sample size of valve replacement patients compared with the CABG patient sample could be responsible for the fact that in our patient population CABG surgery alone or combined with valve surgery, and not valve surgery, is associated with the development of postoperative delirium.
In our study, the time frame for early post-cardiac surgery delirium is defined as 2-6 days after the operation, since delirium diagnosed on the first or after the sixth day following cardiac surgery might not be directly linked to the surgery [16].
In the literature there are not many studies that examine the role of exogenous melatonin in the prevention of postoperative delirium, especially in the group of patients after cardiac surgery which we examined, and this may be considered one of the strengths of this study. Also in the melatonin group of patients, we tried to identify potential predictors of postoperative delirium.
Melatonin administration significantly decreased the overall incidence of postoperative delirium and may decrease the effect of various postoperative delirium predictors. Other perioperative strategies should be developed, despite the positive effect of the melatonin treatment, in order to further reduce the incidence of postoperative delirium in cardiac surgery patients.
The study has some limitations. Firstly, this is a prospective observational study. A more powerful, randomized, placebo-controlled, double-blind trial should be performed in order to confirm the results of this study. Secondly, we did not perform baseline psychiatric and cognitive screening tests as preoperative mental disorders are strong predictors of postoperative delirium. Any psychiatric disorders that were examined in our study were obtained from the medical history of the patient, and their incidence may have been underestimated. Thirdly, the CAM-ICU assessment was performed in the cardiovascular ICU and was not extended to the cardiac surgical floor. As a result, our findings can only be applied to early postoperative delirium.

Conclusions

The administration of melatonin significantly decreases the incidence of postoperative delirium after cardiac surgery and decreases the effect of various risk factors that are found in patients who did not have melatonin treatment. Even after melatonin treatment, risk factors such as age, EuroSCORE II value, CPB and ACC time, sufentanil dose, ventilation time and operation type may increase to a lesser degree the risk of postoperative delirium. Other perioperative strategies should be developed, in order to further reduce the incidence of postoperative delirium in cardiac surgery patients. Prophylactic treatment with exogenous melatonin should be considered in every patient scheduled for cardiac surgery.

Acknowledgements

This paper was orally presented at the 1st World Meeting of the Hellenic Cardiothoracic Diaspora in Athens, 20-22 November 2014.

Dislocure

Authors report no conflict of interest.

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