|Year : 2019 | Volume
| Issue : 2 | Page : 147-155
The efficacy of dexmedetomidine versus melatonin in patients undergoing modified radical mastectomy
Enas M Ashrey, Ruqaya M Elsayd
Department of Anesthesia and Intensive Care, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
|Date of Submission||14-Jul-2018|
|Date of Acceptance||03-Nov-2018|
|Date of Web Publication||12-Jun-2019|
Enas M Ashrey
Department of Anesthesia and Intensive Care, Faculty of Medicine for Girls, Al-Azhar University, Abbasia , Cairo, 11517
Source of Support: None, Conflict of Interest: None
Background Elderly patients are more susceptible to the adverse effects of anesthesia due to reduction of the margin of safety. So, premedication before operation in elderly patients has become an important issue.
Objective The aim was to evaluate the efficacy of premedication with dexmedetomidine versus melatonin on sedation, analgesia, and inflammatory response in elderly patients.
Patients and methods This study was conducted on 80 healthy female patients of American Society of Anesthesiologists physical status I, II scheduled for modified radical mastectomy under general anesthesia. The patients were randomly divided into two equal groups: Group I (n=40) received 5 mg melatonin and group II (n=40) received 1 μg/kg dexmedetomidine by intravenous infusion. The heart rate, mean arterial blood pressure, and oxygen saturation were measured perioperatively. Visual analog scale (VAS) for anxiety and pain and the sedation score were measured. Also, biochemical analyses for interleukin-6 (IL6) and liver function tests were measured and any adverse effects reported.
Results There was no statistically significant difference in hemodynamics between the groups. VAS for anxiety was significantly lower in the melatonin group. VAS pain scores was significantly lower in the dexmedetomidine group (P=0.0001). The sedation score showed that the sedation level in the melatonin group was lower than dexmedetomidine groups preoperatively and postoperatively but with significant difference only at 30 min postoperatively. Plasma levels of IL6 before premedication (T0) showed highly significant difference between the studied groups (P<0.0001), but 6 h after skin incision (T6) IL6 increased in the melatonin group, while it decreased in the dexmedetomidine group (P=0.0600). Also, plasma levels of alanine aminotransferase, aspartate aminotransferase, and the adverse effects recorded for each drug showed no statistically significant difference between the two groups.
Conclusion Premedication with dexmedetomidine has good postoperative analgesia and sedation with less inflammatory stress response than melatonin, with superiority of melatonin in the reduction of anxiety.
Keywords: dexmedetomidine, elderly patients, melatonin, premedication
|How to cite this article:|
Ashrey EM, Elsayd RM. The efficacy of dexmedetomidine versus melatonin in patients undergoing modified radical mastectomy. Res Opin Anesth Intensive Care 2019;6:147-55
|How to cite this URL:|
Ashrey EM, Elsayd RM. The efficacy of dexmedetomidine versus melatonin in patients undergoing modified radical mastectomy. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Oct 14];6:147-55. Available from: http://www.roaic.eg.net/text.asp?2019/6/2/147/260148
| Introduction|| |
Preoperative anxiety and postoperative pain are the two major concerns of anesthesiologists . Morbidity and mortality increase with advancing age, as they are more susceptible to the adverse effects of anesthesia because of their reduced margin of safety. Perioperative medication before anesthesia in elderly patients has become an extremely important issue .
Dexmedetomidine (Precedex), the α2-adrenoceptor agonist, that provides anxiolysis and cooperative sedation without respiratory depression. It decreases the central nervous system sympathetic outflow in a dose-dependent manner and has analgesic effects best described as opioid sparing. There is increasing evidence that dexmedetomidine has organ-protective effects against ischemic and hypoxic injuries, including cardioprotection, neuroprotection, and renoprotection . It is believed that the spinal cord is probably the major site of analgesic action, where the activation of α2c-adrenoreceptor agonist subtype seems to increase the analgesic action of opioids in lowering the transmission of nociceptive signals to brain centers. Dexmedetomidine also inhibits the release of substance P from the dorsal horn of the spinal cord, leading to primary analgesic effects . It has a number of unique pharmacodynamic properties, which also make it useful in anesthesia: decreased minimum alveolar concentration of inhalational anesthetic agent (MAC), analgesia without respiratory depression, and a significant reduction in catecholamine secretion . In recent years, its anti-inflammatory effects have been highlighted .
Melatonin (the pineal hormone melatonin (N-acetyl-5-methoxytryptamine) has several functions: antioxidant, oncostatic, and sedative, analgesic, anti-inflammatory, antioxidative, and anticonvulsant effects ,. The hypnotic property of melatonin supports its possible use in the different stages during anesthetic procedures, from premedication to induction of general anesthesia for the modulating effects of melatonin on anesthesia drugs . The analgesic effects of melatonin may be linked to Gi-coupled melatonin receptors, to Gi-coupled opioid µ-receptors, or GABA-B receptors. The exact site of action of melatonin to induce antinociception is not clear. Possibly, it augments GABA-ergic systems and morphine antinociception, enhancing GABA-induced currents and inhibiting the glycine effects. Melatonin may enhance the levels of β-endorphins and the antinociception induced by δ-opioid receptor agonists and could activate MT2 melatonin receptors in the dorsal horn of the spinal cord. Melatonin is involved in the modulation of nociceptive transmission .
This study was aimed to evaluate the effectiveness of premedication with dexmedetomidine, and melatonin on perioperative hemodynamic stability, anxiety and pain scale, sedation score, and inflammatory responses for elderly patients.
| Patients and methods|| |
This study was performed in Al-Zahraa University Hospitals on 80 female patients of American Society of Anesthesiologists physical status I, II aged more than 60 years undergoing general anesthesia for modified radical mastectomy. Exclusion criteria include current anticoagulation therapy, major renal, hepatic and cardiac insufficiency, continuous medication for psychiatric disorders, regular medication with opioids and benzodiazepines, alcohol abuse, respiratory insufficiency, and morbid obesity.
After approval of the local ethics committee and providing informed consent, patients were randomly allocated into two equal groups, each group included 40 patients: group I (n=40) received 5 mg melatonin (melatonin tablet=5 mg) and group II (n=40) received 1 μg/kg, dexmedetomidine (precedex ampule, 200 μg/2 ml). The patient is transported to the operating room ∼15 min after intravenous infusion of dexmedetomidine 1 μg/kg in 20 ml saline in group I and 1 h after premedication with one oral tablet of 5 mg melatonin for group II, and an intravenous infusion of ringer lactate solution was started. All patients were monitored for heart rate (HR), oxygen saturation (SpO2), and noninvasive mean arterial blood pressure (MABP).
Anesthesia was induced with fentanyl 1 µg/kg and thiopental 3–5 mg/kg. Cisatracurium 0.15 mg/kg and isoflurane in oxygen with FiO2, 0.6 (3 l/min) were administered to maintain the adequate depth of anesthesia. After intubation, ventilation was adjusted to maintain normocapnia (35–40 mmHg). Incremental doses of the injection fentanyl and cisatracurium (0.03 mg/kg) were given as required. After completion of surgery, intravenous neostigmine (50 µg/kg) and atropine (10 µg/kg) were given to reverse the residual muscle paralysis.
Parameters of assessment
- Hemodynamic changes: all patients were monitored for HR, SpO2, and noninvasive MABP. Baseline readings were measured and every 5 min preoperatively, intraoperatively, and postoperatively until complete recovery.
- Visual analog scale (VAS) of anxiety and postoperative pain: this is a self-assessment of anxiety or pain where the subjects grade their own anxiety or pain at the time of the test by placing a vertical stroke along a horizontal line of a certain length. A 10 cm linear VAS was used to assess their anxiety levels. The extremes of the VAS anxiety scale and pain were marked as ‘no anxiety’ at the 0 end and ‘anxiety or pain as bad as ever can be’ at the 10 cm end .
- Anxiety VAS scores were evaluated before and 15, 30, 45, and 60 min after the administration of premedication at the preoperative period. Also, anxiety VAS scores were evaluated at 15, 30 min postoperatively.
- Pain VAS scores were evaluated at 15, 30 min postoperatively. Postoperative pain was treated with a NSAID and paracetamol when the VAS score for pain was less than three and with incremental intravenous doses of fentanyl for a score of greater than or equal to three.
- The sedation score (Bloomsbury score): also known as the University College London Hospitals sedation protocol, this scale spans from −3 (unarousable) to +3 (agitated and restless). There is also categorization for natural sleep ([Table 1]) . The sedation was measured by the score of Bloomsbury before, and 15, 30, 45, and 60 min after the administration of premedication in the preoperative period. Also, sedation score was measured at 10, 20, and 30 min postoperatively.
- Biochemical analysis: blood samples were collected from antecubital veins, 2 ml for interleukin-6 (IL6) analyses, before administration of the drug (T0), and at 6 h after skin incision (T6). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also measured. The last two analyses were collected before administration of the drug (T0) and at 24 h after surgery (T24). Blood samples collected for IL‐6 analyses were centrifuged and the serum was stored at −20°C until analysis. Enzyme‐linked immunosorbent assay was used to analyze the samples. The enzyme‐linked immunosorbent assay method has high specificity and sensitivity for IL‐6 analysis. Blood samples for AST and ALT were measured by chemoillumination using a gas analyzer.
- Adverse effects: patients were observed for any episodes of bradycardia, dizziness, hypotension, nausea, vomiting, headache, and restlessness in the perioperative period. Intravenous ondansetron (4 mg) was given slowly to treat postoperative nausea and vomiting.
Data were collected, coded, revised, and entered to the statistical package for the social sciences (IBM SPSS, Chicago, Illinois, USA) version 20, whereas the sample size was calculated. Qualitative data were presented as numbers and percentages, whereas quantitative data were presented as means and SDs. The unpaired t-test, the χ2-test, and the Mann–Whitney U-test were used to compare the two groups. A P value of more than 0.05 was considered as nonsignificant, whereas a P value of 0.05 or less was considered significant and a P value of 0.01 or less was considered highly significant.
| Results|| |
There were no statistically significant difference in demographic data between the two groups as regards patients, age, sex, weight, height, American Society of Anesthesiologists 1–11, and duration of surgery (P>0.05) ([Table 2]).
- Hemodynamic changes: as regards HR (baseline, intraoperative, and postoperative) there was no statistically significant difference between the study groups and in all subsequent recordings HR values lowered but with no significant difference between the two groups ([Figure 1]).
- MABP: as regards MABP (baseline, intraoperative, postoperative) there was no statistically significant difference between the study groups and in all subsequent recordings MABP values lowered but with no significant difference between the two groups ([Figure 2]).
- SpO2): SpO2 perioperatively showed no significant difference between the study groups, and in all subsequent recordings SpO2 values slightly changed but with no significant difference between the two groups (P>0.05) ([Figure 3]). The change in SpO2 values was within the normal level, which means that premedication with melatonin and dexmedetomidine did not cause respiratory depression or hypoxia in patients.
- VAS pain scores: regarding pain scores as evaluated by VAS, 15 min after surgery there were highly significant difference between the two groups (3.00±2.67 cm for melatonin and 1.30±1.06 cm for dexmedetomidine) (P=0.0003). The scores at 30 min after surgery were 1.00±0.67 cm for melatonin, 0.40±0.52 cm for dexmedetomidine (P=0.0001) which showed a highly significant difference that dexmedetomidine has good analgesic effects ([Table 3]).
- VAS of anxiety: VAS anxiety score (baseline), 15, 30, 45, 60 min after, showed that with comparison between the two groups, the melatonin group has a score lower than the dexmedetomidine group with no significant difference at every time preoperatively (P>0.05). Postoperatively also the melatonin group has a score lower than the dexmedetomidine group with highly significant difference at 15 min postoperatively 0.40±0.70, 1.20±0.92 cm for melatonin, dexmedetomidine groups (P=0.0001) and at 30 min postoperatively were 0.40±0.70, 1.30±0.95 cm (P=0.0001) ([Figure 4]).
- Sedation scores: the sedation scores before premedication showed no statistically significant difference between the two groups. Also, when the sedation scores were compared at each time point intraoperatively in between groups, there is no significant difference noted (P>0.05). At 10 min postoperatively it was 0.90±0.57 for melatonin and 0.60±0.70 for dexmedetomidine groups and 20 min postoperatively were 1.20±0.63, 0.80±0.42, which showed that the postoperative sedation score in the melatonin group was higher than dexmedetomidine groups with no significant difference, but at 30 min postoperatively were 1.30±0.68, 0.80±0.42 (P=0.0002), which demonstrated a statistically significant difference between the two groups ([Figure 5]), which means that the sedation level in the melatonin group was lower than dexmedetomidine groups preoperatively and postoperatively but with significant difference only at 30 min postoperatively.
- Biochemical changes: As regards IL6, the plasma levels of IL6 before premedication (T0) showed a highly significant difference between the studied groups (3.61±3.61 for melatonin, 95.37±43.45 pg/ml for dexmedetomidine) (P<0.0001), but 6 h after skin incision (T6) were 20.43±9.94, 16.00±10.08 pg/ml, which demonstrated that the postoperative mean plasma levels of IL6 increased in the melatonin group, while decreased in the dexmedetomidine group (P=0.0600) ([Table 4]). As regards ALT and AST the plasma levels of ALT before premedication (T0) showed no statistically significant difference between the study groups (P>0.05). Postoperative 1 day after surgery the plasma levels of ALT increased in the melatonin group while decreased in the dexmedetomidine group, with no statistically significant difference by comparison between the two groups, as the ALT levels at 24 h after surgery (T24) were 21.70±14.51, 16.89±8.42 U/l. Plasma levels of AST before premedication (T0) were 23.50±12.04, 23.59±9.49 U/l, for melatonin and dexmedetomidine which showed no statistically significant difference between the study groups, but postoperative plasma levels of AST were increased in dexmedetomidine while decreased in the melatonin group. But there was no significant difference by comparison between the two groups, as at 24 h after surgery the levels of (T24) were 22.70±11.78, 22.69±10.24 U/l ([Table 4]).
|Table 4 Assessed mean plasma levels of interleukin-6, alanine aminotransferase, and aspartate aminotransferase in the three groups|
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- Adverse effects: there was no statistical significant difference between the two groups in the occurrence of bradycardia, dizziness, hypotension, or nausea ([Table 5]).
| Discussion|| |
The most common and anticipated problems in the perioperative setting are anxiety and pain. Patients’ preoperative anxiety influences postoperative anxiety and pain .
Dexmedetomidine, an α2-adrenoceptor agonist, has been used for sedative and analgesic purposes in intensive care units. In recent years, its anti-inflammatory effects have been highlighted . The pineal hormone melatonin (N-acetyl-5-methoxytryptamine) has several functions that may make it an attractive option for premedication, including regulation of circadian rhythms, sedative, analgesic, anti-inflammatory, and antioxidative effects .
As regards hemodynamic measurements, our study showed that the changes in HR, MABP, SpO2 in the two groups without any significant impact on preoperative, intraoperative, or postoperative hemodynamic parameters or respiratory function, which indicated that premedication with melatonin and dexmedetomidine by doses in the present study did not cause hemodynamic instability or respiratory dysfunction. And premedication with these drugs attenuated the stress response to surgical stimulation.
In agreement with our study, Kucukakin  reported that administration of up to 60 mg of intravenous melatonin during major vascular surgery was safe and without a significant impact on intraoperative or postoperative hemodynamic parameters.
Additionally, Bekker et al.  conducted a prospective, randomized double-blinded study on 54 patients undergoing multilevel spinal fusion under general anesthesia, and assessed the effect of intraoperative infusion of dexmedetomidine on the quality of recovery after surgery. They reported that all patients remained hemodynamically stable perioperatively. In the same year, Kang et al.  examined the effects of intraoperative infusion of dexmedetomidine on hemodynamic parameters in patients undergoing laparoscopic cholecystectomy in comparison with the saline-treated group. They reported that both HR and MAP at the end of surgery were lower in the dexmedetomidine group than in the placebo group. And this was thought to be caused by central sympatholytic effects due to α2-adrenoceptor stimulation.
The results of the current study regarding anxiety score demonstrated that premedication with oral melatonin 5 mg and dexmedetomidine infusion by 1 μg/kg were effective in decreasing the anxiety level at the preoperative period, yet the melatonin group had a lower score than dexmedetomidine groups with nonsignificant difference, but the values of the melatonin group were lower than the dexmedetomidine groups with significant statistical difference in the postoperative period.
In agreement with our results, Acil et al.  performed a prospective, randomized, double-blinded, placebo‐controlled study on 66 patients undergoing laparoscopic cholecystectomy, to compare perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores, and psychomotor performance. They demonstrated that melatonin and midazolam groups showed a greater decrease in preoperative anxiety compared with the placebo group after premedication. Postoperative anxiety levels were lower in the melatonin group than midazolam and placebo groups by a significant value. Also, Şenses et al.  compared the influences of midazolam and dexmedetomidine infusion on anxiety scores in patients undergoing surgery with regional anesthesia. They reported that in equal sedative doses dexmedetomidine and midazolam demonstrated the same level of anxiolysis during regional anesthetic practice.
Postoperative pain (VAS scores) in the present study showed a significant difference between the two groups at 15, 30 min after surgery, as the dexmedetomidine group showed a lower level than melatonin groups, which indicates the analgesic effect of dexmedetomidine. Supporting the present study, Akin et al.  compared the effect of dexmedetomidine versus midazolam on postoperative analgesia requirement on 90 pediatric patients undergoing an elective adenotonsillectomy and reported that the number of children requiring postoperative analgesia was lower in the dexmedetomidine group. However, another study  observed that there were no differences between melatonin and midazolam groups in terms of pain VAS scores at any time during their stay in the recovery room.
Premedication with melatonin and dexmedetomidine in our study showed increased sedation levels relative to baseline at various time points in all groups (preoperative and postoperative). However, the sedation score in the melatonin group was higher than dexmedetomidine groups at every time points but with significant difference only at 30 min postoperatively. In accordance with our results, Naguib and Samarkandi  who compared the perioperative effects of different doses of melatonin and midazolam with placebo reported a significantly greater effect of both midazolam and melatonin compared with the placebo for increasing the levels of sedation at 60 and 90 min after premedication. Postoperatively, there was no significant difference in the level of sedation between the groups except at 90 min in which patients of the 0.2 mg/kg midazolam group showed an increased level of sedation compared with 0.05 and 0.1 mg/kg in the melatonin groups.
In disagreement with the present study Akin et al.  compared dexmedetomidine versus midazolam for premedication in pediatric patients undergoing anesthesia and reported higher sedation levels in the midazolam group than in the dexmedetomidine group at the 10th minute after administration of the drug and in the operating room and it was statistically significant. The difference from our study could be explained by higher dose of midazolam used in their study (0.2 mg/kg).
By comparison between the two groups, the present study has shown preoperative and postoperative significant difference value for the plasma level of IL6,with a reduction in surgical inflammatory response in the dexmedetomidine group, which was superior to melatonin in attenuation of inflammatory response of surgery.
Supporting the current results Kucukakin  evaluated the effect of various doses of melatonin administered during or after operation on surgical stress after major vascular surgery. They reported that there was a significant increase in the proinflammatory parameter (IL6) as a consequence of surgery and was not influenced by melatonin treatment. Furthermore Ueki et al.  found that dexmedetomidine infusion suppressed the rise in IL6 levels after cardiopulmonary bypass, and they suggested that intraoperative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischemia–reperfusion injury during cardiopulmonary bypass.
Our study shown that 24 h postoperative plasma levels of ALT increased in the melatonin group and decreased in the dexmedetomidine group with no statistically significant difference by comparing the two groups. Also, postoperative plasma levels of AST were increased in the dexmedetomidine group while decreased in the melatonin group, with no significant difference by comparison between the two groups. Supporting the current study Gonciarz et al.  examined the effects of long-term melatonin treatment on plasma liver enzymes levels, and revealed a significant improvement in plasma ALT and AST among patients with a 12-week course of melatonin which sustained throughout the next 12 weeks in which the patients were receiving treatment. However, the AST level returned practically to the baseline value after discontinuation of melatonin.
Furthermore Ueki et al.  reported that the levels of AST counts were significantly increased at the postoperative period, in dexmedetomidine and saline groups, but by comparison with the saline group the dexmedetomidine group had decreased postoperative AST levels. Also, the ALT levels decreased at the postoperative period compared with the saline group. They explained these attenuation of liver enzymes by organoprotective properties of dexmedetomidine.
Our study recorded no statistical difference between the groups in adverse effects (nausea, dizziness, hypotension, or bradycardia).
This coincides with the study of Ionescu et al.  which found no side effects of melatonin. And Kucukakin  reported that there were no significant differences in the reported side effects between the two groups: melatonin and placebo. Additionally Celinski et al.  reported that no side effects of melatonin and tryptophan were observed; for instance none of the patients complained of excessive sleepiness and/or dizziness.
| Conclusion|| |
The premedication with dexmedetomidine was superior to melatonin in the reduction of VAS of pain and surgical inflammatory response. Melatonin and dexmedetomidine had an effective decrease in anxiety level and modest sedation in the perioperative period without a significant impact on the hemodynamic parameters or liver function in elderly patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]