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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 4  |  Page : 361-366

Effect of midazolam, propofol, and dexmedetomidine on postoperative cognitive dysfunction after cardiac surgery in the elderly


Department of Anesthesia and Intensive Care, Al-Azhar Faculty of Medicine for Boys, Cairo, Egypt

Date of Submission19-Jun-2019
Date of Decision02-Sep-2019
Date of Acceptance14-Oct-2019
Date of Web Publication14-Feb-2020

Correspondence Address:
Mofeed A Abdelmaboud
El-Shiiekh El-Shami Street, Seqil Ausim, Giza 12992
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_87_19

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  Abstract 


Background Postoperative cognitive dysfunction (POCD) is among the most prevalent and serious life-threatening postoperative complications.
Aim The primary outcome was to compare the efficacy of dexmedetomidine, propofol, and midazolam on prevention of POCD during cardiac surgery in the elderly. The secondary outcome is to determine possible complications during the first postoperative day.
Patients and methods Ninety elderly patients undergoing cardiac surgery were randomly divided during the cardiopulmonary bypass period into three equal groups. group M: received midazolam 0.1 mg/kg/h, group P: received propofol 1 mg/kg/h, and group D: received dexmedetomidine 0.5 µg/kg/h. Mini-Mental State Examination (MMSE), incidence of POCD, and interleukin 6 (IL-6) were recorded on the day before surgery (M0, F0, L0, respectively), 1 h after extubation (M1, F1, L1, respectively), and 1 week postoperatively (M2, F2, L2, respectively). POCD was diagnosed when the MMSE score decreased two points or more from the preoperative value. Adverse effects (hypotension, bradycardia, laryngospasm, postoperative nausea and vomiting, and hypertension) were recorded.
Results As regards MMSE, there were no significant differences among groups except at M1 where it was higher in group D than the other two groups. In groups M and P only, MMSE was significantly higher at M1 than M0 and returned to near preoperative value at M2 in the same group. There were no significant differences regarding the incidence of POCD at F0, F1, and F2. There were no significant differences with respect to blood IL-6, among groups except at L1 where it was significantly higher in both group M and group P than group D. In groups M and P only, IL-6 was significantly higher at L1 than L0 and then returned to near preoperative value at L2 in the same group.
Conclusion Dexmedetomidine was a good choice for reducing POCD in cardiac surgery in elderly patients with less side effects.

Keywords: cardiac surgery, elderly, midazolam, postoperative cognitive dysfunction, propofol and dexmedetomidine


How to cite this article:
Abdelmaboud MA. Effect of midazolam, propofol, and dexmedetomidine on postoperative cognitive dysfunction after cardiac surgery in the elderly. Al-Azhar Assiut Med J 2019;17:361-6

How to cite this URL:
Abdelmaboud MA. Effect of midazolam, propofol, and dexmedetomidine on postoperative cognitive dysfunction after cardiac surgery in the elderly. Al-Azhar Assiut Med J [serial online] 2019 [cited 2020 Feb 29];17:361-6. Available from: http://www.azmj.eg.net/text.asp?2019/17/4/361/278402




  Introduction Top


Postoperative cognitive dysfunction (POCD) is a common complication frequently observed after general anesthesia in the immediate postoperative period or sometimes up to 4 weeks postoperatively and can persist for months or even be lifelong [1],[2].

Clinical evidence has shown higher incidence of POCD in elderly patients following surgery [3].

Several studies have noted that the incidence of POCD was 53% following on-pump coronary artery bypass grafting surgery [4].

Several factors can influence the incidence of POCD such as aging, genetics, comorbidities, education, type of anesthesia, type of surgery, and preoperative cognition. This is why there is no specific drugs that can prevent POCD or treating it once it develops [5].

Benzodiazepines are sedative, hypnotic, and anxiolytic drugs due to their effects on GABA receptors [6]. Midazolam is a benzodiazepine used immediately before anesthesia induction and causes loss of ability to form new memories. However, it does not relieve pain and a high dosage can lead to delayed recovery, respiratory depression, and decreased oxygen saturation (SpO2) [7].

Propofol is 2,6-diisopropylphenol that introduced in 1989. It has a very short half-life with rapid recovery. Propofol produces a dose-dependent decrease in cerebral metabolic rate and cerebral blood flow [8].

Dexmedetomidine is a highly selective α2-adrenoceptor agonist with analgesic, sedative, and sympatholytic effects. It is widely used as an adjunct sedative in elderly patients [9]. Adrenergic pathway plays an important role in the formation of cognition. Moreover, α2-adrenoceptors regulate the formation of learning, memory, and selective attention by the dorsal ascending noradrenergic bundles from the locus ceruleus in the brain stem. It has been confirmed that dexmedetomidine provides its neuroprotective effects by inducing extracellular signaling-regulated kinase phosphorylation [10].

An association between inflammatory response and POCD has been reported. Surgical trauma stimulates the immune cascade with release of inflammatory cytokines, which may induce POCD. A number of animal studies have shown that dexmedetomidine can reduce inflammation and incidence of POCD [11].


  Aim Top


The primary outcome was to compare the efficacy of dexmedetomidine, propofol, and midazolam on the prevention of POCD during cardiac surgery in elderly patients. The secondary outcome is to determine possible complications [hypotension, bradycardia, laryngospasm or bronchospasm, postoperative nausea and vomiting (PONV), and hypertension] during the first postoperative day.

Sample size justification

Med Cal, Version 12.3.0.0 program (Ostend, Belgium) was used for sample size calculation, statistical calculator based on confidence interval 95%, and power of study 80% with an α error of 5%, according to a previous study by Rajaei et al. [12], so this study can be relied, and based on this assumption, and according to this value, minimum sample size of 84 cases was enough to find such difference. Assuming a 5% dropout, the sample size will be 90 cases, subdivided into three equal groups.


  Patients and methods Top


After taking approval from Anesthesia and Intensive Care Department, Al-Azhar Faculty of Medicine and from local ethics committee and informed written consent from each participant, this study was done at El-Hussein University Hospital in the period from March 2018 to May 2019.

Inclusion criteria

Age more than or equal to 65 years of both sexes, American Society of Anesthesiologists physical status of II or III, scheduled for valve surgeries or on-pump coronary artery bypass grafting with operative time within 4–5 h, no significant serious cerebral, cardiovascular, respiratory, hepatic disease or renal, no history of benzodiazepine, antidepressant use, alcohol or drug dependence, no allergy to study medications, with the ability to understand Mini-Mental State Examination (MMSE), and preoperative MMSE scores of more than 23.

Exclusion criteria

Emergency cases, MMSE of less than or equal to 23, central nervous system or mental disease, need for moderate hypothermia, and patient’s refusal.

After reaching the operating room, 18 G intravenous cannula and arterial cannula were inserted to all participants and the patients were monitored with ECG, SpO2, end-tidal CO2 (ETCO2), and invasive blood pressure.

MMSE [1], incidence of POCD, and IL-6 were recorded on the day before surgery (M0, F0, L0, respectively).

POCD was diagnosed when there was a decrease in MMSE score of two points or more from preoperative value ([Table 1]).
Table 1 Mini-Mental State Examination test [13]

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Anesthesia was standardized to all patients. Following preoxygenation for 5 min with 100% oxygen anesthesia was induced with intravenous thiopental 5 mg/kg, intravenous fentanyl 5 µg/kg, and intravenous atracurium 0.5 mg/kg followed 3 min later by intubation with appropriate size cuffed endotracheal tube. Anesthesia was maintained with isoflurane (1.2%) in oxygen, intravenous atracurium (0.15 mg/kg) as needed, and fentanyl infusion at a rate of 1–3 µg/kg/h (500 µg diluted in 40 ml normal saline 0.9% with a concentration of 10 µg/ml). Ventilation was adjusted to maintain an ETCO2 of between 35 and 40 mmHg.

Oropharyngeal thermometer was inserted for temperature monitoring. Central venous line was inserted to all patients under complete aseptic condition.

Continuous monitoring in the form of invasive blood pressure, heart rate, SpO2, ETCO2, oropharyngeal temperature, urine output, and arterial blood gases were recorded on demand.

Once patients were connected to cardiopulmonary bypass (CPB), and separated from anesthesia machine, 90 patients fulfilling the inclusion criteria were randomly divided during the CBP period using computer randomization into three equal groups (30 patients each):
  1. Midazolam group (group M): received midazolam (Amoun Pharmaceuticals Co, El-Obour City, Cairo, Egypt) at an infusion rate of 0.1 mg/kg/h (50 mg in 50 ml syringe with a concentration of 1 mg/ml).
  2. Propofol group (group P): received propofol (Fresenius Kabi Deutschland GmbH, Bad Homburg vd.H., Germany) at an infusion rate of 1 mg/kg/h (500 mg in 50 ml syringe with a concentration of 10 mg/ml).
  3. Dexmedetomidine group (group D): received dexmedetomidine (RL-4409; Hospira Inc., Lake Forest, Illinois, USA) at an infusion rate of 0.5 μg/kg/h.


During CPB, the blood flow was adjusted to maintain a mean blood pressure of between 50 and 60 mmHg, the temperature was kept at 34°C during cooling, the PaCO2 between 36 and 45 cmH2O, the pH was kept above 7.36, and hematocrit at about 30. Any changes in these parameters were adjusted by the perfusionist.

Once patients are weaned from CPB, dexmedetomidine, propofol, and midazolam infusions were discontinued and the patients are reconnected to the anesthesia machine with 1.2% isoflurane in 100% O2 and the lungs are re-expanded manually and anesthesia was maintained till skin closure.

The patients were extubated in the cardiac surgical unit. MMSE test, incidence of POCD, and plasma levels of interleukin 6 (IL-6) (pg/ml) at 1 h after extubation (M1, F1, L1, respectively) and 1 week after surgery (M2, F2, L2, respectively) were taken.

IL-6 was measured by enzyme-linked immunosorbent assay, using the kit supplied by the Bioscience Company (Schloss-Rahe-Str. 1552072 Aachen, Germany) (IL-6 enzyme-linked immunosorbent assay kit product, ABIN365163).

Possible complications (including hypotension, bradycardia, laryngospasm or bronchospasm, PONV, and hypertension) during the first postoperative day were recorded.


  Results Top


The three groups were comparable regarding patient characteristics ([Table 2]).
Table 2 Patient characteristics

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Group M: midazolam group, group P: propofol group, group D: dexmedetomidine. Data are represented as mean±SD and n (%). P value more than 0.05, statistically not significant; P value less than 0.05, statistically significant; P less than 0.001, highly significant.

As regards MMSE, there were no significant differences among groups except at M1 where it was higher in group D than the other two groups. In group M and group P only, MMSE was significantly higher at M1 than M0 and returned to near preoperative value at M2 in the same group. There were no significant differences regarding incidence of POCD at F0, F1, and F2 ([Table 3]).
Table 3 Surgical details among groups

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There were no significant differences with respect to blood IL-6, among groups except at L1 where it was significantly higher in both group M and group P than group D. In group M and group P only, IL-6 was significantly higher at L1 than L0 and then returned to near preoperative value at L2 in the same group ([Table 4]).
Table 4 Mini-Mental State Examination test and incidence of cognitive dysfunction among groups

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As regard adverse effects among groups, there were no significant differences except PONV where it was significantly higher in group P than the other two groups (P=0.041, 0.017, respectively) ([Figure 1]).
Figure 1 Adverse effects among groups.

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  Discussion Top


The current study showed that there were no significant differences among groups regarding MMSE except at 1 h after extubation where it was higher in the dexmedetomidine group than both midazolam and propofol groups. It was significantly higher in both midazolam and propofol groups only at 1 h after extubation than preoperative level and returned to near preoperative value at 7 days postoperatively in the same group. Yang et al. [13] observed that perioperative dexmedetomidine improved MMSE score on first postoperative day. Zhang et al. [14] demonstrated that dexmedetomidine increased the MMSE score on first, third, and seventh postoperative days after sevoflurane anesthesia in elderly patients. Zhou et al. [15] showed that dexmedetomidine improved MMSE on the first postoperative day and after the first postoperative day in elderly patients after general anesthesia. Mansouri et al. [16] showed that there were no significant differences between dexmedetomidine and midazolam groups in the MMSE score at 1 and 7 days postoperatively (P>0.05), but it was significantly higher in these two groups than control (P<0.05). Rajaei et al. [12] observed that the MMSE results were not statistically different between the midazolam and dexmedetomidine groups at 5 days postoperatively (24.8076±3.16 vs. 22.4±4.9, respectively) (P=0.12). Metry et al. [1] demonstrated that with respect to MMSE at 1 h postoperatively, there was a decrease in both dexmedetomidine and propofol groups (32.3±0.408 vs. 23.2±0.41) but without significant difference (P=1.0) and returned back to baseline (30) at 7 days postoperatively (P=1.0).

This study showed no significant differences regarding the incidence of POCD among three groups. Yang et al. [13] observed that perioperative dexmedetomidine significantly reduced the incidence of POCD on first postoperative day. Zhang et al. [14] demonstrated that dexmedetomidine could improve POCD caused by sevoflurane in elderly patients by decreasing IL-6 and TNF-α concentration at the first, third, and seventh postoperative days. Zhou et al. [15] showed that dexmedetomidine significantly reduced the incidence of POCD in elderly patients after general anesthesia on the first postoperative day and after the first postoperative day. Man et al. [17] observed that perioperative dexmedetomidine was associated with significant better postoperative neurocognitive function in comparison with both saline controls and anesthetics predominantly midazolam. Chen et al. [18] demonstrated that dexmedetomidine significantly reduces the incidence of POCD compared with control group (9.2 vs. 21.31%, respectively, with P<0.05) by reducing the increase of postoperative TNF-α and IL-6 levels (P<0.05). Mansouri et al. [16] showed that regarding the incidence POCD at 1 and 7 days postoperatively, there were no significant differences between dexmedetomidine groups (12 and 12%, respectively) and midazolam (14 and 8%, respectively) (P>0.05) but there was significant differences between both groups and control (it was 24 and 20%, respectively, in the control group) (P<0.05). Wang et al. [19] showed that the incidence of POCD at 5–7 postoperative days was 24.5% in the dexmedetomidine group and 28.0% in the midazolam group but with no significance (P=0.575).

Dexmedetomidine reduces the incidence of POCD and improves MMSE by acting at the locus ceruleus in the brain stem which contain the highest concentration of α2-adrenoceptors thus inhibiting neuronal discharge and activity of the sympathetic nervous system [20].

The current study demonstrated that, regarding blood IL-6, there were no significant differences among groups except at 1 h after extubation where it was significantly higher in both midazolam and propofol groups than dexmedetomidine group, and it was significantly higher in midazolam and propofol groups only at 1 h after extubation than preoperative level and then returned to near preoperative value at 7 days postoperatively in the same group. Yang et al. [13] observed that perioperative dexmedetomidine significantly reduced IL-6 on the first postoperative day compared with the control group.

The present study showed that there were no significant differences among groups respecting adverse effects except PONV where it was higher in the propofol group than the other two groups. Zhang et al. [14] observed that, in propofol group, the incidence of hypotension was 13.3%, bradycardia 3.1%, laryngospasm or bronchospasm 3.1%, PONV 31.3%, and hypertension 10.3%. Lu et al. [21] demonstrated that, in the dexmedetomidine group, the incidence of bradycardia is 0%, postoperative nausea is 9.2%), and vomiting is 6.6%.


  Conclusion Top


First dexmedetomidine was more effective than midazolam and propofol in reducing the incidence of POCD in elderly patients in cardiac surgery with better MMSE score and lower blood level of IL-6. Second midazolam and dexmedetomidine showed a lower incidence of PONV. So, this study concluded that dexmedetomidine was a good choice for reducing POCD in cardiac surgery in elderly patients with less side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Metry AA, Hussain NS, Nakhla GM, Ragaei MZ, Wahba RM. The effect of continuous propofol versus dexmedetomidine infusion on regional cerebral tissue oxygen saturation during cardiopulmonary bypass. Rom J Anaesth Intensive Care 2019; 26:17–23.  Back to cited text no. 1
    
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Xiong B, Shi Q, Fang H. Dexmedetomidine alleviates postoperative cognitive dysfunction by inhibiting neuron excitation in aged rats. Am J Transl Res 2016; 8:70–80.  Back to cited text no. 10
    
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Rajaei M, Tabari M, Soltani G, Alizadeh K, Nazari A, Noroozian M, Morovatdar N. Dexmedetomidine and midazolam on postoperative cognitive impairment after coronary artery bypasses graft surgery: a randomized clinical trial. J Teh Univ Heart Ctr 2019; 14:67–73.  Back to cited text no. 12
    
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Yang W, Suo Kong L, Xing Zhu X, Wang R-X, Liu Y, Chen LR. Effect of dexmedetomidine on postoperative cognitive dysfunction and inflammation in patients after general anaesthesia. Medicine 2019; 98:18.  Back to cited text no. 13
    
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Zhang H, Wu Z, Zhao X, Qiao Y. Role of dexmedetomidine in reducing the incidence of postoperative cognitive dysfunction caused by sevoflurane inhalation anesthesia in elderly patients with esophageal carcinoma. J Can Res Ther 2018; 14:1497–1502.  Back to cited text no. 14
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Wang W, Feng N, Zhao W, Luo F, Zhu X, Zhao W et al. Dexmedetomidine reduces brain neuronal injuries but not clinical neurocognitive function in the elderly, compared to midazolam. Int J Clin Exp Med 2019; 12:4210–4217.  Back to cited text no. 19
    
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