Study design and Objectives
The program is designed according to the preferred reporting project guidelines for systematic reviews and meta-analysis programs (PRISMA-P)[29]. It has been registered in the PROSPERO database (CRD42021221897). It aims to provide a systematic review on the effect between Dexmedetomidine and Midazolam in elderly patients. Additionally, meta-analysis of RCTs will be performed in order to assess the safety and efficacy of Dexmedetomidine and Midazolam on primary and secondary outcomes of RCTs.
Search Strategy
Four English databases (PubMed, Embase, Web of Science, Cochrane Library) and four Chinese databases (Chinese Biomedical Literature Database, Chinese Science and Technology Journals VIP Database, China national knowledge infrastructure (CNKI), Wan-fang Database) were searched for literatures published between October 2001 and May 2021. Only clinical randomized controlled trials (RCTs) published in English or Chinese were included. The search strategy will be conducted according to the Participants, Intervention, Comparison, Outcomes and Studies (PICOS) components (Table 1), The complete search strategy used a combination of PICOS framework, Search strategy in PubMed was seen in Table 2. Any differences can be resolved through discussion with other reviewers (ZW, DBH).
Table 1
Participants, Intervention, Comparison Outcomes and Studies (PICOS) framework.
PICOS
|
Searched items
|
Patients (a + b)
|
|
a
|
The elderly; The old man; The old patient; The elderly patients; The aged;
|
b
|
Intraoperative sedation; Sedation; Surgery sedation, Surgical sedation; Anesthesia and analgesia; Anesthesia sedation; Intraoperative anesthesia; Surgery anesthesia; Surgical anesthesia
|
Intervention
|
Dexmedetomidine, Dexmedetomidine Hydrochloride, Hydrochloride Dexmedetomidine
|
Comparison
|
Midazolam, Benzodiazepine, Compounds, Benzodiazepine, Benzodiazepinones, devazepide
|
Outcome
|
|
Primary outcomes
|
Hemodynamic changes (MAP, HR, SBP, DBP, RR, SPO2), Sedative effect (OAA/S, BIS) and Cognitive function (MMSE, POCD)
|
Secondary outcomes
|
Analgesic effect (RASS, VAS), Surgical characteristics (operation time, the volume of intraoperative blood loss, time of extubation), Complications or adverse reactions (agitation, hypotension, bradycardia, respiratory depression, postoperative nausea and vomiting, bradycardia and shivering)
|
Studies
|
Random control study, Control study, Random control trial, Clinical control trial, Clinical trial, Randomized control trial, Randomized controlled trial
|
Table 2
Search strategy of PubMed for randomized control trials
Searched strategy in PubMed
|
Block 1: The elderly
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#1
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“The elderly” [tiab]
|
#2
|
“The old man” [tiab]
|
#3
|
“The old patient” [tiab] OR “The elderly patients” [tiab]
|
#4
|
“The aged” [tiab] OR “The greybeard” [tiab]
|
#5
|
#1 OR #2 OR #3 OR #4
|
Block 2: Intraoperative sedation
|
#6
|
“Intraoperative sedation” [Mesh] OR “Intraoperative anesthesia” [Mesh] OR “Intraoperative analgesia” [Mesh]
|
#7
|
“Surgical sedation” [tiab]
|
#8
|
“Surgical anesthesia” [tiab] OR “Surgical analgesia” [tiab]
|
#9
|
#6 OR #7 OR #8
|
Block 3: Participants
|
#10
|
#5 AND #9
|
Block 4: Intervention in experimental group
|
#11
|
“Dexmedetomidine” [Mesh]
|
#12
|
“Dexmedetomidine hydrochloride” [tiab] OR “Hydrochloride, dexmedetomidine” [tiab] OR “Dexmedetomidine” [tiab]
|
#13
|
#11 OR #12
|
Block 5: Intervention in control group
|
#14
|
“Midazolam” [Mesh]
|
#15
|
“Benzodiazepine” [tiab] OR “Benzodiazepines” [tiab]
|
#16
|
“Azepines” [tiab]
|
#17
|
“Hydrochloride, midazolam” [tiab] OR “Midazolam hydrochloride” [tiab]
|
#18
|
“Midazolam maleate” [tiab] OR “Maleate, midazolam”
|
#19
|
#14 OR #15 OR #16 OR #17 OR #18
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Block 6: Study type
|
#20
|
“Randomized controlled trial” [pt]
|
#21
|
“Controlled clinical trial” [pt]
|
#22
|
“Randomized” [tiab] OR “randomly” [tiab] OR “trial” [tiab] OR “groups” [tiab]
|
#23
|
#20 OR #21 OR #22
|
Block 6: Final merge
|
#24
|
#10 AND #13 AND #19 AND #23
|
Selection criteria
Two independent reviewers (HCX, LZJ) screen relevant trials by examining titles and abstracts of the identified studies. Any studies that were not meet with the PICOS framework would be excluded. Full articles will be obtained and checked for extracted details (LYX, LDL). Any reason for extraction would be recorded. Possible divergency will be resolved by discussion or a third reviewer (DBH). The selection process will be presented in a PRISMA flow diagram (Fig. 1).
Eligibility criteria
Types of Participants
Patients with surgery age more than 60 or older and receive anesthetics intervention, whose ASA status have been identified as I-III. Regardless of sex, region, race, and the type of surgery.
Types of intervention in the experimental group and control group
Patients in the experimental group and control group received Dexmedetomidine or Midazolam respectively, with or without conventional treatment and combination with use of other anesthetics.
Type of included indicators or outcomes
The primary results contain hemodynamic changes (MAP, HR, SBP, DBP, SPO2), sedative effect (OAA/S, BIS) and cognitive function (MMSE, POCD). The secondary results include analgesic effect (RASS, VAS), surgical characteristics (operation time, the volume of intraoperative blood loss, and extubation time), complications or adverse reactions (hypotension, agitation, postoperative nausea and vomiting, bradycardia, respiratory depression, delirium, and shivering).
Data extraction and risk of bias assessment
We will extract each qualified data. The differences will be settled through discussion with a third author (ZW). Data were extracted including year of publication, author’s name, study type, randomized methodology, and basic characteristics of participants (ASA classification, mean age, sample size, type of surgery, body mass index/weight, duration of anesthesia, duration of surgery, medication use, and outcomes) (Table 3 − 1&2). Cochrane collaborative tool is used to assess the risk and quality of bias for each included trial, and any differences will be adjusted by the reviewers (ZW, DBH). The Cochrane Collaborative Tool consists of seven quality items: random sequence generation, allocation hiding, blinding of participants and personnel, blinding of result evaluation, incomplete result data, selective reporting and other deviations. Each item is classified as low, unclear or high risk of bias.
Data analysis
RevMan (version 5.4.1) software is used to complete the meta-analysis. For dichotomous results, odds ratio (ORs) and corresponding 95% confidence intervals (95% CI) are calculated for comparison. For continuous data, standard mean difference (SMD) and corresponding 95% CI are calculated for comparison. P values less than 0.05 are considered statistically significant. Quantitative calculation of heterogeneity is evaluated using I2 statistics. I2 statistics are considered to represent the heterogeneity of no (0%), low (0%-25%), medium (25%-75%) and high (75%-100%) possibility [19]. The random effects model would be adopted if medium or high heterogeneity existed between the studies.
Sensitivity analysis and Subgroup analysis
When it occurs relatively high heterogeneity of the results, sensitivity analysis is performed to explore the source of high heterogeneity in order to enhance the credibility of the results. Any possibility (methodological quality, heterogeneity, studies quality, surgery duration, number of samples etc.) resulted in high heterogeneity will be considered for subgroup analysis.
Potential publication and reporting bias analysis
After preliminary meta-analysis, potential publication bias is assessed visually using funnel plots, Egg regression and Begg test will be utilized to detect the funnel plot asymmetry.
Table 3-1
Characteristics of included RCTs assessing effect of Dexmedetomidine and Midazolam for elderly surgery patients (eg.)
NO.
|
Author(year)
|
Type of study (random method)
|
ASA status
|
Sample size (M/F)
|
Age(year)
|
BMI/Weight(kg)
|
D
|
M
|
D
|
M
|
D
|
M
|
1
|
Wenfei Tan (2016)
|
double blind-RCT (sealed envelopes)
|
I-III
|
22
|
22
|
70.1 ± 7.0
|
73.1 ± 9.3
|
23.5 ± 3.9
|
22.9 ± 2.3
|
2
|
|
|
|
|
|
|
|
|
|
3
|
|
|
|
|
|
|
|
|
|
……
|
|
|
|
|
|
|
|
|
|
……
|
|
|
|
|
|
|
|
|
Note: ND: Not described in the study; D: Dexmedetomidine; M: Midazolam. ASA status: American Society of Anesthesiologists Physical Status; M/F: Male/Female; BMI: Body mass index. |
Table 3-2
Characteristics of included RCTs assessing effect of Dexmedetomidine and Midazolam for elderly surgery patients (eg.)
NO.
|
Author(year)
|
Anesthesia duration
|
Operation duration
|
Dosage and Usage of D
|
Dosage and Usage of M
|
Type of Disease
|
D(min)
|
M(min)
|
D(min)
|
M(min)
|
Anesthesia induction
|
Anesthesia maintenance
|
Anesthesia induction
|
Anesthesia maintenance
|
1
|
Wenfei Tan (2016)
|
91.9 ± 28.0
|
99.9 ± 46.3
|
69.9 ± 23.4
|
78.2 ± 46.9
|
1ug/kg for 10min
|
12ug/(kg·h)
|
22.5ug/(kg·h) for 10min
|
45ug/(kg·h)
|
elective transurethral prostatic resection
|
2
|
|
|
|
|
|
|
|
|
|
|
3
|
|
|
|
|
|
|
|
|
|
|
……
|
|
|
|
|
|
|
|
|
|
|
Note: ND: Not described in the study; NOT: No dosage and usage of anesthesia; D: Dexmedetomidine; M: Midazolam. |
Test sequential analysis (TSA)
For further illustrating and confirming the reliability of final results, trial sequential analysis is performed on the analyzed outcomes via TSA software (version 0.9.5.10 Beta; Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark), aiming to rule out the possibility of false positives and confirm firm evidence of final results.
Rating quality of evidence and strength of recommendations (GRADE)
Finally, we will conduct evaluation on the quality of evidence regarding to the main positive outcomes using the GRADE Profiler 3.6.1 evaluation tool. Briefly, the quality of the evidence is divided into four levels: high, medium, low and very low, and strength of recommendations are divided into strong recommendation and weak recommendation. RCT trials are regarded as high quality of evidence, and then the evidence quality level of the outcomes are assessed from the five downgrading factors of research limitations, inconsistency, indirectness, imprecision, and publication bias.