Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials

Abstract

Objective:

The purpose of this meta-analysis is to assess the effect of dexmedetomidine on delirium in elderly surgical patients.

Data Sources:

The Cochrane Library, Web of Science, PubMed, EMBASE, and Google Scholar were searched (January 1, 2000, to February 4, 2020) for randomized controlled trials (RCTs).

Study Selection and Data Extraction:

RCTs without language restrictions were included if delirium incidence was assessed in elderly surgical patients receiving dexmedetomidine. Intervention and basic information were extracted.

Data Synthesis:

21 studies were included. Dexmedetomidine reduced delirium occurrence (risk ratio [RR] = 0.55; 95% CI = 0.45 to 0.67) in elderly surgical patients with sufficient evidence from trial sequential analysis. Dexmedetomidine did not prevent delirium incidence for cardiac surgery (RR = 0.71; 95% CI = 0.44 to 1.15) with insufficient evidence. Dexmedetomidine decreased mortality incidence (RR = 0.47; 95% CI = 0.25 to 0.89), shortened the length of intensive care unit (ICU; standard mean difference [SMD] = −0.46) and hospital stays (SMD = −0.41), and increased bradycardia incidence (RR = 1.60).

Relevance to Patient Care and Clinical Practice:

This review revealed that dexmedetomidine could reduce delirium incidence for elderly noncardiac surgical patients, and the effect of dexmedetomidine on delirium for elderly cardiac surgical patients needs further studies to guide clinicians.

Conclusion:

Dexmedetomidine reduced delirium incidence in elderly surgical patients. The efficacy of dexmedetomidine on delirium for elderly cardiac surgical patients warrants further studies. Furthermore, dexmedetomidine was associated with an increased bradycardia incidence, shorter length of ICU/hospital stays, and a lower incidence of mortality.

Keywords

dexmedetomidine delirium elderly surgical patients meta-analysis

Introduction

Delirium is a major postoperative complication, occurring in 51% of patients after surgery.¹ The incidence of delirium in elderly patients is approximately 10% to 20% and varies by surgical procedure.² Delirium is relevant to higher mortality, prolonged duration of hospital stays, and increased health care costs.^3-5 Different sedative agents (benzodiazepines, opiates, and anticholinergics) have been widely used to reduce delirium,⁶ and their ability to prevent and treat delirium still remain controversial. Therefore, an effective and safe sedative agent would be advantageous.⁷

Dexmedetomidine, a highly selective a₂-adrenergic receptor agonist, provides anxiolytic, sedative, and modest analgesic properties.^8,9 Compared with other agents, dexmedetomidine can maintain calm yet easily rousable states in intensive care unit (ICU) patients without respiratory depression.^10-12 Some studies showed that the administration of dexmedetomidine in the ICU after surgery could reduce delirium occurrence for elderly patients.^13-17 Recently, several meta-analyses focused on the use of dexmedetomidine to reduce delirium in geriatric patients with noncardiac surgery. These meta-analyses revealed that dexmedetomidine reduced delirium occurrence, mechanical ventilation, and the duration of hospital stay.^18-20 Furthermore, most randomized controlled trials (RCTs) have found similar results on the efficacy of dexmedetomidine in treatment of delirium for geriatric patients undergoing cardiac surgery.^21-25 However, Deiner et al²⁶ compared dexmedetomidine with placebo and published inconsistent findings after noncardiac surgery. To date, the safety and efficacy of dexmedetomidine in delirium for elderly surgical patients is controversial.

In our included studies, dexmedetomidine was used for sedation in either surgical areas or the ICU, and the delirium incidence of most participants was assessed in the ICU. The primary aim of our meta-analysis was to investigate whether the administration of dexmedetomidine affected delirium in elderly surgical patients after both noncardiac and cardiac surgery. We performed a subgroup analysis to estimate the effect of dexmedetomidine dosing strategy and type of surgery (noncardiac surgery and cardiac surgery) on delirium incidence. The secondary aim was to assess the efficacy of dexmedetomidine on mortality and the duration of ICU/hospital stay and examine its adverse effects—namely, hypotension and bradycardia.

Material and Methods

Literature Search

We used the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) statement to conduct our analysis.²⁷ A systematic search of EMBASE, Cochrane Library, Web of Science, PubMed, and Google Scholar was conducted from January 1, 2000, to February 4, 2020, by 2 reviewers (Chunmei L and HT). We also searched the references of previous systematic reviews and of our included studies to identify further eligible studies. There were no restrictions on languages. RCTs were included in our study design. We performed a basic search using the following terms: (dexmedetomidine OR “dexmedetomidine” [MeSH]) AND (delirium OR “Delirium” [MeSH]) AND (elderly OR aged OR “aged” [MeSH]). The complete search terms and strategies are provided in the appendix (Supplementary file 1, available online).

Inclusion Criteria

Inclusion criteria were defined as follows: (1) elderly patients with cardiac surgery and noncardiac surgery (either ≥60 or ≥65 years old); (2) comparing dexmedetomidine with anesthetic drugs (such as propofol, midazolam, morphine, and ketamine) or placebo; (3) evaluating delirium incidence; (4) RCTs; and (5) the Confusion Assessment Method (CAM) or CAM for ICU (CAM-ICU) applied to assess delirium.

Exclusion Criteria

Exclusion criteria were defined as follows: (1) experimental studies on animal models; (2) review articles, editorial letters, and meta-analyses; (3) case reports; (4) conference abstracts and comments; (5) retrospective and prospective cohort studies; (6) studies with irrelevant articles and unavailable data; (7) studies of elderly surgical patients receiving dexmedetomidine where delirium was not assessed; and (8) nonelderly patients.

Data Extraction

The data extraction and eligible study selection were conducted by ZJ and XZ based on reading the full text of each article carefully. Disagreements at this stage between 2 authors were resolved by a third author (Chaoyang L). The information collected was as follows: (1) year of publication; (2) first author; (3) number of patients; (4) age; (5) surgery type; (6) loading dose, infusion rate, starting time, and duration of dexmedetomidine; (7) methods of delirium assessment; (8) adverse effects (hypotension and bradycardia); and (9) mortality.

Risk-of-Bias Assessment

Two authors (Chunmei L and HT) assessed the quality of all selected studies using the Cochrane Risk-of-Bias tool.²⁸ Discrepancies among the 2 authors were reconciled by a third author (Chaoyang L).

Statistical Analysis

Data analysis was performed with Review Manager 5.3 (Cochrane). A random-effects model was used because of methodological and clinical heterogeneity in studies. I² was applied to assess statistical heterogeneity: high (75%-100%), moderate (25%-75%), low (0%-25%), and no (0%) heterogeneity.²⁹ Additionally, 95% CIs and risk ratios (RRs) were applied to evaluate treatment effects. P <0.05 was identified as statistically significant. To decrease the risk of type 1 error arising from repeated testing, trial sequential analysis (TSA) was used to assess the effect of dexmedetomidine on delirium incidence by TSA software version 0.9 beta. The risk of type 1 error was set at 1-sided 5%, with a power of 80%. We used funnel plots to examine publication bias with the Egger and Begg tests (Stata 13.0). A sensitivity analysis was conducted by removing each study individually. The quality of evidence was rated by Grading of Recommendations Assessment, Development, and Evaluation (GRADE), which was divided into very low, low, moderate, and high. Criteria included imprecision, indirectness, inconsistency, risk of bias, and other considerations. GRADE Proversion 3.6 software was used.

Subgroup Analysis

Elderly surgical patients undergo different strategies of dexmedetomidine administration, with variations in starting time, infusion rate, duration of administration, and use of loading dose. Dexmedetomidine was compared with various control drugs among included studies. Several kinds of surgeries were performed for elderly patients. Therefore, subgroup analyses were applied to evaluate any potential source of heterogeneity.

Results

Trial Identification

As shown in Figure S1 (available online), we identified 772 studies, including 122 studies in EMBASE, 82 studies in PubMed, 121 studies in Web of Science, 28 studies in Cochrane Library, and 419 studies in Google Scholar. There were 308 duplicate articles among them. After screening the abstracts and titles, we removed 436 studies. Another 10 articles were excluded by reading the full text of each study. We also included 3 additional studies based on searching the references of our included studies. Therefore, 21 studies with 6328 patients were included in our studies.

Study Characteristics

Overall, data from 6328 participants were analyzed in our study; a total of 3191 patients received dexmedetomidine, 2368 participants used saline, and 769 participants used sedative drugs (374 patients with propofol, 147 patients with morphine, 142 patients with clonidine, 76 patients with midazolam, and 30 patients with ketamine). Among the 21 included studies, 16 studies included noncardiac surgery, including thoracic,³⁰ abdominal,^31,32 spine,³³ oral,¹³ and orthopedic surgeries,^34-37 but we did not show outcome separated by each surgical procedure (Table 1). Five studies included cardiac surgery.^21-25

Table 1.

Characteristics of All Included Studies.

Studies	Age (years)	Surgery type	No. of patients	DEX loading dose	DEX infusion dose	Time and duration of DEX	Delirium assessment methods
Ma et al, 2013³⁵	DEX: 69.1 ± 7.0 KET: 66.2 ± 8.1 NS: 67.6 ± 7.5	Noncardiac surgery	DEX: 30 KET: 30 NS: 30	1.0 µg/kg for 10 min	0.5 µg/kg/h	Started 10 minutes before induction; maintained until 30 minutes before end of surgery	CAM
Huang et al, 2014¹⁷	DEX: 73.7 ± 3.1 PRO: 74.2 ± 4.2	Noncardiac surgery	DEX: 54 PRO: 54	N/A	(0.2-0.7) µg/kg/h	Started immediately after arrival in ICU; maintained during mechanical ventilation	CAM-ICU
Guo et al, 2015¹³	DEX: 71.9 ± 5.1 NS: 70.7 ± 4.6	Noncardiac surgery	DEX: 78 NS: 78	N/A	0.2 µg/kg/h	Started immediately after arrival in SICU; maintained for 12 hours	CAM-ICU
Liu et al, 2016³⁷		Noncardiac surgery	DEX: 99NS: 98	N/A	(0.2-0.4) µg/kg/h	Infusion during surgery; stopped 20 minutes before end of surgery	CAM
Wu et al, 2016³⁶	DEX: 74 ± 5NS: 76 ± 6	Noncardiac surgery	DEX: 38NS: 38	N/A	0.1 µg/kg/h	Started from 5:00 pm on the day of surgery to 8:00 am on the first day after surgery for 15 hours	CAM-ICU
Su et al, 2016¹⁴		Noncardiac Surgery	DEX: 350NS: 350	N/A	0.1 µg/kg/h	Started within 1 hour after ICU admission to 8:00 am on the first day after surgery	CAM-ICU
Deiner et al, 2017²⁶	DEX: 74.0(71.0-78.0)NS: 74.0(71.0-78.0)	Noncardiac surgery	DEX: 189NS: 201	N/A	0.5 µg/kg/h	Started on entering operating room; maintained until 2 hours into recovery	CAM-ICU
Yu et al, 2017³⁰	DEX: 68.69 ± 4.27MID: 69.12 ± 4.86	Noncardiac surgery	DEX: 46MID: 46	N/A	(0.2-0.7) µg/kg/h	Infusion during surgery; stopped at the end of surgery	CAM
Li et al, 2017²²	DEX: 66.4 ± 5.4NS: 67.5 ± 5.3	Cardiac surgery	DEX: 142NS: 143	0.6 µg/kg For 10 minutes	0.4 and 0.1 µg/kg/h	Started from induction; maintained until the end of mechanical ventilation	CAM and CAM-ICU
Lee et al, 2018³¹	DEX1: 72.2 ± 5.4DEX2: 73.1 ± 6.4	Noncardiac surgery	DEX1: 95DEX2: 114NS: 109	1 µg/kg1 µg/kg	(0.2-0.7) µg/kg/h; N/A	Started from induction; maintained until end of surgery bolus at 15 minutes before the end of surgery	CAM
Mei et al, 2018³⁴	DEX: 76 ± 7PRO: 74 ± 6	Noncardiac surgery	DEX: 148PRO: 148	(0.8-1) µg/kg For 15-20 minutes	(0.1-0.5) µg/kg/h	Started with loading dose over 15-20 minutes; maintained until end of surgery	CAM
Xuan et al, 2018¹⁵	DEX: 66.6 ± 7.5NS: 66.9 ± 5.1	Noncardiac surgery	DEX: 227NS: 226	N/A	0.1 µg/kg/h	Started within 1 hour after arrival in ICU; maintained for 3 days	CAM and CAM-ICU
Cheng et al, 2019³²	DEX: 71(65-89)NS:70(65-85)	Noncardiac surgery	DEX: 269NS: 266	0.5 µg/kg For 15 minutes	0.4 µg/kg/h	Started 15 minutes before induction; stopped 30 minutes before surgery	CAM and CAM-ICU
Shi et al, 2019²⁴	DEX: 74.7 ± 7.2PRO: 74.2 ± 7.7	Cardiac surgery	DEX: 84PRO: 80	N/A	(0.4-0.6) µg/kg/h	Started from induction; maintained until end of surgery	CAM
Sun et al, 2019³⁹	DEX: 68.0(66.0-73.0)NS: 69.0 (65.0-74.0)	Noncardiac surgery	DEX: 281NS: 276	N/A	0.1 µg/kg/h	Started immediately after surgery, maintained for 48 hours	CAM and CAM-ICU
Zhang et al, 2019¹⁶	DEX: 74.2 ± 6.6NS: 74.2 ± 6.8	Noncardiac surgery	DEX: 221NS: 213	N/A	0.1 µg/kg/h	Started from 1 hour after ICU admission until 08:00 am on the first day after surgery	CAM and CAM-ICU
Li et al, 2020³⁸	DEX: 69.0 ± 6⋅6NS: 69.0 ± 6⋅4	Noncardiac surgery	DEX: 309NS: 310	0.6 µg/kg for 10 minutes	0.5 µg/kg/h	Started 10 minutes before induction; maintained until 1 hour before the end of surgery	CAM and CAM-ICU
Shokri and Ali, 2020²⁵	DEX: 63.75 ± 3.29CLO: 64.38 ± 4.81	Cardiac surgery	DEX: 144CLO: 142	N/A	(0.1-1.2) µg/kg/h	Started after ICU admission, continued for a period of 24 hours or until discharge from ICU (72 hours)	CAM and CAM-ICU
Djaiani et al, 2016²¹	DEX: 72.7 ± 6.4PRO: 72.4 ± 6.2	Cardiac surgery	DEX:91PRO:92	0.4 µg/kg For (10-20) minutes	(0.2-0.7) µg/kg/h	Started immediately after arrival in ICU; maintained during mechanical ventilation	CAM and CAM-ICU
He et al, 2018³³	DEX: 82.5 ± 5.4MID: 81.9 ± 6.2NS: 83.2 ± 5.1	Noncardiac surgery	DEX: 30MID: 30NS: 30	0.5 µg/kg For 10 minutes	0.4 µg/kg/h	Started 10 minutes before induction; maintained until end of surgery	CAM
Shehabi et al, 2009²³	DEX: 71.5 (66-76)MOR: 71.0 (65 -75)	Cardiac surgery	DEX:152MOR:147	N/A	(0.1-0.7) µg/kg/h	Started immediately after arrival in ICU; maintained until discharge from ICU	CAM

Abbreviations: CAM, Confusion Assessment Method; CAM-ICU, CAM for the ICU; CLO, clonidine; DEX, dexmedetomidine; ICU, intensive care unit; KET, ketamine; MID, midazolam; MOR, morphine; NS, normal saline; PRO, propofol; SICU, surgical ICU.

Table 1 shows different strategies of dexmedetomidine administration. Eight of 21 studies administered loading doses, which were 0.4,²¹ 0.5,^32,33 0.6,^22,38 0.8 to 0.1,³⁴ and 1^31,35 µg/kg, accordingly. In our included studies, the infusion rates were 0.1,^14-16,36,39 0.2,¹³ 0.4,^32,33 0.5,^26,35,38 0.2 to 0.4,³⁷ 0.2 to 0.7,^17,21,30,31 0.1 to 0.5,³⁴ 0.4 to 0.6,²⁴ 0.1 to 1.2,²⁵ and 0.1 to 0.7²³ µg/kg/h, accordingly. One study²² exhibited infusion rates for dexmedetomidine of 0.4 and 0.1 µg/kg/h. Dexmedetomidine was administered during surgery,^{24,30-35,37,38} after surgery^{13-17,21,23,25,36,39} and during the perioperative period (intraoperative and postoperative).^22,26 The CAM or CAM-ICU was applied to assess delirium. Nine studies used both CAM and CAM-ICU to evaluate delirium.^{15,17,21,22,25,26,32,38,39}

Risk of Bias Within Studies

According to risk-of-bias assessment, there were 5 included RCTs with unclear risk of bias in 1 domain,^{15,22,31,32,34} 3 with unclear risk of bias in 3 domains,^17,30,33 and 1 with unclear risk of bias in 4 domains.¹³ Additionally, 1 RCT²⁴ was identified as high risk for “selective reporting” bias. The results of quality assessment are described in Figure S2 (available online).

Meta-analysis of Delirium

The prevalence of delirium was reported in 21 articles, with 935 events (14.78%) among 6328 elderly surgical patients. A total of 337 events (10.56%) among the 3191 patients receiving dexmedetomidine were related to delirium, whereas 598 events (19.06%) of the 3137 patients in the control group were related to delirium. The result (RR = 0.55; 95% CI = 0.45-0.67; P < 0.001) indicated that dexmedetomidine obviously decreased delirium occurrence over the control condition with moderate heterogeneity (I² = 53%, P = 0.002; Figure 1A). The z-curve of all included studies crossed trial sequential monitoring boundaries (TSMBs) and reached required information size (RIS), which revealed that there was firm evidence to support the dexmedetomidine effect on delirium incidence (Figures 1B).⁴⁰ GRADE evidence within 21 studies was moderate, owing to “serious inconsistency” (Table S1, available online).

We performed a subgroup analysis according to whether a loading dose was administered. The analysis of subgroups of patients receiving dexmedetomidine with or without a loading dose showed similar results (RR = 0.53, 95% CI = 0.42-0.66, P < 0.001; RR = 0.56, 95% CI = 0.41-0.76, P < 0.001) to the pooled outcome of all included studies (RR = 0.55, 95% CI = 0.45-0.67, P < 0.001; Figure 2A). TSA showed sufficient information for each subgroup (Figures 2B and 2C). GRADE evaluation recorded high and low quality of evidence for the loading dose and without loading dose subgroups, respectively (Table S1).

Another subgroup analysis was conducted for different control drugs. There were 2 comparators in addition to dexmedetomidine (groups 1 and 2) in 2 studies.^33,35 The RR for delirium was similar in the control drugs subgroups; RR was 0.53 (95% CI = 0.44-0.65; P < 0.001) for the saline subgroup and 0.56 (95% CI = 0.37-0.85; P = 0.006) for the anesthetic drugs subgroup (Figure 3A). The number of participants did not reach RIS in the anesthetic drugs subgroup, but z-curves for each subgroup superseded TSMBs, which revealed sufficient information for the dexmedetomidine effect on delirium (Figures 3B and 3C). A high and low quality of evidence was graded for the normal saline and anesthetic drugs subgroups, respectively (Table S1).

We conducted further subgroup analyses based on different periods of dexmedetomidine administration. We identified 10 studies comprising 3252 patients who were administered dexmedetomidine after surgery, and the occurrence of delirium was reduced (RR = 0.50; 95% CI = 0.42-0.61; P < 0.001). A total of 2401 patients in 9 RCTs received dexmedetomidine during surgery, and this group exhibited a reduced delirium incidence (RR = 0.54; 95% CI = 0.37-0.77; P < 0.001). However, there was no statistical difference in delirium occurrence in the perioperative subgroup (RR = 0.95, 95% CI = 0.64 to 1.40, P = 0.79; Figure 4A). Sufficient evidence was found in both postoperative and intraoperative subgroups (Figures 4B and 4C). However, TSA revealed that the sample size was too small to calculate RIS and monitoring boundary in the perioperative subgroup (Figure 4D) and was of low quality as shown by GRADE (Table S1). In addition, GRADE suggested low and high quality of evidence for postoperative and intraoperative subgroups, respectively (Table S1).

Five studies assessed delirium incidence in 1217 patients undergoing cardiac surgery, and the remaining 16 studies included 5111 patients for noncardiac surgery. Figure 5A shows that there was a significant difference in the incidence of delirium (RR = 0.51; 95% CI = 0.42-0.62; P < 0.001) for noncardiac surgery, although dexmedetomidine did not prevent delirium incidence for cardiac surgery (RR = 0.71; 95% CI = 0.44-1.15; P = 0.17) with moderate heterogeneity (I² = 67%; P = 0.02). As shown in Figures 5B and 5C, there was firm evidence with moderate quality in the noncardiac surgery subgroup, but TSA revealed insufficient evidence with low quality in the cardiac surgery subgroup.

Meta-analysis of Secondary Outcomes

As shown in Table 2, the occurrence of hypotension was mentioned in 10 RCTs with 3821 participants, and the result revealed no significant differences (RR = 1.12; 95% CI = 0.91-1.38; P = 0.27). Dexmedetomidine significantly decreased the risk of mortality (RR = 0.47; 95% CI = 0.25-0.89; P = 0.02) and increased the incidence of bradycardia (RR = 1.60; 95% CI = 1.29-1.98; P < 0.001). Seven RCTs with 2564 patients indicated a shorter stay in the ICU for elderly surgical patients who received dexmedetomidine (standard mean difference [SMD] = −0.46; 95% CI = −0.80 to −0.11; P = 0.01). Statistical heterogeneity (I² = 94%; P < 0.001) was high. Additionally, 11 studies including 4177 patients showed that dexmedetomidine reduced the duration of hospital stay (SMD = −0.41; 95% CI = −0.73 to −0.09; P = 0.01). The test of heterogeneity (I² = 96%; P < 0.001) was high in the pooled effect.

Table 2.

Secondary Outcomes of This Meta-analysis.

Outcome	No. of studies	No. of participants	RR or SMD	95% CI	Heterogeneity/I²	Analysis model	P value
Hypotension	10	3821	1.12	0.91 to 1.38	53%	Random effect	0.27
Bradycardia	9	3368	1.60	1.29 to 1.98	23%	Random effect	<0.001
Mortality	10	4288	0.47	0.25 to 0.89	0%	Random effect	0.02
Length of ICU stay	7	2564	−0.46	−0.80 to −0.11	94%	Random effect	0.01
Length of hospital stay	11	4177	−0.41	−0.73 to −0.09	96%	Random effect	0.01

Abbreviations: ICU, intensive care unit; RR, risk ratio; SMD, standard mean difference.

Sensitivity Analysis and Publication Bias

Sensitivity analysis was performed by excluding each study in sequence. Statistical heterogeneity (I² = 20%; P = 0.20) was absent when the study was removed.²⁴ The result (RR = 0.52; 95% CI = 0.45 to 0.61; P < 0.001) was similar to that of primary analysis for all included studies.

The funnel plot was used to evaluate publication bias of all RCTs (Figure S3, available online). Two different kinds of statistical tests were applied to estimate the dissymmetry of the funnel plot—the Egger (bias coefficient = −1.059; standard error = 0.898; t = −1.18; P = 0.253) and Begg (z = 0.39; P = 0.695) tests—demonstrating that there was no significant publication bias.

Discussion

The meta-analysis including 21 RCTs with 6328 patients suggested that dexmedetomidine decreased the risk of delirium in elderly surgical patients with firm evidence from TSA. Further evidence is needed to assess the effect of dexmedetomidine on delirium in elderly patients with cardiac surgery.

There was moderate heterogeneity among all RCTs in our meta-analysis (I² = 53%). One of the cardiac studies was associated with this statistical heterogeneity.²⁴ This study including 164 participants exhibited high risk for selective reporting bias and showed that dexmedetomidine may not reduce the risk of delirium compared with propofol. In this study, dexmedetomidine was administered during the intraoperative period. This is a short duration compared with the other 4 studies, which used dexmedetomidine until discharge from the ICU^23,25 or during the whole mechanical ventilation duration.^21,22 Additionally, Shi et al²⁴ did not administer dexmedetomidine with a loading dose, resulting in a lower total dose of dexmedetomidine. A small sample size was another limitation in this RCT. Furthermore, this is a multiple-center study, and there would be variations in skills of anesthesiologists and surgeons.

Additionally, we conducted a subgroup analysis for noncardiac surgery and cardiac surgery. The subgroup analysis confirmed the results of recent meta-analyses,^19,20 which demonstrated a reduced delirium incidence after dexmedetomidine administration in elderly patients for noncardiac surgery with sufficient evidence from TSA and moderate quality rated by GRADE. Additionally, 5 cardiac surgical studies in this analysis demonstrated that dexmedetomidine did not prevent delirium incidence in elderly patients, with moderate heterogeneity (I² = 67%). Statistical heterogeneity (I² = 0%) was absent after excluding the study by Shi et al,²⁴ but the pooled result revealed a significant difference in delirium incidence for cardiac surgery. Besides, studies in this subgroup do not have sufficient evidence from TSA and low quality of evidence was evaluated by GRADE. Therefore, further evidence is needed to verify the effectiveness of dexmedetomidine on delirium occurrence in geriatric patients undergoing cardiac surgery.

Subgroup analysis revealed that dexmedetomidine decreased the incidence of delirium during surgery, with moderate heterogeneity (I² = 66%; GRADE, low) and after surgery, with low heterogeneity (I² = 6%; GRADE, high). There was no heterogeneity when the study performed by Shi et al²⁴ was removed, but the pooled outcome changed minimally. TSA demonstrated firm evidence in both subgroups. However, no significance was found in the incidence of delirium in studies that used dexmedetomidine during the perioperative period. This may be a result of the lack of evidence for dexmedetomidine on delirium incidence in the perioperative subgroup and a low quality of evidence assessed by GRADE. As a result, more convincing evidence is required to support the result in the perioperative period subgroup.

We conducted further subgroup analysis by the administration of dexmedetomidine with or without a loading dose. The results showed a statistical significance in delirium occurrence among studies with (GRADE, high) or without (GRADE, low) a loading dose. TSA revealed that there was sufficient information to support the results in both subgroups. Of note, the outcome of patients receiving a loading dose was accompanied by moderate heterogeneity (I² = 71%). Two studies were crucial to this significant heterogeneity.^24,26 One of the 2 studies, conducted by Deiner et al,²⁶ showed low risk of bias and revealed that dexmedetomidine did not prevent delirium incidence. This study administered dexmedetomidine during surgery and for 2 subsequent hours in the recovery room, which was shorter than the durations in the other studies.^{13-17,23,25,36,39} Furthermore, the bispectral index was applied to monitor the depth of anesthesia in some studies,^{13,15,23,37,39} whereas anesthesia depth was not monitored by Deiner et al,²⁶ resulting in potentially deeper anesthesia. Most patients in this study were reported to have presurgical cognitive impairment (63%). Patients with American Society of Anesthesiology (ASA) status >III or planned admission to the ICU were excluded. The limited data collection (CAM-ICU only) may have resulted in the low rate of the postanesthesia care unit delirium in this study. Additionally, Deiner et al performed a delirium assessment once a day, indicating that delirium at night may have been undetected. Based on all these factors, Deiner et al published opposite findings.

Additionally, the type of sedative used in geriatric surgical patients is related to delirium incidence. We conducted a subgroup analysis of different control drugs (anesthetic drugs or normal saline). The pooled results revealed that the dexmedetomidine group had a significant decrease in the occurrence of delirium compared with the controls. Although TSA demonstrated that RIS was not reached for the anesthetic drugs subgroup, the z-curves in both subgroups crossed TSMBs. This suggests that it was sufficient to support a preventive effect of dexmedetomidine on delirium incidence in both subgroups. GRADE analyses showed high (normal saline subgroup) and low (anesthetic drugs subgroup) quality of evidence. Therefore, more powerful evidence is needed to confirm the result of the anesthetic drugs subgroup.

The property of dexmedetomidine to reduce delirium incidence may be a result of its actions on inflammation.^41,42 It is possible that shorter duration of medication does not influence the neurochemical milieu of a general anesthetic. Dexmedetomidine can improve sleep quality by activating the endogenous sleep-promoting pathway,⁴³ which means that overnight continuous infusion of study drug may increase its sedation effects. Additionally, prophylactic pharmacological intervention should be started early because the highest prevalence of delirium is during the early postoperative hours.⁴⁴

Bradycardia and hypotension have been reported as important adverse effects of dexmedetomidine, and they are the side effects of acting on the α₂-adrenergic receptor.⁴⁵ Our analysis revealed that dexmedetomidine was related to the increase in bradycardia incidence, but no significant differences in hypotension were demonstrated. Dexmedetomidine also decreased the risk of mortality. The different routes of administration of dexmedetomidine (with loading, high infusion rate, and long-term infusion) may lead to the adverse effects of dexmedetomidine. It was reported that an infusion rate from 0.2 to 1.7 µg/kg/h of dexmedetomidine was related to incidences of bradycardia and hypotension.^46,47 Patients with dexmedetomidine had a shorter duration of hospital/ICU stay, which may be a result of a decreased incidence of delirium and its complications. However, the pooled estimate effects need to be further interpreted before making generalizations on the advantage of dexmedetomidine to all elderly surgical patients because of the high heterogeneity across studies. The problem will be resolved by including increasingly high-quality RCTs.

There are several limitations in our analysis. First, the quality of the eligible RCTs has some restrictions. Nine included RCTs were with unclear risk of bias in at least 1 domain. One study was considered to have high risk of bias. Additionally, TSA revealed that the number of participants in the cardiac surgery and perioperative subgroups did not reach RIS. Second, moderate heterogeneity was detected among subgroup analyses, including the anesthetic drugs group, intraoperative group, cardiac surgery group, and no loading dose group. Moreover, the heterogeneities of the length of ICU/hospital stay were high. More high-quality studies are needed to arrive at more accurate conclusions. Third, the infusion rate of dexmedetomidine in some studies was adjusted by sedative scores or hemodynamic changes, whereas others had a fixed dose. Therefore, it is difficult to draw a correct conclusion about what dose will be optimal. Finally, many possible factors (intubation, hypoxemia, educational level, and surgical time) are associated with the prevalence of delirium. Unfortunately, we were not able to control the aforementioned confounding factors in this analysis.

Relevance to Patient Care and Clinical Practice

Many meta-analyses have demonstrated a decrease in delirium occurrence after noncardiac surgery among geriatric surgical patients.^18-20,48 There are several advantages in our analysis. First, studies with elderly patients undergoing cardiac surgery were not included in these analyses. In our analysis, we have addressed this deficiency. Second, our meta-analysis included 21 studies with 6328 participants, which improved the reliability of the result. Third, to have sufficient statistical power to detect intervention effects, we conducted TSA to reduce the risk of type 1 error and GRADE to evaluate the quality of the evidence. Finally, many possible factors are associated with the heterogeneity; therefore, we performed subgroup analyses, including noncardiac surgery or cardiac surgery, different periods of dexmedetomidine administration, with or without a loading dose, and with anesthetic drugs or normal saline. Besides, we also conducted sensitivity analyses to evaluate any potential source of heterogeneity.

Our review showed that dexmedetomidine could reduce delirium occurrence for elderly noncardiac surgical patients with sufficient evidence from TSA. It is a crucial guideline for clinicians to reduce delirium incidence with the administration of dexmedetomidine in elderly patients undergoing noncardiac surgery. Nevertheless, we found that dexmedetomidine did not prevent delirium incidence for cardiac surgery, with insufficient evidence, which means that further evidence with delirium as an important clinical outcome is needed for elderly cardiac surgical patients.

Conclusion

In this meta-analysis of 21 RCTs, dexmedetomidine reduced delirium incidence in elderly surgical patients with firm evidence from TSA. The effect of dexmedetomidine on delirium in elderly patients with cardiac surgery warrants further studies. Furthermore, dexmedetomidine was associated with an increased incidence of bradycardia, shorter length of ICU/hospital stays, and a lower incidence of mortality.

In the future, the main focus of clinicians should be the effect of dexmedetomidine on delirium for elderly cardiac surgical patients. We should also focus on the effect of perioperative dexmedetomidine administration on delirium and the effect of dexmedetomidine on secondary outcomes such as incidence of bradycardia, the length of ICU/hospital stays, and incidence of mortality.

Supplemental Material

Supplementary_Figures_AOP – Supplemental material for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials

Supplemental material, Supplementary_Figures_AOP for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials by Chunmei Lin, Hankun Tu, Zhixuan Jie, Xinkai Zhou and Chaoyang Li in Annals of Pharmacotherapy

Supplemental Material

Supplementary_file_1 – Supplemental material for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials

Supplemental material, Supplementary_file_1 for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials by Chunmei Lin, Hankun Tu, Zhixuan Jie, Xinkai Zhou and Chaoyang Li in Annals of Pharmacotherapy

Supplemental Material

Supplementary_Table_S1 – Supplemental material for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials

Supplemental material, Supplementary_Table_S1 for Effect of Dexmedetomidine on Delirium in Elderly Surgical Patients: A Meta-analysis of Randomized Controlled Trials by Chunmei Lin, Hankun Tu, Zhixuan Jie, Xinkai Zhou and Chaoyang Li in Annals of Pharmacotherapy

Footnotes

Acknowledgements

We would like to thank AJE () for linguistic assistance.

Authors’ Note

Study design: Chunmei L and Chaoyang L; literature search: Chunmei L and HT; hits screened and reviewed: ZJ and XZ; analysis of data: Chunmei L and Chaoyang L; interpretation of data: all authors; manuscript drafting: Chunmei L; manuscript revision, editing, and approval: all authors.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Chaoyang Li

Supplemental Material

Supplemental material for this article is available online.

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