# Pharmacological Prevention of Postoperative Delirium: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Authors: Yong Liu; Xiao-Jin Li; Yi Liang; Yan Kang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2019)

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## Abstract

Background. The high prevalence of delirium among postoperative patients has increased morbidity and mortality. The kind of drug that can effectively reduce the incidence of delirium has become the focus of discussion in recent years. However, a consensus in this respect has yet to be reached.Methods. Randomized controlled trials (RCTs) were retrieved from the PubMed, Cochrane Library, ClinicalTrials.gov, and Embase databases from their inception through October 12, 2018. We included RCTs of pharmacological prevention for postoperative delirium in adults (at least 18 years), and the Cochrane risk of bias tool was used to evaluate the methodological quality of trials. The primary outcomes were the risk ratios (RRs) of incidence of postoperative delirium, and the secondary outcomes were the RRs of mortality and adverse events in the intervention and control groups.Results. Thirty-eight trials, which comprised 20302 patients and 18 different drugs, were included in the analysis. Of the 38 studies, 17 were rated as low risk with respect to methodological quality. Dexmedetomidine administration (RR 0.58, 95%CI 0.44-0.76, P<0.01) was associated with a significantly lower incidence of postoperative delirium than the control conditions. However, the findings from the studies with a low risk of bias did not show a significant difference in this beneficial effect (RR 0.64, 95%CI 0.39-1.04, P=0.07). The antipsychotic drugs olanzapine (RR 0.44, 95%CI 0.30- 0.65, P<0.01) and risperidone (RR 0.42, 95%CI 0.19-0.92, P=0.03) had promising effects, but there was a lack of sufficient evidence to obtain a definitive conclusion. The beneficial effect of other drugs, including haloperidol, methylprednisolone, dexamethasone, gabapentin, ketamine, cyproheptadine, donepezil, hypertonic saline, melatonin, nimodipine, ondansetron, pregabalin, rivastigmine, TJ-54, and tryptophan, was not proven on the basis of present evidence.Conclusion. Among the pharmacological prophylactic measures for postoperative delirium, dexmedetomidine, olanzapine, and risperidone showed higher efficacy than other drugs. However, more high-quality evidence is needed to confirm these results.


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## Body

## 1. Introduction

Delirium, a change in neuropsychiatric state from a previous baseline level of mental function, typically involves a set of symptoms such as changes in arousal, cognitive deficits, and perceptual dysfunction, as well as hallucinations and delusions. Delirium itself is not a disease but rather a set of symptoms. Delirium not only is a challenge for medical staff but also has adverse effects on the duration of the hospital stay and mechanical ventilation and the cognitive state, and delirium contributes to increased morbidity and mortality.Several classes of drugs, such asα2-receptor agonists, atypical antipsychotics, and sleep-regulatory drugs, have received widespread attention for the potential prevention or treatment of delirium [1].Dexmedetomidine, an agonist ofα2-adrenergic receptors in certain parts of the brain, is an anxiolytic, sedative, and modest analgesic [2, 3]. Dexmedetomidine has been promoted for its ability to achieve sedation without risk of respiratory depression (unlike other commonly used sedatives such as midazolam and propofol) and can achieve levels of semiarousable and cooperative sedation. However, the administration of dexmedetomidine has been associated with hypertension and arrhythmia due to peripheral α2-receptor stimulation [4].Atypical antipsychotics are less likely to cause extrapyramidal side effects, such as body rigidity, bradykinesia, and involuntary tremors, than haloperidol, one of the most widely used typical antipsychotics [5–7]. Although atypical antipsychotics are deemed safer than typical antipsychotics, they still have the potential to induce severe side effects in accordance with their respective side effect profiles, and they more commonly increase the risk of metabolic side effects, such as weight gain and glycemic and lipid imbalances.Melatonin, a hormone secreted by the pineal gland, is regarded as an important molecular sleep–wake cycle regulator that is used to treat insomnia [8]. Some studies have shown that low or delayed melatonin levels in elderly patients are associated with delirium in intensive care units [9–11]. Several RCTs have been registered and are ongoing to prove the benefits of melatonin in preventing postoperative delirium.A number of randomized controlled trials (RCTs) have been published focusing on the pharmacological prevention of postoperative delirium. This systematic review was performed to identify recent advances in the pharmaceutical prophylaxis of postoperative delirium and to offer clinicians an updated summary to help make clinical decisions.


## 2. Materials and Methods

### 2.1. Retrieval Protocol and Selection Criteria

We searched MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Embase through October 12, 2018, for RCTs investigating the prevention of postoperative delirium. We also examined the reference lists of the included relevant RCTs and systematic reviews for additional eligible references. Search terms mainly included delirium, confusion, disorientation, surgery, and RCTs.RCTs that investigated the pharmacological prevention of postoperative delirium were included, with language restricted to English. Patients were adults (at least 18 years of age) and received drugs in the perioperative phase. Studies were excluded if risk ratios (RRs) for analysis were not available or if they investigated the therapeutic effects of the drugs for emergency agitation and anesthesia. The studies in which several drugs were simultaneously used to prevent postoperative delirium were also excluded.


### 2.2. Data Extraction and Quality Assessment

Data extraction was conducted independently by the 1st and 2nd authors (Liu Y and Liang Y) with a predesigned spreadsheet, and discrepancies were resolved by a 3rd author (Li XJ).The Cochrane risk of bias tool was used to assess the risk of bias, with items including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and incomplete outcome data [12]. A risk of bias table was created to display the results of the risk assessment.


### 2.3. Primary and Secondary Results

The primary outcomes were the RRs of the incidence of postoperative delirium between the intervention and control groups after the patients received the drugs, and the secondary outcomes were the RRs of mortality and adverse events. Other results, such as adverse events, side effects, and hospital stays, were also collected for evaluating the safety of the drugs. To maintain consistency between studies with regard to the control groups, only studies using placebo, normal saline, and blank (meaning “no injection”) as control agents were included in the final data analysis.


### 2.4. Statistical Analysis

All statistical analyses were completed by Stata 13.0 (Stata Corp., College Station, TX). Considering the clinical heterogeneity between studies, the random effects model using the DerSimonian and Laird method was used to merge data. The heterogeneity was evaluated using the I2 statistic, and I2 > 30% indicated the presence of heterogeneity between studies [13]. Subgroup analyses were adopted to identify the effect of different characteristics of the studies on the results. Publication bias was assessed by Egger’s asymmetry test and funnel plots [14]. This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [15].


## 2.1. Retrieval Protocol and Selection Criteria

We searched MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Embase through October 12, 2018, for RCTs investigating the prevention of postoperative delirium. We also examined the reference lists of the included relevant RCTs and systematic reviews for additional eligible references. Search terms mainly included delirium, confusion, disorientation, surgery, and RCTs.RCTs that investigated the pharmacological prevention of postoperative delirium were included, with language restricted to English. Patients were adults (at least 18 years of age) and received drugs in the perioperative phase. Studies were excluded if risk ratios (RRs) for analysis were not available or if they investigated the therapeutic effects of the drugs for emergency agitation and anesthesia. The studies in which several drugs were simultaneously used to prevent postoperative delirium were also excluded.


## 2.2. Data Extraction and Quality Assessment

Data extraction was conducted independently by the 1st and 2nd authors (Liu Y and Liang Y) with a predesigned spreadsheet, and discrepancies were resolved by a 3rd author (Li XJ).The Cochrane risk of bias tool was used to assess the risk of bias, with items including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and incomplete outcome data [12]. A risk of bias table was created to display the results of the risk assessment.


## 2.3. Primary and Secondary Results

The primary outcomes were the RRs of the incidence of postoperative delirium between the intervention and control groups after the patients received the drugs, and the secondary outcomes were the RRs of mortality and adverse events. Other results, such as adverse events, side effects, and hospital stays, were also collected for evaluating the safety of the drugs. To maintain consistency between studies with regard to the control groups, only studies using placebo, normal saline, and blank (meaning “no injection”) as control agents were included in the final data analysis.


## 2.4. Statistical Analysis

All statistical analyses were completed by Stata 13.0 (Stata Corp., College Station, TX). Considering the clinical heterogeneity between studies, the random effects model using the DerSimonian and Laird method was used to merge data. The heterogeneity was evaluated using the I2 statistic, and I2 > 30% indicated the presence of heterogeneity between studies [13]. Subgroup analyses were adopted to identify the effect of different characteristics of the studies on the results. Publication bias was assessed by Egger’s asymmetry test and funnel plots [14]. This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [15].


## 3. Results

### 3.1. Search Results and Study Characteristics

We identified 2723 records, of which 1308 were duplicates (Figure1). Of the 223 full-text articles reviewed, 38 RCTs were identified as eligible after improving the retrieval protocol [16–53]. Baseline information is listed in Table 1. To maintain consistency between studies, 32 studies involving 19539 patients (including 34 datasets) treated with placebo, normal saline, or blank as controls were included in the final data analysis.Table 1
Summary of the baseline characteristics of included trials.
Study Country Dosing Information Control Begin Time Following Time Type of Surgery Age(years) Male (%) Incidence (%) N Avidan2017 [16] USA 0.5 or 1.0 mg/kg ketamine by injection as single dose. placebo before surgery 3d major surgery 70 62.2 19.6 672  Clemmesen2017 [17] Denmark 125 mg methylprednisolone by injection for once. saline before surgery 3d hip 80 35.9 24.8 117  de Jonghe2014 [18] Netherlands 3 mg melatonin taken orally for 5 days. placebo before surgery 8d hip 84 29.9 27.5 378  Deiner2017 [19] USA 0.5μg/kg/h dexme by infusion continued until 2 hours into recovery. saline before surgery 30d cardiac 74 48.7 15.4 390  Dieleman2012 [20] Netherlands 1 mg/kg dexamethasone by injection for once. placebo during surgery 30d cardiac 66 72.5 10.4 4482  Dighe2014 [21] Canada 200 mg gabapentin taken orally tid for 4 days. placebo after surgery NA knee 63 49.7 10.6 161  Djaiani2016 [22] Canada a bolus of 0.4μg/kg dexme followed by 0.2-0.7 μg/kg/h infusion for maximum 24 h. propofol after surgery 5d cardiac 73 75.4 24.6 183  Farlinger2018 [23] Canada 150 mg pregabalin preoperatively and 75 mg bid postoperatively for 7 days. placebo before surgery NA hip 60 50.9 0.6 163  Fukata2014 [24] Japan 2.5 mg haloperidol for 3 days. blank after surgery 7d abdominal, orthopedic 80 52.9 37.2 121  Gamberini2009 [25] Switzerland 1.5 mg oral rivastigmine tid for 7 days. placebo before surgery 6d cardiac 74 68.1 31 113  Hudetz2009 [26] USA 0.5 mg/kg ketamine intravenous bolus for once. saline before surgery 5d cardiac 64 NA 17.2 58  Kalisvaart2005 [27] Netherlands 0.5 mg haloperidol tid until 3 days after surgery saline before surgery 14d hip 79 20.2 15.8 430  Kaneko1999 [28] Japan 5 mg haloperidol intravenous for 5 days saline after surgery 5d gastrointestinal 73 64.1 21.8 78  Larsen2010 [29] USA 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. placebo before surgery 8d joint 74 45.8 27.5 400  Lee2018 [30] Korea 1μg/kg bolus dexme followed by 0.2-0.7 μg/kg/h infusion during surgery. saline before surgery 5d laparoscopic 73 44.3 17.9 318  Leung2017 [31] USA 900 mg gabapentin administered preoperatively and for the first 3 postoperative days. placebo before surgery 3d orthopedic 73 49.6 22.4 697  Li.X2017 [32] China 0.6μg/kg dexme for 10 minutes followed by 0.4 μg/kg/h during surgery. placebo before surgery 5d cardiac 67 68.6 6.3 287  Li.YN2017 [33] China 7.5μg/kg/h nimodipine was injected continually 30minutes before anesthesia induction. saline before surgery 7d spine 70 40 11.7 60  Liu. YZ2016 [34] China 0.2-0.4μg/kg/h dexme during surgery saline before surgery 7d joint 73 48.7 29.4 197  Maldonado2009 [35] USA received one of three postoperative sedation regimens: dexme, propofol and midazolam. propofol, midazolam after surgery 3d cardiac 58 63.8 34.4 90  Mardani2013 [36] Iran 8 mg of intravenous dexamethasone before surgery and followed by 8 mg q8h for 3 days. placebo before surgery 3d cardiac 62 NA 18.3 93  Mei2018 [37] China a bolus of dexme at 0.8-1.0μg/kg followed by 0.1-0.5 μg/kg/h infusion or propofol. propofol before surgery 7d hip 75 45.6 11.8 296  Mohammadi2016 [38] Iran 4 mg cyproheptadine tid for 7 days. placebo after surgery 7d non-cardiac 60 65 25 40  Papadopoulos2014 [39] Greece 8 mg intravenous ondansetron daily for 5 days. placebo after surgery 5d femoral, hip 72 44.3 44.3 106  Park2014 [40] Korea loading dose of 0.5μg/kg dexme followed by 0.2-0.8 μg/kg/h or remifentanil 1-2.5 mg/h during ICU. remifentanil after surgery 3d cardiac 53 55.6 16.2 142  Prakanrattana2007 [41] Thailand 1 mg risperidone sublingually when regained consciousness placebo after surgery 3d cardiac 61 58.7 21.4 126  Priye2015 [42] India 0.4μg/kg/h dexme for 12 hours. saline after surgery ICU cardiac 43 51.6 9.4 64  Robinson2014 [43] USA 1g tryptophan enterally tid for 3 days. placebo after surgery ICU mixed 69 98 38.5 301  Royse2017 [44] Australia 250 mg methylprednisolone at induction and 250 mg methylprednisolone before surgery. placebo during surgery 3d cardiac 74 64.1 9.2 298  Sampson2007 [45] UK 5 mg donepezil after surgery and continuing for a further 3 days. placebo after surgery 4d hip 69 51.5 21.2 33  Shehabi2009 [46] Australia received dexme 0.1–0.7g/kg/h or morphine 10-70g/kg/h to maintain target sedation & analgesia. morphine after surgery 5d cardiac 71 75.3 11.7 299  Sheikh2018 [47] India 1μg/kg dexme bolus followed by infusion 0.2–0.6 μg/kg/h or 0.25–1 mg/kg/h propofol propofol before surgery ICU cardiac 35 NA 13.3 60  Su2016 [48] China dexme 0.1μg/kg/h from ICU admission on the day of surgery until 08:00 h on postoperative day 1. saline after surgery 7d non-cardiac 74 60.4 15.9 700  Sugano2017 [49] Japan 2.5g TJ-54 tid for 7 days prior to surgery and 4 days after surgery, except for the operation day. blank before surgery NA gastrointestinal, lung 77 64.5 8.1 186  Wang2012 [50] China 0.5 mg haloperidol intravenous bolus followed by infusion at a rate of 0.1 mg/h for 12 hours. saline after surgery 7d non-cardiac 74 41.1 19.3 457  Whitlock2015 [51] Canada 250 mg methylprednisolone at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass. placebo during surgery 3d cardiac 67 60.4 7.8 7507  Xin2017 [52] China 4ml/kg 7.5% hypertonic saline was given before surgery. saline before surgery 3d hip 76 51.7 25 120  Yang2015 [53] China 0.5 mg/kg dexme was given for 1 hour. saline before surgery 5d free flap 50 53.2 8.9 79 Note: dexme: dexmedetomidine; N: the number of participants; NA: not available.Figure 1
Flow diagram of the study selection process.


### 3.2. Quality Assessments

The overall methodological quality of the studies was distributed from low to high (Figure2). Five items, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and incomplete outcome data, were adequately and unambiguously described in 31 (82%), 25 (66%), 23 (61%), 24 (63%), and 29 (76%) of 38 trials, respectively.Figure 2
Summary of risk of bias assessment.


### 3.3. Prophylactic Efficacy Assessments

Out of concern about the risk of bias, the RRs for the incidence of postoperative delirium were analyzed at two levels: studies with different levels of bias risk and studies with low risk. First, drugs that were investigated in at least two studies were evaluated, and we found that dexmedetomidine (RR 0.58, 95%CI 0.44-0.76, P<0.01) was associated with the beneficial effect of decreasing the incidence of postoperative delirium, but haloperidol, methylprednisolone, dexamethasone, gabapentin, and ketamine did not display this effect (Figure3). In contrast, the results of only the studies with low risk showed that dexamethasone (RR 0.81, 95%CI 0.68-0.96, P=0.01) showed a beneficial benefit, while the effects of dexmedetomidine (RR 0.64, 95%CI 0.39-1.04, P=0.07), haloperidol, methylprednisolone, gabapentin, and ketamine were not significantly different from those of controls.Figure 3
Forest plot of risk ratios (RRs) for the incidence of postoperative delirium in all studies or studies with a low risk of bias (at least 2 studies for each drug).The preventive effect of drugs with 1 eligible study on postoperative delirium was also evaluated. Olanzapine (RR 0.44, 95%CI 0.30-0.65, P<0.01) and risperidone (RR 0.42, 95%CI 0.19-0.92, P=0.03) had protective effects in the prevention of delirium, but cyproheptadine, donepezil, hypertonic saline, melatonin, ondansetron, rivastigmine, TJ-54, and tryptophan did not (Figure4).Figure 4
Forest plot of risk ratios (RRs) for the incidence of postoperative delirium (only one available study for each drug).The prophylactic effect of drugs on overall mortality was assessed in our review. The RR from all studies did not show a significant difference between the intervention and control groups (RR 0.85, 95%CI 0.71-1.02, P=0.08). Merging data from the 8 studies with a low risk had a similar result (RR 0.85, 95%CI 0.71-1.03, P=0.10) (Figure5).Figure 5
Forest plot of risk ratios (RRs) for mortality in the included studies.Adverse events and side effects were also collected to evaluate the balance between the benefits and risks produced by these drugs. We found that dexmedetomidine increased the incidence of bradycardia (RR 1.24, 95%CI 1.01-1.52, P=0.04) and reduced the incidence of tachycardia (RR 0.51, 95%CI 0.32-0.82, P=0.01) and hypertension (RR 0.67, 95%CI 0.52-0.87, P<0.01). Significant differences in adverse events and side effects were not found with the atypical antipsychotics, the acetylcholinesterase inhibitors, ketamine, and the glucocorticoids, as well as for other effects of dexmedetomidine, in part because of insufficient data (TableS2, supplementary materials).


### 3.4. Subgroup Analysis

We performed the subgroup analysis against only dexmedetomidine because there were 9 datasets, and the other drugs did not have enough data for further analyses. When the datasets were categorized by type of surgery, age, methodological quality, and timing of drug administration, we found that dexmedetomidine had clear protective effects in patients from datasets without cardiac surgery, aged > 65 years, and with insufficient quality. The timing of drug administration, before surgery or after surgery, did not influence postoperative delirium (TableS1, supplementary materials).


### 3.5. Publication Bias

Egger’s test for asymmetry, an indication of publication bias, was performed for all the studies, and P=0.001 indicated significant publication bias among the included studies (Fig.S1, supplementary materials). Nevertheless, the publication bias among studies with low risk did not show a significant difference with P=0.30 (Fig. S2, supplementary materials).


## 3.1. Search Results and Study Characteristics

We identified 2723 records, of which 1308 were duplicates (Figure1). Of the 223 full-text articles reviewed, 38 RCTs were identified as eligible after improving the retrieval protocol [16–53]. Baseline information is listed in Table 1. To maintain consistency between studies, 32 studies involving 19539 patients (including 34 datasets) treated with placebo, normal saline, or blank as controls were included in the final data analysis.Table 1
Summary of the baseline characteristics of included trials.
Study Country Dosing Information Control Begin Time Following Time Type of Surgery Age(years) Male (%) Incidence (%) N Avidan2017 [16] USA 0.5 or 1.0 mg/kg ketamine by injection as single dose. placebo before surgery 3d major surgery 70 62.2 19.6 672  Clemmesen2017 [17] Denmark 125 mg methylprednisolone by injection for once. saline before surgery 3d hip 80 35.9 24.8 117  de Jonghe2014 [18] Netherlands 3 mg melatonin taken orally for 5 days. placebo before surgery 8d hip 84 29.9 27.5 378  Deiner2017 [19] USA 0.5μg/kg/h dexme by infusion continued until 2 hours into recovery. saline before surgery 30d cardiac 74 48.7 15.4 390  Dieleman2012 [20] Netherlands 1 mg/kg dexamethasone by injection for once. placebo during surgery 30d cardiac 66 72.5 10.4 4482  Dighe2014 [21] Canada 200 mg gabapentin taken orally tid for 4 days. placebo after surgery NA knee 63 49.7 10.6 161  Djaiani2016 [22] Canada a bolus of 0.4μg/kg dexme followed by 0.2-0.7 μg/kg/h infusion for maximum 24 h. propofol after surgery 5d cardiac 73 75.4 24.6 183  Farlinger2018 [23] Canada 150 mg pregabalin preoperatively and 75 mg bid postoperatively for 7 days. placebo before surgery NA hip 60 50.9 0.6 163  Fukata2014 [24] Japan 2.5 mg haloperidol for 3 days. blank after surgery 7d abdominal, orthopedic 80 52.9 37.2 121  Gamberini2009 [25] Switzerland 1.5 mg oral rivastigmine tid for 7 days. placebo before surgery 6d cardiac 74 68.1 31 113  Hudetz2009 [26] USA 0.5 mg/kg ketamine intravenous bolus for once. saline before surgery 5d cardiac 64 NA 17.2 58  Kalisvaart2005 [27] Netherlands 0.5 mg haloperidol tid until 3 days after surgery saline before surgery 14d hip 79 20.2 15.8 430  Kaneko1999 [28] Japan 5 mg haloperidol intravenous for 5 days saline after surgery 5d gastrointestinal 73 64.1 21.8 78  Larsen2010 [29] USA 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. placebo before surgery 8d joint 74 45.8 27.5 400  Lee2018 [30] Korea 1μg/kg bolus dexme followed by 0.2-0.7 μg/kg/h infusion during surgery. saline before surgery 5d laparoscopic 73 44.3 17.9 318  Leung2017 [31] USA 900 mg gabapentin administered preoperatively and for the first 3 postoperative days. placebo before surgery 3d orthopedic 73 49.6 22.4 697  Li.X2017 [32] China 0.6μg/kg dexme for 10 minutes followed by 0.4 μg/kg/h during surgery. placebo before surgery 5d cardiac 67 68.6 6.3 287  Li.YN2017 [33] China 7.5μg/kg/h nimodipine was injected continually 30minutes before anesthesia induction. saline before surgery 7d spine 70 40 11.7 60  Liu. YZ2016 [34] China 0.2-0.4μg/kg/h dexme during surgery saline before surgery 7d joint 73 48.7 29.4 197  Maldonado2009 [35] USA received one of three postoperative sedation regimens: dexme, propofol and midazolam. propofol, midazolam after surgery 3d cardiac 58 63.8 34.4 90  Mardani2013 [36] Iran 8 mg of intravenous dexamethasone before surgery and followed by 8 mg q8h for 3 days. placebo before surgery 3d cardiac 62 NA 18.3 93  Mei2018 [37] China a bolus of dexme at 0.8-1.0μg/kg followed by 0.1-0.5 μg/kg/h infusion or propofol. propofol before surgery 7d hip 75 45.6 11.8 296  Mohammadi2016 [38] Iran 4 mg cyproheptadine tid for 7 days. placebo after surgery 7d non-cardiac 60 65 25 40  Papadopoulos2014 [39] Greece 8 mg intravenous ondansetron daily for 5 days. placebo after surgery 5d femoral, hip 72 44.3 44.3 106  Park2014 [40] Korea loading dose of 0.5μg/kg dexme followed by 0.2-0.8 μg/kg/h or remifentanil 1-2.5 mg/h during ICU. remifentanil after surgery 3d cardiac 53 55.6 16.2 142  Prakanrattana2007 [41] Thailand 1 mg risperidone sublingually when regained consciousness placebo after surgery 3d cardiac 61 58.7 21.4 126  Priye2015 [42] India 0.4μg/kg/h dexme for 12 hours. saline after surgery ICU cardiac 43 51.6 9.4 64  Robinson2014 [43] USA 1g tryptophan enterally tid for 3 days. placebo after surgery ICU mixed 69 98 38.5 301  Royse2017 [44] Australia 250 mg methylprednisolone at induction and 250 mg methylprednisolone before surgery. placebo during surgery 3d cardiac 74 64.1 9.2 298  Sampson2007 [45] UK 5 mg donepezil after surgery and continuing for a further 3 days. placebo after surgery 4d hip 69 51.5 21.2 33  Shehabi2009 [46] Australia received dexme 0.1–0.7g/kg/h or morphine 10-70g/kg/h to maintain target sedation & analgesia. morphine after surgery 5d cardiac 71 75.3 11.7 299  Sheikh2018 [47] India 1μg/kg dexme bolus followed by infusion 0.2–0.6 μg/kg/h or 0.25–1 mg/kg/h propofol propofol before surgery ICU cardiac 35 NA 13.3 60  Su2016 [48] China dexme 0.1μg/kg/h from ICU admission on the day of surgery until 08:00 h on postoperative day 1. saline after surgery 7d non-cardiac 74 60.4 15.9 700  Sugano2017 [49] Japan 2.5g TJ-54 tid for 7 days prior to surgery and 4 days after surgery, except for the operation day. blank before surgery NA gastrointestinal, lung 77 64.5 8.1 186  Wang2012 [50] China 0.5 mg haloperidol intravenous bolus followed by infusion at a rate of 0.1 mg/h for 12 hours. saline after surgery 7d non-cardiac 74 41.1 19.3 457  Whitlock2015 [51] Canada 250 mg methylprednisolone at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass. placebo during surgery 3d cardiac 67 60.4 7.8 7507  Xin2017 [52] China 4ml/kg 7.5% hypertonic saline was given before surgery. saline before surgery 3d hip 76 51.7 25 120  Yang2015 [53] China 0.5 mg/kg dexme was given for 1 hour. saline before surgery 5d free flap 50 53.2 8.9 79 Note: dexme: dexmedetomidine; N: the number of participants; NA: not available.Figure 1
Flow diagram of the study selection process.


## 3.2. Quality Assessments

The overall methodological quality of the studies was distributed from low to high (Figure2). Five items, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and incomplete outcome data, were adequately and unambiguously described in 31 (82%), 25 (66%), 23 (61%), 24 (63%), and 29 (76%) of 38 trials, respectively.Figure 2
Summary of risk of bias assessment.


## 3.3. Prophylactic Efficacy Assessments

Out of concern about the risk of bias, the RRs for the incidence of postoperative delirium were analyzed at two levels: studies with different levels of bias risk and studies with low risk. First, drugs that were investigated in at least two studies were evaluated, and we found that dexmedetomidine (RR 0.58, 95%CI 0.44-0.76, P<0.01) was associated with the beneficial effect of decreasing the incidence of postoperative delirium, but haloperidol, methylprednisolone, dexamethasone, gabapentin, and ketamine did not display this effect (Figure3). In contrast, the results of only the studies with low risk showed that dexamethasone (RR 0.81, 95%CI 0.68-0.96, P=0.01) showed a beneficial benefit, while the effects of dexmedetomidine (RR 0.64, 95%CI 0.39-1.04, P=0.07), haloperidol, methylprednisolone, gabapentin, and ketamine were not significantly different from those of controls.Figure 3
Forest plot of risk ratios (RRs) for the incidence of postoperative delirium in all studies or studies with a low risk of bias (at least 2 studies for each drug).The preventive effect of drugs with 1 eligible study on postoperative delirium was also evaluated. Olanzapine (RR 0.44, 95%CI 0.30-0.65, P<0.01) and risperidone (RR 0.42, 95%CI 0.19-0.92, P=0.03) had protective effects in the prevention of delirium, but cyproheptadine, donepezil, hypertonic saline, melatonin, ondansetron, rivastigmine, TJ-54, and tryptophan did not (Figure4).Figure 4
Forest plot of risk ratios (RRs) for the incidence of postoperative delirium (only one available study for each drug).The prophylactic effect of drugs on overall mortality was assessed in our review. The RR from all studies did not show a significant difference between the intervention and control groups (RR 0.85, 95%CI 0.71-1.02, P=0.08). Merging data from the 8 studies with a low risk had a similar result (RR 0.85, 95%CI 0.71-1.03, P=0.10) (Figure5).Figure 5
Forest plot of risk ratios (RRs) for mortality in the included studies.Adverse events and side effects were also collected to evaluate the balance between the benefits and risks produced by these drugs. We found that dexmedetomidine increased the incidence of bradycardia (RR 1.24, 95%CI 1.01-1.52, P=0.04) and reduced the incidence of tachycardia (RR 0.51, 95%CI 0.32-0.82, P=0.01) and hypertension (RR 0.67, 95%CI 0.52-0.87, P<0.01). Significant differences in adverse events and side effects were not found with the atypical antipsychotics, the acetylcholinesterase inhibitors, ketamine, and the glucocorticoids, as well as for other effects of dexmedetomidine, in part because of insufficient data (TableS2, supplementary materials).


## 3.4. Subgroup Analysis

We performed the subgroup analysis against only dexmedetomidine because there were 9 datasets, and the other drugs did not have enough data for further analyses. When the datasets were categorized by type of surgery, age, methodological quality, and timing of drug administration, we found that dexmedetomidine had clear protective effects in patients from datasets without cardiac surgery, aged > 65 years, and with insufficient quality. The timing of drug administration, before surgery or after surgery, did not influence postoperative delirium (TableS1, supplementary materials).


## 3.5. Publication Bias

Egger’s test for asymmetry, an indication of publication bias, was performed for all the studies, and P=0.001 indicated significant publication bias among the included studies (Fig.S1, supplementary materials). Nevertheless, the publication bias among studies with low risk did not show a significant difference with P=0.30 (Fig. S2, supplementary materials).


## 4. Discussion

In this review, we retrieved 38 RCTs from 2723 records investigating the pharmaceutical prevention of postoperative delirium, and 32 of these studies used placebo, saline, or blank as a control. We also systematically evaluated these RCTs of drugs to prevent delirium after surgery, and the overall results showed thatα2-adrenergic receptor agonists and atypical antipsychotics could reduce the incidence of postoperative delirium. However, there were no drugs that showed an ability to prevent postoperative delirium based on the evidence from studies with low risk.Although dexmedetomidine had the advantage of reducing postoperative delirium, the results obtained when all studies, regardless of quality level, were examined were inconsistent with the results obtained when only the high-quality studies were examined. This difference means that a definitive conclusion could not be drawn due to the lack of high-quality evidence. It should be noted that dexmedetomidine has both sedative and analgesic effects, which means that the use of dexmedetomidine can reduce the consumption of other sedative drugs and opioid analgesics, which possibly changes the incidence of delirium in patients and limits our ability to interpret the results [54, 55]. In view of the high risk of delirium with benzodiazepines, dexmedetomidine is deemed to be an alternative to benzodiazepines to achieve the target sedation [56]. High-quality evidence is still needed to determine whether dexmedetomidine can truly reduce the occurrence of delirium when compared with placebo.Atypical antipsychotics have the risk of serious side effects, such as acute hemorrhagic pancreatitis, status epilepticus, leucopenia, tardive dyskinesia, and neuroleptic malignant syndrome [57]. Although the incidence of these severe adverse events with atypical antipsychotics is lower than that with typical antipsychotics, there is not enough evidence to put atypical antipsychotics into widespread use to prevent delirium in all susceptible patients because of the potential adverse effects [58]. Therefore, the pros and cons of using antipsychotics to prevent and treat delirium need be balanced, and the therapeutic regimens must also be tailored according to the specific situation of individual patients.This review also has some limitations. First, the relevant information provided by the authors and the evaluation process featured subjectivity, which might lead to a certain degree of deviation from the real situation. Second, some studies had not documented in detail the adverse events and side effects caused by the drugs, which may result in difficulties in weighing the risks and benefits of drug use. Third, although the average age of the patients in 2 of the studies in this review was less than 60 years old, we did not think this difference would influence the results, considering the consistency of the baseline between the intervention and control groups.Dexmedetomidine and two atypical antipsychotic drugs (olanzapine and risperidone) showed prophylactic effects on postoperative delirium. However, the results of the meta-analysis of all studies on dexmedetomidine were inconsistent with the results from the low-risk studies, and there was not enough evidence to support the use of atypical antipsychotics for preventing delirium. Therefore, we need to carefully understand these results and develop reasonable regimens for delirium prevention according to the specific situation.



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