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Intensive care medicine

Dexmedetomidine versus propofol sedation in reducing delirium among older adults in the ICU

A systematic review and meta-analysis

Pereira, Jarett V.; Sanjanwala, Rohan M.; Mohammed, Mohammed K.; Le, Me-Linh; Arora, Rakesh C.

Author Information
European Journal of Anaesthesiology: February 2020 - Volume 37 - Issue 2 - p 121-131
doi: 10.1097/EJA.0000000000001131

Abstract

Introduction

Delirium is a common and serious acute neurocognitive syndrome that is characterised by inattention, altered consciousness, cognitive dysfunction and a fluctuating course.1 It can lead to mortality, functional decline, institutionalisation and dementia.2,3 Economically, delirium is associated with a 1.4-fold increase in ICU costs and 1.3-fold increase in total hospital costs.4 The incidence of delirium is particularly high in the ICU, with rates reported to be upwards of 70% in surgical and trauma ICU.5 Although ICU sedation aims to maximise patient comfort, common sedative agents such as benzodiazepines are associated with the development of delirium.6,7 A sedative agent free of delirium would therefore reduce morbidity and mortality.

Accumulating evidence indicates that dexmedetomidine sedation may reduce ICU delirium. A highly-selective α2 adrenoceptor agonist, dexmedetomidine has sedative, sympatholytic, anxiolytic and analgesic effects. Compared with other sedatives, dexmedetomidine is less likely to cause respiratory depression.8

Randomised controlled trials (RCTs) have shown that dexmedetomidine sedation is associated with a reduced incidence of ICU delirium compared with placebo9–11 and benzodiazepines.12 A meta-analysis of studies on cardiac surgery patients also found that dexmedetomidine reduced delirium incidence compared with propofol, a common nonbenzodiazepine sedative agent.13 However, cardiac surgery patients represent a unique subset of general ICU admissions. No recent review has compared these two sedative agents in general ICU patients, a heterogenous cohort comprising both medical and surgical patients.

Furthermore, no review has compared dexmedetomidine with propofol sedation in the reduction of delirium among older adults (age ≥60). It is unclear whether the benefits of dexmedetomidine are applicable to this group as age is a strong risk factor for delirium, whereas other significant risk factors such as cognitive impairment and diminished physiological reserve are also more common in older adults.5 Limiting the investigation to older adults would also improve understanding of the incidence of adverse effects and safety profile of dexmedetomidine. Bradycardia and hypotension, for example, have been reported to be more common in older adults.14

We comprehensively reviewed existing RCTs and cohort studies comparing dexmedetomidine with propofol sedation in older adult (age ≥60) ICU patients. Our aim was to determine if dexmedetomidine was associated with reduced incidence of delirium compared with propofol, and to compare safety outcomes of bradycardia and hypotension. We also compared their effect on ICU length of stay (LOS), hospital LOS and duration of mechanical ventilation.

Methods

Protocol registration

The article was prepared in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement guidelines.15 The study protocol was registered in PROSPERO (CRD42018099339).

Literature search

A medical librarian performed a comprehensive electronic search of MEDLINE, EMBASE, Evidence-based Medicine Reviews, International Pharmaceutical Abstracts, Scopus, ClinicalTrials.gov and WHO Trials for articles published from database inception to 8 April 2019. The search strategy was formulated using a combination of controlled vocabulary and keywords including: delirium, dexmedetomidine, propofol, ICU and sedation. There were no date or language restrictions applied but results were limited to human studies only. The strategy for Ovid MEDLINE is shown in Supplemental Fig. 1, http://links.lww.com/EJA/A250, and all other strategies are available on request. In addition, one researcher (JP) hand-searched the bibliographies of relevant articles that were captured by our search strategy for additional articles and performed forward citation searches using Google Scholar. All references were uploaded into EndNote (v. X7, Clarivate Analytics, Philadelphia, Pennsylvania, USA) and double hits removed.

Eligibility criteria

RCTs and cohort studies that met all of the following criteria were deemed eligible: mean or median sample age of study cohort of 60 years or older; study setting in the adult medical or surgical ICU; direct comparison of dexmedetomidine and propofol as a sedative used in the ICU; measurement of occurrence of delirium as an outcome. We excluded case reports, case series, editorials and letters. Studies that examined intra-operative use of dexmedetomidine and propofol as part of general anaesthesia were also excluded.

Study selection

Two reviewers (JP and RS) independently screened the retrieved articles for eligibility. The article screening process was divided into a title and abstract screening phase and a full-text screening phase. Interrater agreement (Kappa statistic) was calculated for each phase of article screening to ensure optimal consistency between the reviewers in the selection of eligible articles. To further facilitate the screening phases, a checklist based on the inclusion and exclusion criteria was drafted and used by both reviewers so as to maximise accuracy in determining study suitability. Any disagreements between the reviewers were resolved via consensus and discussion with a third reviewer (MM). The researchers screened articles with the Rayyan platform.16

Risk of bias in individual studies

The risk of bias for cohort studies was assessed using the Newcastle-Ottawa Scale (NOS).17 The NOS assesses study selection, study groups’ comparability and study exposure. A study was awarded a maximum of one star for each numbered item within the selection and exposure categories. A maximum of two stars was given for comparability. Two reviewers (RS and JP) independently reviewed each study to evaluate the risk of bias, with disagreements resolved by consensus or via consultation with a third reviewer. Each selected study was given an overall score ranging from 0 to 9. A score of zero suggests high risk of bias and a higher score suggests a lower risk of bias. The loss to follow-up of less than 5% was considered to introduce minimal bias, whereas more than 20% was considered to introduce bias affecting the validity of the study results. However, the risk of bias for RCTs was assessed using the Cochrane risk of bias assessment tool.18 Each included study was evaluated on the following domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, selective outcome reporting and other biases. Each domain was assessed as ‘high’ if bias was present and likely to affect outcomes, or ‘low’ if bias was either not present or ‘present but unlikely to affect outcomes’.

Data extraction

The data extraction process was conducted by one reviewer (JP) and independently verified by a second (MM). Prior to this, a data collection trial was conducted to frame an all-inclusive data extraction template. The extracted data included descriptive information about the study such as the following: sample size, setting, patients’ characteristics, comorbidity status and short description of the cohort under consideration. Methodological data extracted included our outcomes of interest, study design, sedation protocol, method of delirium evaluation, methods of reducing bias including population selection, variables adjusted for, and proportion of patients lost to follow-up. For studies with incomplete or missing data relating to our outcomes of interest, we contacted the authors to request the relevant information.

Statistical analysis

The primary outcome was incidence of delirium during ICU stay, whereas secondary outcomes were incidence of bradycardia, incidence of hypotension, duration of mechanical ventilation, length of ICU stay and hospital LOS. For categorical outcome data such as delirium incidence, bradycardia incidence and hypotension incidence, we extracted the number of outcome events in each group. Continuous outcome data were extracted as means and SD in each group. For studies reporting continuous outcome data as median and interquartile range, the data were converted into mean and SD using the method recommended by Wan et al.19

Meta-analysis was conducted using Review Manager 5.3. by the Cochrane Collaboration.20 Categorical outcome data were reported as pooled risk ratio with 95% confidence interval (CI), while continuous outcome data were reported as pooled weighted mean difference with 95% CI. A P value of less than 0.05 was considered to be statistically significant. Statistical heterogeneity was assessed using the I2 statistic, which represents the percentage of total variation among the included studies that is due to heterogeneity. I2 values of 25, 50 and 75% are classified as low, moderate and high heterogeneity respectively.21 Random effects models were used for all our analysis. As our sample size was small, tests of funnel plot symmetry were not conducted due to the high risk of type 2 error in detecting symmetry.22 Instead, publication bias was assessed by visual inspection of the funnel plot, which plots standard error as a function of effect size (relative risk).

Posthoc sensitivity analysis was performed based on study design to explore whether the inclusion of cohort studies contributed to study heterogeneity. Of the eight included studies, two were retrospective cohort studies. We stratified the studies based on study design and subsequently obtained the effect estimate for randomised trials.

Results

Identification of studies

In total, 2555 articles were identified from our electronic search after removal of double hits. After the title and abstract screen 2520 records were excluded (Kappa statistic κ: 0.9). A total of 35 articles underwent a thorough full-text review (Kappa statistic κ:1); 28 were excluded based on reasons given in Fig. 1. We also identified one article from hand-searching the bibliographies of relevant articles which met our eligibility criteria. As such, a total of eight articles were included, consisting of six RCTs and two retrospective cohort studies.23–30

Fig. 1
Fig. 1:
Preferred Reporting Items for Systematic reviews and Meta-Analysis flow chart outlining the identification and selection of articles for the systematic review and meta-analysis.

Description of included studies

A descriptive summary of the studies that were included in our meta-analysis are presented in Table 1. A total of 1407 patients from eight studies were analysed. The cohorts that were studied include those who underwent cardiac surgery (four studies),23,25,27,29 mixed medical and surgical ICU patients (two studies),24,28 major abdominal surgical patients (one study)30 and general surgical patients (one study).26 The incidence of delirium was evaluated using the Confusion Assessment Method (CAM)-ICU in six of the eight studies, the CAM in one study, while the instrument for delirium diagnosis was not disclosed in the remaining study. In only two out of the eight studies was a loading dose of dexmedetomidine administered.23,27

Table 1
Table 1:
Summary and description of included studies

Risk of bias assessment

Results from the risk of bias assessment of RCTs and cohort studies are presented in Table 2. In general, the risk of bias varied significantly among studies. While all of the randomised studies performed random sequence allocation well, studies varied widely in terms of blinding of participants, personnel and outcome assessment, thus risk of bias ranged from high-risk to low-risk. Some factors such as bias due to selective reporting were difficult to assess. Furthermore, the study by Susheela et al.29 did not report its methodology in adequate detail, which limited our efforts to comprehensively assess risk of bias, particularly in the domains of blinding and selective reporting. It is also unclear whether the small sample size was related to poor response or participation rates, which would increase the likelihood of selection bias. The retrospective design of our cohort studies makes them susceptible to potential limitations. These studies may be more prone to information bias compared with prospective studies, due to misclassification of study variables and outcomes. Furthermore, as retrospective studies depend on the accuracy and completeness of recorded information, potential patients with missing information may be excluded from the study. This was not explicitly acknowledged in either study, raising the possibility of selection bias. However, based on assessment using the NOS, the two cohort studies that were included were deemed to be at low risk of bias, with good overall quality in terms of selection of cohorts and measurement and assessment of outcomes of interest.

Table 2
Table 2:
Summary of risk of bias assessment

Outcomes of pooled studies

Incidence of delirium

Eight studies reported the incidence of ICU delirium for dexmedetomidine compared with propofol. In one study,30 no delirium was observed in either group. In total, 55/481 (11.4%) in the dexmedetomidine group were reported as having experienced delirium, versus 103/768 (13.4%) in the propofol group. Following meta-analysis, dexmedetomidine was significantly associated with lower risk of delirium as compared with propofol: 1249 patients; risk ratio 0.70; 95% CI 0.52 to 0.95; P = 0.02 (Fig. 2). There was no evidence of statistical heterogeneity between the studies (I2 = 0%; P = 0.86). A sensitivity analysis including randomised trials and excluding cohort studies revealed that our effect estimate remained statistically significant, reflecting the stability of our results (Supplemental Fig. 2, http://links.lww.com/EJA/A250).

Fig. 2
Fig. 2:
Forest plot of the effects of dexmedetomidine and propofol sedation on delirium incidence.

Incidence of hypotension

Six studies reported the incidence of hypotension as an outcome. Analysis of pooled data found no significant difference in incidence of hypotension between the dexmedetomidine and propofol groups: 867 patients; risk ratio 1.12; 95% CI 0.86 to 1.45; P = 0.42. Heterogeneity between the studies was not statistically significant (I2 = 43%, P = 0.12) (Fig. 3a). The sensitivity analysis revealed that these findings were consistent even after exclusion of cohort studies (Supplemental Fig. 3, http://links.lww.com/EJA/A250).

Fig. 3
Fig. 3:
Forest plot showing the risk of hypotension and bradycardia associated with dexmedetomidine and propofol use.

Incidence of bradycardia

The incidence of bradycardia was measured as an outcome in three studies. Meta-analysis of the pooled data demonstrated no statistically significant difference in bradycardia incidence between dexmedetomidine and propofol sedation: 279 patients; risk ratio 1.52; 95% CI 0.85 to 2.72; P = 0.16 (Fig. 3b). There was no statistically significant heterogeneity between the studies (I2 = 0%; P = 0.68). Sensitivity analysis for outcome of bradycardia incidence was not performed as only three studies measured incidence of bradycardia.

ICU length of stay

Eight studies (n=1407) reported on the ICU LOS as an outcome, although two were excluded due to missing data that was not retrievable. Data from the six suitable studies (n=1293) were pooled and meta-analysis showed that there was no significant difference in the ICU LOS between dexmedetomidine and propofol groups: 1293 patients; mean difference 0.19 days; 95% CI −0.39 to 0.77, P = 0.25 (Fig. 4a). There was significant heterogeneity across studies (I2 = 92%; P < 0.001). Based on the sensitivity analysis performed (Supplemental Fig. 4A, http://links.lww.com/EJA/A250), the cohort studies only partially accounted for the heterogeneity observed as it remained high after their exclusion (I2 = 77%; P = 0.005).

Fig. 4
Fig. 4:
Forest plot showing the effects of dexmedetomidine on ICU length of stay, hospital length of stay and duration of mechanical ventilation.

In-hospital length of stay

Five studies evaluated the outcome of in-hospital LOS (n=1204). There was no statistically significant difference in the hospital LOS between dexmedetomidine and propofol: 1204 patients; mean difference −0.85 days; 95% CI −5.45 to 3.74, P = 0.52 (Fig. 4b). There was significant heterogeneity between the studies (I2 = 97%; P < 0.001). For this outcome, removal of cohort studies and repeating the meta-analysis resulted in the detection of a statistically significant reduction in hospital LOS for dexmedetomidine compared with propofol: mean difference −3.42 days; 95% CI −6.68 to −0.17; P = 0.04 (Supplemental Fig. 4B, http://links.lww.com/EJA/A250). There was a slight decrease in heterogeneity (P < 0.001; I2 = 90%). However, as only three studies were included in the analysis and considering the high heterogeneity between studies, our mean estimate is likely to be unstable.

Duration of mechanical ventilation

A meta-analysis of four studies (n=1047) that reported on the duration of mechanical ventilation showed no significant difference between the dexmedetomidine and propofol groups: 1047 patients; mean difference 0.14 days; 95% CI −0.29 to 0.00; P = 0.05 (Fig. 4c). There was considerable heterogeneity across the studies (I2 = 86%, P < 0.0001). Due to the small number of studies measuring this outcome, sensitivity analysis was not performed.

Publication bias

Visual analysis of the funnel plot revealed possible risk of publication bias for the outcome of incidence of delirium (Supplemental Fig. 5, http://links.lww.com/EJA/A250). The unequal distribution of the study estimates suggests a relative scarcity of published data with negative results. However, considering the small number of studies included in the funnel plot analysis and the inability to further test statistical significance with Egger's method, limited conclusions can be drawn from visual inspection of the funnel plot.

Discussion

The current review shows that dexmedetomidine sedation in older adults in the ICU was associated with a lower incidence of delirium compared with propofol, without a significant increase in risk of bradycardia and hypotension. There were no significant differences in hospital LOS, ICU LOS and duration of mechanical ventilation.

Despite the high morbidity, mortality and economic costs associated with delirium, no pharmacological therapy has been approved for its prevention and treatment.31 The incidence of delirium is expected to increase as our population ages and as more critically ill older patients with greater comorbidities are admitted to the ICU.32 As such, our finding that dexmedetomidine sedation was associated with significantly less ICU delirium compared with propofol is timely and important. To the best of our knowledge, this is the first review to compare the incidence of delirium with dexmedetomidine and propofol sedation among older adults in the ICU.

The mechanisms underlying dexmedetomidine effects on delirium remain poorly understood. While it has been shown to confer neuroprotective effects in animal models, it is unclear whether a similar effect occurs in humans, and whether this is responsible for delirium reduction.33,34 Future research into the pharmacological properties of dexmedetomidine may help to determine whether dexmedetomidine has intrinsic neuroprotective properties; such a discovery would facilitate the development of analogues with fewer cardiorespiratory side effects.35 Other mechanisms that may explain the greater reduction of delirium with dexmedetomidine include its λ-amino butyric acid (GABA) a receptor-sparing properties, better pain management due to its analgesic effects,36 improved sleep quality via promotion of natural sleep patterns11 and reduction of postoperative hypoxaemia.9 Alternatively, the reduction in delirium associated with dexmedetomidine may be due to avoidance of drugs associated with increased delirium, such as GABA agonists, opioids and anticholinergics. Studies on dexmedetomidine generally have patients in the dexmedetomidine group receiving lower amounts of benzodiazepines and propofol.37 Furthermore, propofol's lack of analgesic properties may necessitate adjunctive opioid therapy, which increases delirium risk.

Comparing the safety profile of dexmedetomidine and propofol, there were no significant differences in the incidence of bradycardia and hypotension in critically ill older adults. This finding differs from the results of previous studies, which show that dexmedetomidine administration is associated with an increased incidence of hypotension and bradycardia compared with propofol.13,38 Theoretically, dexmedetomidine is an α2 adrenoceptor agonist that causes vasodilation and decreased sympathetic response,39 which can result in haemodynamic side-effects. A possible explanation for our findings is that only two out of our eight studies administered a loading dose of dexmedetomidine. One did not measure outcomes of hypotension and bradycardia, while the other only measured hypotension. Bradycardia and hypotension are more common after administering a loading dose of dexmedetomidine, due to a fall in cardiac output following the loading infusion secondary to a transient afterload increase after α2 adrenoceptor-mediated vasoconstriction.40 As such, avoidance of a loading dose when administering dexmedetomidine may reduce the incidence of bradycardia and hypotension. It is important to note, however, that propofol sedation is also associated with hypotension and bradycardia even at standard doses.41 In our study, we have only shown no difference in the incidence of bradycardia and hypotension for dexmedetomidine compared with propofol sedation. Close haemodynamic monitoring is therefore still recommended when administering these agents.

Another possible explanation is that haemodynamic side-effects of dexmedetomidine are more likely to occur in patients with cardiac disease, possibly due to inhibition of sympathetic activity or altered parasympathetic activity caused by increased activation of central postsynaptic α2 receptors.42 The inclusion of noncardiac surgical patients and medical ICU patients in our study may have confounded the effect estimates and explain the nonsignificant association between dexmedetomidine and bradycardia and hypotension. In particular, the study by Jiang et al. was a highly weighted study in our analysis and it included noncardiac medical and surgical patients. As such, it is important for future trials to confirm this finding.

Based on I2 estimates, no significant heterogeneity was detected for the incidence of delirium, hypotension and bradycardia, even with the inclusion of cohort studies in our meta-analysis. These outcomes are more likely to be influenced by the properties of dexmedetomidine and propofol, and our findings show that the effect size is consistent and stable. However, significant heterogeneity was observed for hospital LOS, ICU LOS and duration of mechanical ventilation. The diversity of our patient population is one possible explanation for this heterogeneity. Medical and surgical patients would probably have differed in terms of illness severity and this could influence the total hospital or ICU LOS. Furthermore, postcardiac surgery ICU patients generally have shorter ICU LOS and time on mechanical ventilation compared with medical ICU patients. The type and number of ICU/hospital complications, which would prolong duration of stay, was also not reported in most studies. In addition, differences in ICU protocol across various centres represents another possible explanation for the heterogeneity. There were interhospital differences in ICU admission criteria, protocols for weaning from mechanical ventilation and quality of ICU care. It is important to note, however, that the inclusion of cohort studies only partially accounted for this heterogeneity based on our sensitivity analysis.

Our study has several limitations. Differences in sedation protocol and target sedation levels across the included studies could have led to variation in the average sedative dose administered, while differences in concomitant drugs and underlying comorbidities may influence our outcomes. One study in particular,28 did not report the dose of dexmedetomidine or propofol that was administered to the participants. If the dosing regimen and sedation protocol differed vastly from the other studies, it would have further contributed to the overall heterogeneity. Furthermore, the same study also found significantly increased hospital and ICU LOS with dexmedetomidine sedation compared with propofol, which differed from the results of our other included studies. This may be due to important differences in participant characteristics such as hospital/ICU-acquired complications, such as infections, and duration of delirium being unreported, which influence the hospital/ICU LOS. In addition, interstudy differences in ICU/hospital protocols may influence the duration of mechanical ventilation and ICU/hospital LOS. However, a further analysis of these factors was not conducted as our studies did not report them in adequate detail. Furthermore, there were insufficient studies to perform a subgroup analysis comparing medical and surgical ICU patients, which could have helped to ascertain the source of heterogeneity. Due to the high heterogeneity and small sample size for outcomes of duration of mechanical ventilation and ICU/hospital LOS, results for these outcomes should be interpreted with caution. Second, similar to most meta-analyses, our findings were at risk of type I or type II error. Although trial sequential analysis (TSA) has been proposed as a method to reduce type I and type II errors particularly in smaller meta analyses, we did not perform TSA as the evidence supporting the use of TSA in meta-analyses of both RCTs and cohort studies is very limited, and there is currently inadequate validation for use of TSA for this purpose. Furthermore, our approach was also consistent with the Cochrane Scientific Committee consensus statement,43 which recommends against the use of sequential methods based on current evidence. We maximised inclusiveness by implementing a comprehensive and broad search strategy, including both good-quality cohort studies and RCTs, and broadly analysing the older adult general ICU patients.

Conclusion

The use of dexmedetomidine should be considered in older adult ICU patients requiring sedation who are at risk of developing delirium. Avoidance of a loading dose of dexmedetomidine may lower the incidence of bradycardia and hypotension, although these side effects should still be closely monitored during dexmedetomidine and propofol administration. Further research is needed to confirm the safety and efficacy of dexmedetomidine sedation in reducing delirium, while efforts to understand the possible mechanisms behind delirium reduction may have important therapeutic implications.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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