Neurocognitive assessment was carried out with CAM-ICU in 7, DSST in 4, and MMSE in 4 studies, and 1 study each utilized intensive care delirium screening checklist, trail making test, montreal cognitive assessment test, Stroop color word interference test, and sedation–agitation scores.
Dexmedetomidine treatment was associated with significantly lower risk of neurocognitive dysfunction in the postoperative/postanesthesia period. In the overall meta-analysis, RD (95%) was −0.16 (−0.25, −0.08); P = 0.0002; REM (Figure 3), whereas, it was −0.17 (−0.30, −0.04); P = 0.008; REM between dexmedetomidine and saline-treated patients and −0.16 (−0.28, −0.04); P = 0.009; REM between dexmedetomidine and comparator-treated patients.
In the subgroup analyses, however, there was no significant difference between dexmedetomidine and control/comparators when studies with CAM-ICU only (RD: −0.10 (−0.22, 0.02); P = 0.1; REM; Figure 4) or midazolam as comparator only (RD: −0.26 (−0.60, 0.07); P = 0.12; REM; Figure 5) were meta-analyzed. Outcomes of other subgroup analyses are presented in Table 3.
This meta-analysis has revealed that dexmedetomidine use significantly reduces the risk of neurocognitive dysfunction in the postinfusion period in comparison with saline as well as with comparator anesthetics. However, in the subgroup analyses, a meta-analysis of 7 studies that utilized CAM-ICU for neurocognitive assessment, no significant difference between dexmedetomidine and comparators/controls-treated patients was found. Moreover, meta-analysis of 4 studies that used midazolam as comparator anesthetic also could not meet with any significance difference. These findings indicate that there can be some impact of the neurocognitive assessment method, dexmedetomidine dosage, and clinical heterogeneity on the overall outcomes of postoperative/postinfusion neurocognitive function as well as its assessment.
Some studies with relevant information could not be included in the present meta-analysis because of the eligibility criteria of the present study. Among these, Ji et al,33 who retrospectively analyzed the outcomes of over 1000 patients who underwent coronary artery bypass surgeries, could not find any significant difference in the incidence of neurocognitive events between dexmedetomidine-treated and control patients. These authors defined delirium as “illusions, confusion, and cerebral excitement in the postoperative period and having a comparatively short course.” In a similar retrospective analysis, Dasta et al34 also could not find any significant difference in the incidence of delirium between dexmedetomidine–propofol–midazolam-treated and only propofol–midazolam-treated patients where the diagnosis guidance was based on ICD-9-CM (International Classification of Diseases, 9th Revison, Clinical Modification, codes 292.81, 293.1). Martin et al35 against control, and Herr et al36 and Terao et al37 against propofol found no significantly different effects of dexmedetomidine in the incidence of confusion and agitation as adverse events.
It has been opined that one possible mechanism of dexmedetomidine action can be its dose-sparing effects for other anesthetics such as lorazepam.26 It is well recognized that α-2 agonists especially dexmedetomidine possess anesthetic and analgesic-sparing effects.41,42 Moreover, synergistic effects of dexmedetomidine with benzodiazepines are also reported.43 In the trial of Jakob et al,22 although there was no significant difference in the incidence of neurocognitive dysfunction events in comparison with midazolam, dexmedetomidine administration led to significantly lower incidence of neurocognitive dysfunction when compared with propofol. On the other hand, dexmedetomidine has also been found to prevent sevoflurane-induced emergence agitation in children when administered 5 minutes before the end of surgery44 that shows that interactions with other drugs also play a role in manifesting effects of dexmedetomidine.
Several factors are needed to be taking into account while interpreting the results of trials examining efficacy of dexmedetomidine in postoperative neurocognitive function. Among these, the equivalence of dosing while using a comparator anesthetic45,46 and the outcome measure reliability47 are more important. In the present study, these factors might have also played role in determining the overall effect size as the statistical heterogeneity was higher. Moreover, there was disagreement in the results with different neurocognitive assessment tools. Studies have also shown that hypoactive delirium is more common than agitational delirium (61% vs 8%), but the identification of hypoactive delirium is difficult under normal neurocognitive tests.48
For this meta-analysis, neurocognitive dysfunction events on the first postoperative/postinfusion day were taken into account because of the less availability of data for later days. This is an important limitation. Clinical and methodological heterogeneity between the included studies may also have impact on the overall results that is also evident from statistical heterogeneity that was higher in the overall meta-analysis and some submeta-analyses.
Dexmedetomidine treatment during perioperative conditions or as ICU sedation has been found to be associated with significantly better neurocognitive function of the patients, but factors such as neurocognitive assessment method, drug interactions, and clinical heterogeneity may have impacts on these results. Further studies are required to refine the evidence achieved herein.
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