Postoperative delirium (POD) is a distressing complication of surgery and anesthesia. It is more common in older adults with cardiovascular and neurological comorbidities, having emergency or major surgery.1 There is an association between POD and extended hospital length of stay, progression to long-term cognitive dysfunction, and mortality.2 Unfortunately, these risk factors are not modifiable, but there is an active search for effective interventions to reduce the scale of this problem. One promising strategy has been the use of processed electroencephalographic (pEEG)-guided general anesthesia to prevent unnecessarily deep anesthesia which has been associated with higher incidence of POD.3 Most randomized controlled trials to date investigated the use of bispectral index (BIS). However, the BIS algorithm is known to exhibit a flat dose-response curve, particularly in the elderly, and may not be an ideal device to guide general anesthesia.4

The trial by Wang et al5 in this issue of the Journal is the first large trial to investigate pEEG-guided general anesthesia and its influence on POD using the Patient State Index (PSI) and Spectral Edge Frequency (SEF) (SEDline, Masimo Corporation, CA) to titrate intravenous general anesthesia. The trial recruited 1545 patients aged 50 years and older with American Society of Anesthesiologists physical status classification 1-3, scheduled for laparoscopic surgery with an expected minimum hospital stay of 3 days. Patients with impaired cognition, preexisting neurological disease or requiring emergency surgery were excluded. The intervention group aimed to maintain left and right SEF between 10 and 15, and PSI between 25 and 50, during propofol-remifentanil general anesthesia. In the control group, PSI and SEF readings were concealed. Patients were followed up twice daily for 5 days using the Confusion Assessment Method to diagnose POD as the primary outcome. The incidence of POD was extraordinarily low, 1.0% in the pEEG-guided group and 1.2% in the usual care group, and there were no differences in outcomes between groups (relative risk, 0.89; 95% confidence interval, 0.35-2.3).

Previous trials investigating the effect of pEEG-guided general anesthesia on POD have also shown mixed results for efficacy. However, the incidence of POD in the trial by Wang et al5 (1.1%) was much lower than the expected incidence in this surgical population (14%). While this lower than expected incidence of POD may have been related to their younger age, avoidance of benzodiazepines, use of propofol or an unknown characteristic of the Chinese population included in the study, the consequence of the low event rate is that the trial had limited power for testing clinically relevant differences between groups.

A recent publication has shown that protocol adherence is only adequately reported in 12% of publications in anesthesia and perioperative medicine.6 Provision of information about protocol adherence is fundamental for appropriate interpretation of results. Fortunately, Wang et al5 provided this information; 8 summary statistics of pEEG adherence are reported. Although 2 parameters (SEF left >15 and SEF left/right >15) were statistically different, total propofol dose was similar between groups (median [interquartile range], 900 [600 to 1320] vs. 1000 [600 to 1350] mg in the pEEG-guided and usual care groups, respectively). Consequently, the depth of anesthesia was virtually identical between groups.

Information about group differences is vital when interpreting the presence or absence of a treatment effect. In a similarly sized trial, Wildes et al7 studied older patients and found no difference in POD among those receiving anesthesia to avoid EEG burst suppression and BIS <40 (indicators of overly deep anesthesia) or usual care; there was also little difference in anesthetic delivery between groups (MAC difference 0.11 vol%). Although there was a 6-minute difference in the time spent with burst suppression in the usual care compared with the pEEG-guided group, there was marked overlap between groups. The suspicion remains that there was insufficient difference in overall depth of anesthesia between the groups, and this may have contributed to the lack of a difference in POD. In another trial, Radtke et al8 demonstrated a reduction in POD from 21.4% to 16.7% (P=0.036) with BIS-guided anesthesia compared with routine care, respectively.8 Mean BIS was 39.0 (SD, 7.2) in the BIS-guided group and 38.7 (7.4) in the routine care group, again showing little evidence of a meaningful difference between groups. In this case, the statistically different incidence in POD may be interpreted as either a false positive, or due to a small between group difference in the time spent with burst suppression. In contrast, the trials by Chan et al9 and Evered et al10 investigating the relationship between pEEG-guided anesthetic depth and POD demonstrated a bigger difference in the depth of anesthesia between groups; mean BIS values between groups were 38.6 (6.5) versus 53.2 (8.9)9 and 38.7 (3.9) versus 50.7 (4.4),10 respectively. This wider group separation was associated with significant reductions in POD from 24.1% to 15.6% (P=0.01)9 and from 28% to 19% (P=0.01).10

These trials highlight our concerns with usual care as the control group in the context of contemporary practice. When pEEG is concealed, recent studies have shown a high degree of convergence between groups, possibly because anesthetists are highly familiar with the use of pEEG and have already largely adjusted their typical anesthesia as a result of using it, and that full reporting of the anesthesia in both groups is required to interpret the studies.

Trials of pEEG-guided general anesthesia are challenging, and accurate titration to anesthetic depth can be difficult in the context of a trial. Wang et al5 used SEDline, but titration based on PSI and SEF did not result in between group differences. Whether anesthetic dose titration with PSI and SEF exhibit similar problems to the BIS algorithm is uncertain. Nevertheless, Wang et al5 are to be congratulated on completing the largest randomized controlled trial of this type to date, and for their thorough reporting of the trial. Future studies should concentrate on higher risk groups with higher event rates, and use trial designs that ensure group separation in pEEG or dose to answer this important clinical question.

Doug Campbell, BM*

Timothy G. Short, MD*

Matthew T.V. Chan, PhD† *Department of Anaesthesia and Perioperative Medicine Auckland City Hospital, Auckland, New Zealand †Department of Anaesthesia and Intensive Care The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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