From the Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
Accepted for publication January 6, 2014.
Funding: This work was supported by departmental funds.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Miles Berger, MD, PhD, Department of Anesthesiology, Duke University Medical Center, 4324 Orange Zone (Duke South), Durham NC 27710. Address e-mail to firstname.lastname@example.org.
Ever since Bedford’s seminal 1955 case series in the Lancet titled “Adverse Cerebral Effects of Anesthesia on Old People,” we have known that some patients have cognitive problems after anesthesia and surgery.1 Today, the term postoperative delirium is often used to describe the mental state of many of these patients. Delirium is a syndrome of waxing and waning mental status changes and alterations in the level of consciousness. It is a common (and likely underrecognized) complication correlated with adverse outcomes including decreased quality of life and increased hospital and 6-month mortality.2 More recently, postoperative delirium has also been associated with cognitive decline during the first year after cardiac surgery.3
Is there anything that we as anesthesiologists can do to decrease the incidence of delirium? Processed electroencephalography (EEG) (e.g., Bispectral Index, BIS) is a controversial tool in anesthesiology but may be a useful instrument for preventing postoperative delirium. In this issue of Anesthesia & Analgesia, Whitlock et al.4 examine whether using a BIS monitor decreases the incidence of delirium in cardiothoracic surgery patients. They report a trend toward less delirium in the BIS-guided anesthetic group versus the end-tidal anesthetic concentration (ETAC)-guided group (18.8% vs 28%), although this difference was not statistically significant (P = 0.058) despite adequate statistical power. Nevertheless, this finding is consistent with the results of similar studies in noncardiac surgical patients, which have shown that BIS-guided anesthetic titration (as opposed to typical titration to hemodynamic end points) lowers the incidence of delirium.5,6 Even when spinal anesthesia was the primary anesthetic technique, titrating sedation depth to a BIS ≥80 vs approximately 50 decreased the incidence of delirium.7 In each of these studies, BIS usage (or a higher BIS target range) was associated with lower average anesthetic dosage6,7 or a decreased incidence of deep anesthesia (e.g., BIS values <20).5
Although Whitlock et al.4 also found a trend toward lower delirium incidence in patients enrolled in the BIS arm, neither the average ETAC, nor cumulative anesthetic exposure (e.g., MAC-hours),8 nor the occurrence of deep anesthesia (BIS <20) is given for the BIS versus ETAC titration arms. Thus, it is unclear whether the trend toward less delirium in the BIS group was also associated with less anesthetic delivery. The authors did compare delirious and nondelirious patients and found no differences in the time spent under deep anesthesia in these 2 groups (as measured by duration of BIS <45, proportion of time with a BIS <20, or the percentage of patients in each group whose BIS was ever <20). In a multivariable analysis employing elegant statistical methodology, comorbidity scores, transfusion, and average ETAC were associated with delirium, but BIS usage (i.e., BIS group) was not.4 If that is the case, can we really posit that BIS offers more value than ETAC for preventing delirium? Furthermore, one could argue that the difference in average ETAC (0.79 ± 0.12 vs 0.85 ± 0.11) between delirious and nondelirious patients is not clinically meaningful.
Surprisingly, Whitlock et al.4 show that age-adjusted average ETAC during maintenance was inversely correlated with delirium; patients who received less inhaled agents were more likely to develop delirium. At first glance, this finding appears to contradict the results of the previous studies, which found that BIS usage was associated with decreased anesthetic dosage and lower delirium rates.5–7
Why might less anesthetic administration be associated with increased delirium incidence, if BIS usage lowers delirium incidence by allowing providers to administer less anesthetic? Of course, this curious finding may simply be a consequence of confounding from variables that are not accounted for in the current statistical model. However, the surprising association between lower anesthetic exposure and higher rates of delirium4 can also be reconciled if one imagines a typical patient who develops postoperative delirium. Older, sicker patients are at higher risk of delirium, and simple measures of overall physical status such as the “get up and go” test are strong predictors of postoperative delirium,9 postoperative complications, and 1-year mortality.10 Many anesthesiologists may be “eyeballing” patients to determine who appears “sick” (and would likely perform poorly on the get up and go test) and then subsequently treating these patients with lower anesthetic dosages because of the assumption that these patients cannot tolerate as much anesthetic. Interestingly, data from Whitlock et al.4 do suggest that delirious patients are sicker (median EuroSCORE of 6 vs 4). However, the authors did not assess the interaction between EuroSCORE and average ETAC in their statistical modeling, which may have clarified whether sicker patients indeed received lower average ETAC.
In line with this idea and the authors’ proposed explanations, a previous study showed that patients with mild cognitive impairment (a prodromal stage of Alzheimer’s disease) were more sensitive to propofol,11 and patients with dementia have lower processed EEG values even when awake.12 Perhaps patients with mild cognitive impairment, dementia, and/or others who appear sick remain at high risk of delirium even when treated with appropriate age-adjusted anesthetic dosages. Thus, EEG-guided anesthetic dose titration might help us lower delirium risk by allowing us to further decrease anesthetic dosage and avoid excessively deep anesthesia in patients who are more sensitive to anesthetics.13,14
Where are we now? To demonstrate how these findings fit in with previously reported results, Whitlock et al.4 combine their results in a small meta-analysis with data from 3 similar previous trials.5–7 The use of a post hoc meta-analysis in conjunction with a finding that was not statistically significant may strike some as unusual. However, as the authors note, there is precedent for this type of analysis as a way to place new data into context.15,16 We favor this approach but recommend an additional step. Not only should new trial results be presented within a meta-analysis of existing data, but the meta-analysis should also be conducted with and without the new trial data. Only then will we truly understand the contribution of the new data. For example, the summary odds ratio was 0.61 (0.46–0.82) with the 3 prior studies and now becomes 0.56 (0.42–0.73) when the meta-analysis includes the new study by Whitlock et al.4 (data presented in the journal review process). This analysis shows that the newest trial4 adds minimally to the evidence that BIS usage decreases delirium rates, consistent with the marginal statistical significance (and smaller sample size, compared to the prior trials)5,6 of the Whitlock et al.4 study.
Where do we go from here? Despite the limitations, the data from Whitlock et al.4 are provocative and suggest that EEG-guided anesthetic depth titration may decrease a common complication after cardiothoracic surgery. As our health care system evolves toward value-based delivery, the opportunity to improve the quality of our care, decrease costs, and improve patient outcomes should not be ignored. We therefore support the authors’ call for a larger randomized study to delineate whether EEG-guided anesthetic depth titration decreases delirium rates after cardiothoracic surgery.4 A more fundamental question, however, is how the use of intraoperative BIS monitoring decreases delirium, and for which patients in particular. This is challenging partly because we currently lack an understanding of delirium from a systems’ neuroscience perspective. Future studies will undoubtedly clarify the neurobiological basis of delirium, but our current incomplete understanding of delirium need not discourage clever trials designed to help prevent its occurrence. Our patients deserve no less!
Name: Miles Berger, MD, PhD.
Contribution: This author helped write the manuscript.
Attestation: Miles Berger approved the final manuscript.
Name: Jacob Nadler, MD, PhD.
Contribution: This author helped write the manuscript.
Attestation: Jacob Nadler approved the final manuscript.
Name: Joseph P. Mathew, MD.
Contribution: This author helped write the manuscript.
Attestation: Joseph P. Mathew approved the final manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
1. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955;269:259–63
2. Abelha FJ, Luís C, Veiga D, Parente D, Fernandes V, Santos P, Botelho M, Santos A, Santos C. Outcome and quality of life in patients with postoperative delirium during an ICU stay following major surgery. Crit Care. 2013;17:R257
3. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30–9
4. Whitlock EL, Torres B, Lin N, Helsten DL, Nadelson MR, Mashour GA, Avidan M. Postoperative delirium in a substudy of cardiothoracic surgical patients in the bag-recall clinical trial. Anesth Analg. 2014
5. Radtke FM, Franck M, Lendner J, Krüger S, Wernecke KD, Spies CD. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013;110(Suppl 1):i98–105
6. Chan MT, Cheng BC, Lee TM, Gin TCODA Trial Group. . BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013;25:33–42
7. Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, Mears SC. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010;85:18–26
8. Kertai MD, Palanca BJ, Pal N, Burnside BA, Zhang L, Sadiq F, Finkel KJ, Avidan MSB-Unaware Study Group. . Bispectral index monitoring, duration of bispectral index below 45, patient risk factors, and intermediate-term mortality after noncardiac surgery in the B-Unaware Trial. Anesthesiology. 2011;114:545–56
9. Brouquet A, Cudennec T, Benoist S, Moulias S, Beauchet A, Penna C, Teillet L, Nordlinger B. Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery. Ann Surg. 2010;251:759–65
10. Robinson TN, Wu DS, Sauaia A, Dunn CL, Stevens-Lapsley JE, Moss M, Stiegmann GV, Gajdos C, Cleveland JC Jr, Inouye SK. Slower walking speed forecasts increased postoperative morbidity and 1-year mortality across surgical specialties. Ann Surg. 2013;258:582–8; discussion 588–90
11. Erdogan MA, Demirbilek S, Erdil F, Aydogan MS, Ozturk E, Togal T, Ersoy MO. The effects of cognitive impairment on anaesthetic requirement in the elderly. Eur J Anaesthesiol. 2012;29:326–31
12. Renna M, Handy J, Shah A. Low baseline Bispectral Index of the electroencephalogram in patients with dementia. Anesth Analg. 2003;96:1380–5
13. Grocott HP. Monitoring the brain in cardiac surgery–an evolving area for research. Anaesthesia. 2012;67:216–9
14. Brown EN, Purdon PL. The aging brain and anesthesia. Curr Opin Anaesthesiol. 2013;26:414–9
15. Clark S, Horton R. Putting research into context–revisited. Lancet. 2010;376:10–1
16. Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O’Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JMTACT Trial Management Group; TACT Trialists. . Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009;373:1681–92