Share this article on:

Bispectral Index, Sedation, Spinal Anesthesia and Mortality: Time to Put the Jigsaw Puzzle Together?

Mannion, Stephen MD, MRCPI, FCARCSI*; Lee, Peter MD, FCARCSI

doi: 10.1213/ANE.0000000000000205
Editorials: Editorial

From the *Department of Anaesthesiology, South Infirmary-Victoria University Hospital; and Department of Anaesthesia, Cork University Hospital, Cork, Ireland.

Accepted for publication January 14, 2014.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Stephen Mannion, MD, MRCPI, FCARCSI, Department of Anaesthesiology, South Infirmary-Victoria University Hospital, Cork, Ireland. Address e-mail to

“I have spread my dreams under your feet;

Tread softly because you tread on my dreams.”

W. B. Yeats (1865–1939)

“He Wishes For the Cloths of Heaven”

From the Collected Works of W. B. Yeats

The modern practice of anesthesia is far removed from the era of manual blood pressure readings and feeling the pulse. Advancements in our specialty over the last 4 decades have considerably expanded the horizons and safety of patient care.1 Older patients and those with serious comorbidities are increasingly anesthetized for routine procedures, ambulatory, and office-based surgery. The availability of sophisticated monitoring systems and “cleaner” drugs might lead one to a somewhat smug sense of accomplishment. “Where are we now with anesthesia?” is not an unreasonable enquiry.

It is therefore a bit unsettling when findings from recent articles suggest that all may not be so positive. As well as looking forward, anesthesiologists may have to start looking more closely at their current practices, particularly in certain patient groups.

Concerns that anesthesia in young children may affect cognitive function and learning in later life,2 that general anesthesia may influence cancer recurrence compared with regional techniques,3 and that cumulative periods of deep anesthesia (defined using processed electroencephalography) could result in greater mortality4–7 have stirred the comfortable position anesthesia currently holds.

A reactive defense is that these studies have methodological failings like nonrandomization or inappropriate statistical analysis, or that the outcomes measured reflect an “other” preexisting disease or environmental factors. Often the anesthetic intervention seems minor in the scale of things, of too short a duration to cause long-term or permanent harm.

The reality is that there is already good clinical evidence from prospective randomized trials that “minor” and short duration changes in anesthesia practice can improve patient outcomes.8 Higher levels of inspired oxygen reduce wound infection rates after colorectal surgery.9 Maintaining normothermia during anesthesia reduces blood loss,10 myocardial ischemia,11 and wound infections.12 The intraoperative use of IV lidocaine reduces the incidence of persistent postsurgical pain after breast surgery.13 We currently lack prospective randomized data regarding the effect of depth of anesthesia (as defined by Bispectral Index [BIS] levels) on mortality.

In this issue of the Journal, Brown et al14 from John Hopkins Medical Institutions, Baltimore, MD, present the results of a study comprising 114 patients aged ≥65 years undergoing hip fracture surgery under spinal anesthesia who received either light or deep sedation as defined by BIS levels of >80 or approximately 50, respectively. Patients were randomized to either BIS level. The authors demonstrate that those patients with serious comorbidities (Charlson comorbidity index >4) randomized to light sedation had a lower 1-year mortality of 22.2% compared with 43.6% for those receiving deep sedation. The hazard ratio was 0.43 [95% confidence interval, 0.19–0.97], decreasing to 0.33 [95% confidence interval, 0.12–0.94] among patients with a Charlson index >6. There was no difference among healthier patients (Charlson index <4).15

There are a few points worthy of particular note, especially in any study looking at depth of sedation or anesthesia as determined by BIS values and a subsequent effect on mortality. First, the patients were elderly patients with a mean age of 81.7 years. All patients were undergoing emergency surgery for hip fracture repair. The median ASA physical status was III. These are all recognized risk factors for increased postoperative mortality.16 Importantly, both groups were similar with regard to these confounders.

The only differences between the groups other than BIS levels were that those in the deep sedation group received a median of 8.1 mg/kg propofol vs 1.3 mg/kg for the light group and a median of 2 mg midazolam compared with 10 mg in the light group.

The authors, limited by a short Discussion required of a Brief Report, do not provide any explanation. Why might older patients undergoing emergency surgery under spinal anesthesia with different depths of sedation have a different 1-year mortality rate? We know that propofol causes significantly more hypotension than midazolam when used for sedation in older patients undergoing a spinal anesthetic17; however, there were no differences in duration of hypotension in this study (P = 0.76). The effects of electroencephalogram burst suppression, found at lower BIS values, on increased mortality have been demonstrated in critically ill patients18 and may play a role. We might postulate that clinical levels of anesthetic agents such as propofol and volatile agents acting at γ-aminobutyric acid receptors may be neurotoxic to developing or “deteriorating” brains.16 There are now experimental data19 to show this as well as clinical data that patients at the extremes of life have postoperative cognitive problems after general anesthesia.2,20,21 Regardless of underlying mechanism, we are presented with a study that demonstrates the possibility of a link between mortality and level of sedation when combined with spinal anesthesia.

So what does the reader do with this new information? A 2005 study by Monk et al4 in this journal demonstrating an association between BIS values <45 and increased 1-year mortality in noncardiac surgery generated considerable debate including a reproach of the Editorial Board.22

Dismissing this current study on the grounds of bias and unknown confounders is not easy. Unlike previous nonrandomized studies4–7 that have demonstrated increased mortality in those with low BIS (<45) values, the randomization process in this study14 means that the chances that low BIS values merely represent sicker patients who are therefore at greater risk of dying are remote.

Those seeking statistical flaws in this study may point out that randomization originally occurred in this study to compare the incidence of delirium not mortality in patients undergoing spinal anesthesia under light or deep sedation. Returning to the original randomized data to determine mortality rates as opposed to delirium is appropriate and statistically valid.

The debate, controversy, and ongoing research on the question “does deeper general anesthesia result in greater mortality” cannot be answered here. The data from those studies4–7 leave us with an association that compels us to look further and call for further studies.

This is not the case with the findings that Brown et al14 present us with.

Their data are valid, and their findings are of immense clinical importance. Many of us will provide sedation for older patients with multiple comorbidities undergoing emergency hip surgery with spinal anesthesia this week. This article suggests that those having deeper sedation with high doses of propofol are more likely to die than if lighter sedation is used. Why this might be the case needs research, but that must not delay anesthesiologists from reflecting on their clinical practice today.

Unlike the potential increased risk of awareness with “lighter” general anesthesia, there is no such serious outcome arising from changing from deep to light sedation with spinal anesthesia. Anxiety and patient comfort are multifactorial and can often be managed through a variety of means including lighter sedation, reassurance, and positioning, without apparent additional risk to the patient. As anesthesiologists, we cannot change the age, ASA physical status, or comorbidities of our patients; we can however change how softly we tread on their dreams.

Back to Top | Article Outline


Name: Stephen Mannion, MD, MRCPI, FCARCSI.

Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and conclusion.

Attestation: Stephen Mannion approved the final manuscript.

Name: Peter Lee, MD, FCARCSI.

Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and conclusion.

Attestation: Peter Lee approved the final manuscript.

This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).

Back to Top | Article Outline


1. Bainbridge D, Martin J, Arango M, Cheng DEvidence-based Peri-operative Clinical Outcomes Research (EPiCOR) Group. . Perioperative and anaesthetic-related mortality in developed and developing countries: a systematic review and meta-analysis. Lancet. 2012;380:1075–81
2. Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G, Sun LS. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476–85
3. Ash SA, Buggy DJ. Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence. Best Pract Res Clin Anaesthesiol. 2013;27:441–56
4. Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg. 2005;100:4–10
5. Kertai MD, Pal N, Palanca BJ, Lin N, Searleman SA, Zhang L, Burnside BA, Finkel KJ, Avidan MSB-Unaware Study Group. . Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial. Anesthesiology. 2010;112:1116–27
6. Lindholm ML, Träff S, Granath F, Greenwald SD, Ekbom A, Lennmarken C, Sandin RH. Mortality within 2 years after surgery in relation to low intraoperative bispectral index values and preexisting malignant disease. Anesth Analg. 2009;108:508–12
7. Leslie K, Myles PS, Forbes A, Chan MT. The effect of bispectral index monitoring on long-term survival in the B-aware trial. Anesth Analg. 2010;110:816–22
8. Kavanagh T, Buggy DJ. Can anaesthetic technique effect postoperative outcome? Curr Opin Anaesthesiol. 2012;25:185–98
9. Hovaguimian F, Lysakowski C, Elia N, Tramèr MR. Effect of intraoperative high inspired oxygen fraction on surgical site infection, postoperative nausea and vomiting, and pulmonary function: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2013;119:303–16
10. Winkler M, Akça O, Birkenberg B, Hetz H, Scheck T, Arkiliç CF, Kabon B, Marker E, Grübl A, Czepan R, Greher M, Goll V, Gottsauner-Wolf F, Kurz A, Sessler DI. Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg. 2000;91:978–84
11. Nesher N, Zisman E, Wolf T, Sharony R, Bolotin G, David M, Uretzky G, Pizov R. Strict thermoregulation attenuates myocardial injury during coronary artery bypass graft surgery as reflected by reduced levels of cardiac-specific troponin I. Anesth Analg. 2003;96:328–35
12. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med. 1996;334:1209–15
13. Grigoras A, Lee P, Sattar F, Shorten G. Perioperative intravenous lidocaine decreases the incidence of persistent pain after breast surgery. Clin J Pain. 2012;28:567–72
14. Brown CH, Azman AS, Gottschalk A, Mears SC, Sieber FE. Sedation depth during spinal anesthesia and survival in elderly patients undergoing hip fracture repair. Anesth Analg. 2014;118:977–80
15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83
16. Kalkman CJ, Peelen LM, Moons KG. Pick up the pieces: depth of anesthesia and long-term mortality. Anesthesiology. 2011;114:485–7
17. Mannion S. Sedation, spinal anesthesia and older patients. J Postgrad Med. 2007;53:155
18. Watson PL, Shintani AK, Tyson R, Pandharipande PP, Pun BT, Ely EW. Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med. 2008;36:3171–7
19. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82
20. Zywiel MG, Prabhu A, Perruccio AV, Gandhi R. The influence of anesthesia and pain management on cognitive dysfunction after joint arthroplasty: a systematic review. Clin Orthop Relat Res. 2013 November 2 [Epub ahead of print]
21. Ancelin ML, de Roquefeuil G, Scali J, Bonnel F, Adam JF, Cheminal JC, Cristol JP, Dupuy AM, Carrière I, Ritchie K. Long-term post-operative cognitive decline in the elderly: the effects of anesthesia type, apolipoprotein E genotype, and clinical antecedents. J Alzheimers Dis. 2010;22(Suppl 3):105–13
22. Drummond JC, Patel PM. Editorial Board reproached for publication of BIS-mortality correlation. Anesth Analg. 2005;101:1238–9
© 2014 International Anesthesia Research Society