Circulation 36,825 • Volume 18, No. 3 • Fall 2003

Can We Alter Long-Term Outcome? The Role of Anesthetic Management & the Inflammatory Response

Steffen E. Meiler, MD; Terri G. Monk, MD; James B. Mayfield, MD; C. Alvin Head, MD
Editor’s Note:

The association of inflammatory mediators, cardiovascular disease, and long-term outcome is increasingly recognized by both researchers and clinicians. The American Heart Association and the Centers for Disease Control and Prevention recently published a scientific statement entitled, “Markers of Inflammation and Cardiovascular Disease,” which describes the application of such markers to individual patient care and public health. The perioperative period is characterized by tissue injury and proinflammatory events. The relationship between the type or depth of anesthesia, surgery, the inflammatory response, and long-term outcome is not known, but recent research suggests that events occurring in the perioperative period may have an effect on long-term outcome that persists well beyond discharge from the recovery room and even beyond discharge from the hospital.

The Winter 2002-2003 issue of this Newsletter contained a synopsis of a study by Weldon and colleagues that demonstrated an association between a marker of anesthetic depth and long-term outcome in elderly patients. The mechanism of this association is not known, nor has causation been established, but this study has raised intriguing questions. Emerging outcome data pertaining to perioperative beta-blockade and HMG-CoA reductase inhibitors are also increasing awareness of the potential role of inflammatory mediators in long-term outcome.

The Executive Committee of the APSF believes that this area of inquiry is important and that further research is necessary to understand potential ways in which anesthetic management and/or perioperative modulation of the inflammatory response may improve patient safety and long-term outcome. In order to support and encourage such awareness and investigation, the APSF is launching an initiative that begins with the following article by Steffen E. Meiler, MD and colleagues (part one of a two-part series). Following these articles, a multidisciplinary expert symposium will be held in 2004. Details of this symposium will be available in the next issue of the APSF Newsletter. The goals of this meeting are to review the existing data, prioritize areas of future investigation, and begin to establish an infrastructure that will foster research relevant to perioperative patient safety.

As readers of the APSF Newsletter are well aware, anesthesiology has taken a leadership role among medical professions for its rigorous and innovative approaches to improving patient safety. Most of these risk-reduction efforts have been directed at the immediate perioperative period. Error analysis in system designs, human performance evaluations, and advances in medical management have resulted in an impressive reduction in acute perioperative morbidity and mortality. Despite the fact that adverse events still occur, anesthesia has become safer than ever. Lessons learned from systematic assessments of the complex anesthesia environment have inspired a national effort to reduce medical errors and improve patient safety throughout our health care system.1

In contrast, the relationship between anesthesia care and long-term risk has received scant attention. Recent evidence suggests that acute perioperative management may influence outcome months or even years after the administration of anesthesia. If this long-term influence is confirmed, it may radically alter our perspective on anesthesia care, with the intriguing potential to improve patient safety well beyond the first few days and weeks after surgery.

Considering the very low mortality statistics immediately after surgery, any short-term benefit from new perioperative interventions will be difficult to demonstrate. In a recent editorial, Cooper and Gaba raised the possibility that perioperative anesthesia safety could cease to show improvement because the risk was already so low.2 The situation may be very different for long-term morbidity and mortality. Last year, Weldon et al.3 reported a 1-year mortality rate of 5.4% in a large group of elective surgical patients. This is considerably higher than typical mortality rates for the immediate perioperative period.4 In the Weldon study, survival decreased with patient age, reaching a 1-year mortality of 9.9% in patients over the age of 60. These 1-year survival findings are consistent with previous investigations (Table 1) and indicate a real opportunity for outcome improvement.4 With a 1-year mortality risk of 5% to 14%, even small improvements in survival rates could potentially result in thousands of lives saved.

Table 1. Postoperative Mortality Measured at Different Time Points
0-2 Day
30 Day
1 Year
All Patients, 2 Teaching Hospitals4
All Procedures
Adult, 44 VA Hospitals7
1.2 – 5.4%
Adult, University Hospital3
Adult, Cardiac Risk, VA Hospital, Controls5
Elderly, Ambulatory6

Opportunities To Modify Long-Term Risk May Exist

Anesthesia management has generally not been considered to influence long-term outcomes. Several lines of evidence suggest that this view warrants re-examination:

One perioperative intervention now recognized to improve long-term patient safety is the administration of ß-blockers.8-10 Although it is widely accepted that ß-blocking agents protect against early adverse cardiac outcome after surgery, it is much less appreciated that this protective effect can continue long after their administration. In their seminal paper, Mangano et al. reported that, although ß-blockers failed to lower hospital mortality in patients at risk, their administration did reduce all-cause mortality by almost 55% over 2 years following surgery.5

Early, but highly promising results forecast an important future role for the group of HMG CoA-reductase inhibitors (or statins) in attenuating cardiac risk from anesthesia and surgery. Statins lower cholesterol, but they also have direct anti-inflammatory effects and reverse endothelial dysfunction. Statins may stabilize vulnerable atherosclerotic plaque by several mechanisms including increased production of nitric oxide and scavenging of oxygen-derived free radicals.11 In a recent retrospective study, Poldermans and colleagues demonstrated that statins were associated with a 4.5-fold reduction in perioperative mortality among 2,816 patients who underwent major vascular surgery.12 Whether statins confer a long-term mortality advantage after surgery is presently not known; however, judging by other intervention-based studies,13 this type of pharmacologic strategy appears worthy of prospective trials to measure its effect.

In the study by Weldon et al., the authors reported for the first time an association between anesthetic effect and risk of death during the first year following surgery.3 These authors studied over 1,000 patients undergoing major, non-cardiac surgery to investigate a possible relationship between anesthetic hypnotic depth (as measured by the Bispectral Index [BIS™]) and postoperative cognitive dysfunction. Unexpectedly, they found that the level of hypnotic effect (or the cumulative deep BIS™ time) was a significant predictor of death in the first year. Multivariate analysis showed this effect was independent of co-morbidity and age. Another study by Lennmarken et al., which will be presented at the ASA 2003 Meeting, came to almost identical conclusions.14 Furthermore, a retrospective, risk-adjusted mortality analysis of national hospital data (2001 MEDPAR file) of more than 4,500 US institutions and 1.6 million admissions suggests that hospitals routinely using intraoperative BISª monitoring have lower postoperative, 1-year mortality rates.15

Undoubtedly, future research will have to verify these findings and address some of the important limitations inherent in this work. Anesthetic titration could affect mortality, but it must be recognized that other factors (such as ß-blocker administration) could have decreased the apparent anesthetic requirement and contributed to the observations. Furthermore, total anesthetic dose was not measured in any of these trials, and we cannot exclude the possibility that patients who died in the ensuing year demonstrated increased CNS susceptibility to the effects of anesthetics (which would result in lower BISª values). Alternative explanations for the findings of the MEDPAR study15 include hospital characteristics, anesthesia provider traits, specific technique utilization, or routine policies and procedures, among others.

That being said, the message of these studies is powerful and suggests that anesthetic management, directly, or indirectly may contribute to the biology of remote adverse events, and that practicing anesthesiologists might be able to influence long-term outcomes by adjusting anesthetic and adjuvant regimens at the time of surgery. Interestingly, other observations in support of this notion were published as early as 1978 when Steen at al. reported a strong correlation between the time under anesthesia and myocardial reinfarction rates.16 Two independent, randomized, prospective studies also concluded that there is a significant survival benefit from the use of regional vs. general anesthesia in certain high-risk patients undergoing major surgery.17,18

Future Challenges

The studies cited here are provocative since they suggest that short-term decisions may potentially influence outcome for years. They also indicate that our patient safety initiatives may save the lives of many more patients than previously appreciated. If we assume the majority of risk involved elderly patients, reducing the 1-year mortality by just 5% would translate to 40,000 to 50,000 lives saved each year. This opportunity should come as a welcome challenge to researchers and clinicians alike, and stimulate new thinking about the ways we evaluate medical interventions in patient safety research. Given the complexity and the number of interacting factors in anesthesia care, future studies will require the collection of detailed and consistent perioperative data across multiple clinical sites. Such efforts will be facilitated with the broader deployment of Automated Information Management Systems (i.e., automated record keepers), which will improve both the measurement and implementation of successful management strategies.

Important research always raises more questions than it answers, and these studies are no exception. We should direct our questions beyond phenomenology, to determine the basic biological mechanisms that lead to adverse outcomes. The insights of modern immunology and inflammation research hold particular promise for understanding the basis of cardiovascular morbidity. We now recognize that surgery and anesthesia cause a significant, and potentially sustained burst in the body’s inflammatory response, as well as changes in immune function. It is entirely possible that anesthesia management will affect these responses over the long term, so research in this area is certainly timely. In a subsequent article, the rapidly evolving area of immune system function, inflammatory responses, and their potential impact on perioperative risk stratification and patient safety will be further explored.

Dr. Meiler is an Associate Professor and Vice Chair for Research in the Department of Anesthesiology and Perioperative Medicine, and Director of the Program for Molecular Perioperative Medicine & Genomics at the Medical College of Georgia. Dr. Monk is a Professor in the Department of Anesthesiology at the University of Florida College of Medicine. Dr. Mayfield is an Associate Professor and Vice Chair of Clinical Anesthesia in the Department of Anesthesiology and Perioperative Medicine at the Medical College of Georgia. Dr. Head is Professor and Chair of the Department of Anesthesiology and Perioperative Medicine at the Medical College of Georgia.

Disclosure: Drs. Monk and Mayfield have received honoraria and research support from Aspect Medical Systems.


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