Skip Navigation LinksHome > August 2009 - Volume 111 - Issue 2 > Can Attenuation of the Perioperative Stress Response Prevent...
Anesthesiology:
doi: 10.1097/ALN.0b013e3181adf4b9
Editorial Views

Can Attenuation of the Perioperative Stress Response Prevent Intermediate or Long-term Cardiovascular Outcomes among Patients Undergoing Noncardiac Surgery?

Devereaux, P J. M.D., Ph.D.

Free Access
Article Outline
Collapse Box

Author Information

THERE are at least two potential pathways through which perioperative events may increase the risk of intermediate (i.e., 1 yr or less after surgery) and long-term (i.e., more than 1 yr after surgery) cardiovascular outcomes. First, perioperative events (e.g., myocardial ischemia) may result in unstable coronary artery plaques that are prone to fissure and cause acute thrombosis weeks to months later. Second, perioperative myocardial infarction (MI) may result in myocardial scaring that may lead months to years later to a major cardiovascular outcome (e.g., heart failure, cardiac arrest, cardiovascular death).
Unfortunately, no direct imaging or molecular studies are available for evaluating whether perioperative events result in unstable coronary artery plaques. Less direct evidence that supports the first hypothesized pathway comes from three small prospective studies.1–3 Wallace et al. undertook a nested cohort study within a 200-patient perioperative β-blocker trial.1 This study demonstrated that perioperative myocardial ischemia (detected on Holter electrocardiography) on postoperative days 0–2 was a univariate predictor of 2-yr mortality (36 patients died; relative risk 2.06; 95% confidence interval [CI] 1.04–4.06).
Pasternack et al. undertook a prospective cohort study of 385 patients.2 Logistic regression demonstrated that only total perioperative percentage time ischemic of 1% or more (based on continual electrocardiography monitoring for an average of 31 h after surgery) and age were statistically significant independent predictors of cardiovascular outcomes (44 patients died, and 17 suffered MI during 2-yr follow-up; estimates of association were not reported).2
Mangano et al. undertook a prospective cohort study of 444 consecutive patients with or at high-risk of coronary artery disease who were discharged home after surgery.3 During the 2-yr follow-up, 47 patients suffered cardiac complications as defined by a broad composite that included cardiac death and nonfatal MI. Multivariable analysis demonstrated that postoperative myocardial ischemia (detected on Holter electrocardiography) was an independent predictor of long-term cardiac complications (hazard ratio 2.2; 95% CI 1.1–4.3).3
Several studies support the second hypothesized pathway that perioperative MI may lead to a major cardiovascular outcome months to years later. Five small studies (total of 753 patients) all demonstrated that an elevated troponin measurement after surgery was a statistically significant independent predictor of mortality (total of 98 deaths) within 1 yr of surgery.4–8 Two small studies (total of 840 patients) both demonstrated that an elevated troponin measurement after surgery was a statistically significant independent predictor of mortality (total of 162 deaths) up to 4 yr after surgery.9,10 The prospective cohort study by Mangano et al. also demonstrated that a perioperative MI was an independent predictor of a cardiac complication (hazard ratio, 20.0, 95% CI 7.5–53.0) at 2-yr follow-up.3 Finally, a large (105,951 patients) Veterans Affairs study that used prospective and administrative data demonstrated that a perioperative MI was an independent predictor of 8-yr mortality (37,743 deaths, hazard ratio 1.5, 95% CI 1.4–1.6).11
There are at least two potential explanations for these study results. First, the groups of patients (e.g., patients with and without perioperative myocardial ischemia) in each study had a similar extent of cardiovascular disease and a similar risk of subsequent events before surgery, and the occurrence of the perioperative event changed the patients’ long-term prognosis. A second potential explanation is that perioperative myocardial ischemia and infarction are markers of more severe underlying cardiovascular disease and thus a worse prognosis.
If the first explanation is correct, then preventing perioperative myocardial ischemia or MI may prevent intermediate or long-term cardiovascular outcomes; if the second explanation solely accounts for the demonstrated associations, then preventing perioperative myocardial ischemia or MI is unlikely to affect distant events.
Although it is not possible to draw firm conclusions on the basis of the current evidence, the consistency of the signal in the adjusted analyses across the perioperative studies and the strong evidence that myocardial ischemia and MI alter intermediate and long-term prognosis in the nonoperative setting suggests that perioperative events independently alter intermediate and long-term cardiovascular prognosis. Therefore, exploring whether interventions that prevent perioperative myocardial ischemia or MI result in a decrease in intermediate or long-term cardiovascular complications is warranted.
Back to Top | Article Outline

Can Perioperative β-blockers Prevent Intermediate or Long-term Cardiovascular Outcomes

Before considering the intermediate and long-term impact of administering a β-blocker around the time of noncardiac surgery, it is relevant to determine whether a β-blocker can attenuate the perioperative stress response. A meta-analysis of high quality β-blocker randomized controlled trials (RCTs) among patients undergoing noncardiac surgery demonstrated at 30-day follow-up a lower rate of myocardial ischemia among patients assigned a β-blocker (43 of 1,059 patients) compared to control (76 of 1,059 patients, odds ratio 0.42, 95% CI 0.27–0.65, I2 20%), and a lower rate of nonfatal MI among patients assigned a β-blocker (174 of 5,610 patients) compared to control (240 of 5,426 patients, odds ratio 0.72, 95% CI 0.59-0.87, I2 0%).12
Table 1
Table 1
Image Tools
Five trials have reported whether the favorable perioperative effects of a β-blocker translate into intermediate or long-term cardiovascular benefits (table 1).13–17 Only one small trial (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study [DECREASE]) with few events (112 patients, with 41 patients experiencing the primary outcome) and methodological limitations (unblinded and recruitment was stopped early for an unexpected very large treatment effect)18 demonstrated a statistically significant long-term benefit with β-blocker therapy.14 Unlike all the other trials, patients in this trial continued the study drug during the long-term follow-up14; therefore, DECREASE addresses a different question than the other trials that evaluated the intermediate or long-term effects of a β-blocker only given around the time of surgery.
The largest trial (Diabetic Postoperative Mortality and Morbidity [DIPOM], 921 patients with 192 patients experiencing the primary outcome) demonstrated no effect on major cardiovascular outcomes at 18 months of follow-up. Although some authors have suggested that the difference in results of the β-blocker trials is the result of variations in the dosing (i.e., high dose vs. low dose), the current evidence does not support this perspective (table 1); it is more likely that the differences relate to chance and methodological quality (i.e., the high-quality trials demonstrate a consistent signal).
Although the current trials do not provide encouraging evidence that a perioperative β-blocker affects intermediate or long-term cardiovascular outcomes, there is still a limited amount of data. The PeriOperative ISchemic Evaluation (POISE) Trial (perioperative extended-release metoprolol succinate with a target dose of 50% of the maximum daily therapeutic dose vs. placebo) included 8,351 patients and will report the 1-yr follow-up data next year; 22 countries have completed their direct patient follow-up, and Canada will complete its 1-yr follow-up through its national databases in 2010.19 If POISE demonstrates a benefit from a perioperative β-blocker at 1 yr, clinicians and patients will have to balance this benefit against the 30-day excess of death and stroke with a β-blocker, as demonstrated in POISE and the high-quality RCTs.12,20
The prior perioperative β-blocker discussion, except for a few patients in the trial by Mangano et al., relates to patients who were not taking chronic β-blocker therapy before surgery. Therefore, these trials do not inform the intermediate or long-term effects of continuing, withholding, or titrating β-blockers around the time of noncardiac surgery among patients who have a history of taking a β-blocker chronically. Potentially relevant issues to the short, intermediate, and long-term effects include the following: the potential exacerbation of cardiac ischemia that may occur from stopping a β-blocker acutely before a patient undergoes surgery, and the β-blocker dose that is safe in the nonoperative setting may still exacerbate clinically significant hypotension after surgery and result in the negative consequences demonstrated in POISE.20 Until a large high-quality trial is undertaken to directly inform this issue, physicians will have to use indirect evidence to individualize the perioperative management of each patient who is chronically on a β-blocker.
Back to Top | Article Outline

Can Perioperative α2 Agonists Prevent Intermediate and Long-term Cardiovascular Outcomes

RCT evidence suggests that α2 agonists can attenuate the perioperative stress response (e.g., reduce perioperative myocardial ischemia).21,22 Wallace et al. undertook an RCT evaluating the effect of 4 days of perioperative clonidine in patients undergoing noncardiac surgery.23 Clonidine demonstrated an absolute risk reduction of 5.4% for mortality at 30 days (total of 5 deaths, P = 0.048) and an absolute risk reduction of 14% for mortality at 2 yr (total of 38 deaths, P = 0.035). These encouraging but limited data (Wallace is the only clonidine trial that followed patients beyond 30 days) highlight the need for further RCTs to examine whether perioperative clonidine reduces long-term mortality.
Back to Top | Article Outline

Conclusion

Perioperative cardiovascular events appear to affect intermediate and long-term cardiovascular outcomes. The current β-blocker evidence is not encouraging, but we will have more data in 2010. Although the clonidine evidence is encouraging, there is a need for confirmatory trials. Considering that globally 200 million adults undergo noncardiac surgery annually highlights why there is an urgent need for large high-quality RCTs to establish ways to ensure that patients obtain the benefits of their noncardiac surgery without suffering a major cardiovascular outcome that compromises their quality or duration of life in the short, intermediate, or long-term.
P. J. Devereaux, M.D., Ph.D.
Departments of Clinical Epidemiology and Biostatistics and Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. philipj@mcmaster.ca
Back to Top | Article Outline

References

1. Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, Miller D, Mangano DT: Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology 1998; 88:7–17

2. Pasternack PF, Grossi EA, Baumann FG, Riles TS, Lamparello PJ, Giangola G, Yu AY, Mintzer R, Imparato AM: Silent myocardial ischemia monitoring predicts late as well as perioperative cardiac events in patients undergoing vascular surgery. J Vasc Surg 1992; 16:171–9; discussion 179–80

3. Mangano DT, Browner WS, Hollenberg M, Li J, Tateo IM: Long-term cardiac prognosis following noncardiac surgery. The Study of Perioperative Ischemia Research Group. JAMA 1992; 268:233–9

4. Kim LJ, Martinez EA, Faraday N, Dorman T, Fleisher LA, Perler BA, Williams GM, Chan D, Pronovost PJ: Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 2002; 106:2366–71

5. Filipovic M, Jeger R, Probst C, Girard T, Pfisterer M, Gurke L, Skarvan K, Seeberger MD: Heart rate variability and cardiac troponin I are incremental and independent predictors of one-year all-cause mortality after major noncardiac surgery in patients at risk of coronary artery disease. J Am Coll Cardiol 2003; 42:1767–76

6. Oscarsson A, Eintrei C, Anskar S, Engdahl O, Fagerstrom L, Blomqvist P, Fredriksson M, Swahn E: Troponin T-values provide long-term prognosis in elderly patients undergoing non-cardiac surgery. Acta Anaesthesiol Scand 2004; 48:1071–9

7. Ausset S, Auroy Y, Lambert E, Vest P, Plotton C, Rigal S, Lenoir B, Benhamou D: Cardiac troponin I release after hip surgery correlates with poor long-term cardiac outcome. Eur J Anaesthesiol 2008; 25:158–64

8. Chong CP, Lam QT, Ryan JE, Sinnappu RN, Lim WK: Incidence of post-operative troponin I rises and 1-year mortality after emergency orthopaedic surgery in older patients. Age Ageing 2009; 38:168–74

9. Landesberg G, Shatz V, Akopnik I, Wolf YG, Mayer M, Berlatzky Y, Weissman C, Mosseri M: Association of cardiac troponin,CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery. J Am Coll Cardiol 2003; 42:1547–54

10. Kertai MD, Boersma E, Klein J, Van Urk H, Bax JJ, Poldermans D: Long-term prognostic value of asymptomatic cardiac troponin T elevations in patients after major vascular surgery. Eur J Vasc Endovasc Surg 2004; 28:59–66

11. Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ: Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg 2005; 242:326–41; discussion 341–3

12. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH: Perioperative beta blockers in patients having non-cardiac surgery: A meta-analysis. Lancet 2008; 372:1962–76

13. Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335:1713–20

14. Poldermans D, Boersma E, Bax JJ, Thomson IR, Paelinck B, van de Ven LL, Scheffer MG, Trocino G, Vigna C, Baars HF, van Urk H, Roelandt JR: Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001; 22:1353–8

15. Juul AB, Wetterslev J, Gluud C, Kofoed-Enevoldsen A, Jensen G, Callesen T, Norgaard P, Fruergaard K, Bestle M, Vedelsdal R, Miran A, Jacobsen J, Roed J, Mortensen MB, Jorgensen L, Jorgensen J, Rovsing ML, Petersen PL, Pott F, Haas M, Albret R, Nielsen LL, Johansson G, Stjernholm P, Molgaard Y, Foss NB, Elkjaer J, Dehlie B, Boysen K, Zaric D, Munksgaard A, Madsen JB, Oberg B, Khanykin B, Blemmer T, Yndgaard S, Perko G, Wang LP, Winkel P, Hilden J, Jensen P, Salas N: Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: Randomised placebo controlled, blinded multicentre trial. BMJ 2006; 332:1482

16. Yang H, Raymer K, Butler R, Parlow J, Roberts R: The effects of perioperative beta-blockade: Results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J 2006; 152:983–90

17. Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, Hersberger M, Kalin G, Furrer L, Hofer C, Blumenthal S, Muller A, Zollinger A, Spahn DR, Borgeat A: Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: A double-blinded, placebo-controlled, multicenter trial with 1-year follow-up. Anesthesiology 2007; 107:33–44

18. Devereaux PJ, Yusuf S, Yang H, Choi PT, Guyatt GH: Are the recommendations to use perioperative beta-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence? Cmaj 2004; 171:245–7

19. Devereaux PJ, Yang H, Guyatt GH, Leslie K, Villar JC, Monteri VM, Choi P, Giles JW, Yusuf S: Rationale, design, and organization of the PeriOperative ISchemic Evaluation (POISE) trial: A randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery. Am Heart J 2006; 152:223–30

20. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P: Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): A randomised controlled trial. Lancet 2008; 371:1839–47

21. Nishina K, Mikawa K, Uesugi T, Obara H, Maekawa M, Kamae I, Nishi N: Efficacy of clonidine for prevention of perioperative myocardial ischemia: A critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96:323–9

22. Wijeysundera DN, Naik JS, Beattie WS: Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: A meta-analysis. Am J Med 2003; 114:742–52

23. Wallace AW, Galindez D, Salahieh A, Layug EL, Lazo EA, Haratonik KA, Boisvert DM, Kardatzke D: Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology 2004; 101:284–93

Cited By:

This article has been cited 6 time(s).

Annales Francaises D Anesthesie Et De Reanimation
Betablockers and noncardiac surgery: Time to revisit strategies?
Marret, E; Piriou, V
Annales Francaises D Anesthesie Et De Reanimation, 28(9): 807-808.
10.1016/j.annfar.2009.07.081
CrossRef
Anaesthesia
The pathophysiology of peri-operative myocardial infarction
Biccard, BM; Rodseth, RN
Anaesthesia, 65(7): 733-741.
10.1111/j.1365-2044.2010.06338.x
CrossRef
Anesthesiology
The Registry Imperative
Hannenberg, AA; Warner, MA
Anesthesiology, 111(4): 687-689.
10.1097/ALN.0b013e3181b786f3
PDF (387) | CrossRef
Anesthesiology
Standard Care, Standards for Care, or Standard of Care?
Butterworth, JF; Rathmell, JP
Anesthesiology, 112(2): 277-278.
10.1097/ALN.0b013e3181ca840d
PDF (104) | CrossRef
Anesthesiology
Perioperative Comparative Effectiveness Research: An Opportunity Calling
Kheterpal, S
Anesthesiology, 111(6): 1180-1182.
10.1097/ALN.0b013e3181bfabb4
PDF (438) | CrossRef
Current Opinion in Anesthesiology
Outcomes in perioperative care
Mantz, J; Dahmani, S; Paugam-Burtz, C
Current Opinion in Anesthesiology, 23(2): 201-208.
10.1097/ACO.0b013e328336aeef
PDF (5786) | CrossRef
Back to Top | Article Outline

© 2009 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share