Among inpatients aged 45 years or older having noncardiac surgery, 9% will experience myocardial injury within the 30 days after the procedure. About 80% of these injuries are clinically silent, detected only by troponin elevation. Mortality, however, is nearly identical for symptomatic and asymptomatic troponin elevations. Within 30 days of surgery, 10% of patients with elevated troponin concentrations will die, making myocardial injury the leading cause of postoperative death and the third leading cause of death overall in the United States.
“When mean arterial pressure [MAP] decreases below a threshold of about 65 mm Hg, the risk of myocardial injury starts to increase,” said Daniel I. Sessler, MD, the Michael Cudahy Professor and Chair of the Department of Outcomes Research at the Cleveland Clinic. “By the time MAP reaches 55 mm Hg, it takes just one minute to significantly increase the risk of death. The deeper and longer the hypotension, the greater the risk. These observations are consistent with the theory that supply/demand mismatch contributes to postoperative myocardial injury—although it is not a major cause of nonoperative myocardial infarctions (MIs).”
“The combination of patient characteristics, anesthetic drugs and intraoperative bleeding … [contributes] to hypotension and resulting perioperative myocardial infarction,” P. J. Devereaux, MD, PhD, told Anesthesiology News. “Some MIs that occur within the perioperative setting are due to [intraoperative] supply/demand mismatch,” he said. Dr. Devereaux is a university scholar and professor in the Departments of Clinical Epidemiology & Biostatistics and Cardiology at McMaster University Health Sciences Centre, in Hamilton, Ontario.
“Interestingly,” Andrea Kurz, MD, noted, “few myocardial infarctions occur intraoperatively. They happen during hospitalization, most within two to three days after surgery,” she said. “It might be that intraoperative hypotension causes myocardial injury that just doesn’t become apparent until one to three days after surgery. Or it might be that patients who become hypotensive during surgery also become hypotensive after surgery, and that is when the injury occurs.” Dr. Kurz is professor and chair of the Department of General Anesthesiology at the Cleveland Clinic, where she is also vice chair of the Department of Outcomes Research.
Evidence: The Published Studies
“In a series of huge trials,” Dr. Sessler explained, “investigators from the Population Health Research Institute, the Australian and New Zealand College of Anaesthetists Trials Group, and the Outcomes Research Consortium have shown that perioperative myocardial injury is common, usually clinically silent, deadly and hard to prevent. Hypotension appears to contribute, and several studies show strong associations between intraoperative hypotension and postoperative mortality,” he said. (For more on the Outcomes Research Consortium, see page 26.)
“One in 10 patients with postoperative troponin elevations will be dead within a month,” warned Dr. Sessler. “If the 30 days after surgery were a disease, it would be the third leading cause of death in the United States. And within that period, myocardial injury is the leading cause of postoperative death.”
“Although low mean arterial pressure is strongly associated with mortality, intraoperative blood pressure variability is only mildly associated with mortality after noncardiac surgery,” concluded Edward Mascha, PhD, Dr. Sessler and others, in a review of data on 104,401 patients published in Anesthesiology(2015;123:79-91). The data were extracted from noncardiac surgery cases performed at the Cleveland Clinic.
“In confounder-adjusted models, the authors evaluated the associations between 30-day mortality and both time-weighted average intraoperative mean arterial pressure (TWA-MAP) and measures of intraoperative MAP variability—including the generalized average real variability of MAP (ARV-MAP) and the standard deviation (SD) of MAP (SD-MAP),” according to the article.
In terms of mean ± SD, TWA-MAP was 84±10 mm Hg and ARV-MAP was 2.5±1.3 mm Hg per minute in these cases. TWA-MAP was strongly related to 30-day mortality, which more than tripled as TWA-MAP decreased from 80 to 50 mm Hg. ARV-MAP was only marginally related to 30-day mortality after adjusting for TWA-MAP (P=0.033). Odds of 30-day mortality decreased as five-level categorized ARV-MAP increased (odds ratio, 0.92; 0.87-0.99 for one category increase; P=0.015). Cumulative duration of MAP less than 50, 55, 60, 70 and 80 mm Hg were all associated with increased odds of 30-day mortality (P<0.001 for all), the study found.
The POISE-2 Trial
Drs. Devereaux, Sessler and Kurz and their collaborators conducted a 2×2 factorial design trial (N=10,100) to examine the relationship between perioperative aspirin and perioperative clonidine together with a composite of death or nonfatal MI within a period of 30 postoperative days in patients undergoing noncardiac surgery.
For the aspirin portion of the trial, patients were stratified according to whether they were taking aspirin before the study began; the initiation stratum had 5,628 patients and the continuation stratum had 4,382 patients. Following the first stratification, patients started taking aspirin (200 mg daily) or placebo just before surgery and continued aspirin (100 mg daily for 30 days) in the initiation stratum and for seven days in the continuation stratum.
The primary outcome occurred in 351 of 4,998 patients (7.0%) in the aspirin group and in 355 of 5,012 patients (7.1%) in the placebo group (hazard ratio [HR] in the aspirin group, 0.99; 95% CI, 0.86-1.15; P=0.92), the study authors wrote. “Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding,” they concluded. The study was published in The New England Journal of Medicine(2014;370:1494-1503).
“The significance of the aspirin portion of the POISE-2 trial is that it doesn’t reduce the risk of perioperative MI,” Dr. Kurz said. “But it significantly increased the risk and extent of bleeding intraoperatively. It should not be used routinely in patients having noncardiac surgery as part of an effort to prevent postoperative myocardial infarction.”
In the clonidine portion of the trial, clonidine, compared with placebo, did not reduce the number of primary outcome events (367 and 339, respectively; HR with clonidine, 1.08; 95% CI, 0.93-1.26; P=0.29). MI occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (HR, 1.11; 95% CI, 0.95-1.30; P=0.18), according to the authors. “Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest.”
“Clonidine did not prevent MI, in contrast to β-blockers,” Dr. Devereaux toldAnesthesiology News. “The Achilles heel of trying to control the sympathetic stress response is hypotension. We theorized that clonidine would mitigate the complications associated with β-blockers while still attenuating the surgical stress response, but we didn’t get that result. There is a benefit to controlling the stress response; the issue is how to do it safely.”
The VISION Cohort Study
The VISION (Vascular Events In Noncardiac Surgery Patients Cohort Evaluation) study, which had Dr. Devereaux as first author and Drs. Sessler and Kurz as co-authors, was a prospective international cohort study that enrolled patients who underwent noncardiac surgery from 2006 to 2011. All patients (N=15,133) were aged 45 years or older and required at least one overnight hospital stay.
The VISION study was designed to determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first three days after noncardiac surgery and 30-day mortality. “Patients’ TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables,” the authors wrote.
They concluded, “Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality. Overall, 10% of patients with troponin elevations were dead within a month.” The initial VISION paper was published in Journal of the American Medical Association(2012;307:2295-2304).
What It Means: Beware Hypotension
“All these studies suggest that hypotension is likely a bad actor,” Dr. Sessler suggested. “The threshold for injury seems to be an intraoperative mean arterial pressure less than about 65 mm Hg. The worse the hypotension, the worse the outcome.” But Dr. Sessler also cautione d that “there are not currently randomized data showing that preventing hypotension prevents postoperative myocardial injury. We do know that β-blockers, aspirin, clonidine and avoiding nitrous oxide do not safely prevent infarctions. In the meantime, preventing hypotension seems a reasonable strategy for reducing the risk of myocardial injury, which is the leading cause of postoperative death.”