The relationship between inflammatory biomarkers and outcomes is not well researched in patients undergoing high-risk, noncardiac procedures. Recent research found that a variety of biomarkers produce a robust response to noncardiac surgery. In particular, they found that both suppression of tumorigenicity 2 (ST2) and interleukin-8 (IL-8) showed discriminatory ability to predict complications in these patients.
“The practice of anesthesia has become increasingly safe, which has allowed us to perform higher risk procedures on higher risk patients,” said Raegan Cleven, MD, a resident at the University of Manitoba, in Winnipeg. “Although many scoring systems have been developed to determine who is at risk at a population level, we still don’t know which individuals are going to develop postoperative complications.
“Previous work at our institution suggested that cytokine levels might be able to predict postoperative complications in patients undergoing elective open AAA [abdominal aortic aneurysm] repair,” she said. “So we wanted to see if inflammatory biomarkers have the ability to predict postoperative complications in high-risk, noncardiac surgical patients.” As Dr. Cleven noted, the ability to identify those patients at highest risk might ultimately allow practitioners to intervene in the early postoperative period to prevent or mitigate damage from possible complications.
A Small Observational Study
The investigators enrolled 153 patients into the prospective observational study, 131 of whom completed the trial. High-risk patients were defined as those older than 60 years of age, with at least one medical comorbidity. High-risk procedures included:
- AAA repair
- major hepatic resection
- colonic resection
- pulmonary resection
Blood samples were drawn preoperatively and again 24 hours after surgery. A variety of cytokines were measured, including:
- Acute-Phase Proteins
- C-reactive protein
- Proinflammatory Biomarkers
- Macrophage chemotactic protein-1
- Tumor necrosis factor-alpha (TNF-alpha)
- Anti-Inflammatory Biomarkers
- TNF receptor type II (TNF-RII)
“There’s a mix here with respect to acute-phase proteins, proinflammatory markers and anti-inflammatory markers,” Dr. Cleven said.
Patients’ charts were reviewed 30 days after surgery to assess a composite outcome, including arrhythmia, myocardial injury/infarction (MI), congestive heart failure, sepsis/septic shock, acute kidney injury, pneumonia, respiratory failure requiring mechanical ventilation, stroke/transient ischemic attack and death. “And there were no interventions done by the study team in the patients’ preoperative, intraoperative, postoperative care,” she added.
As Dr. Cleven reported at the 2017 annual meeting of the Canadian Anesthesiologists’ Society (abstract 285153), the postoperative levels of all biomarkers increased significantly after surgery, with the exceptions of TNF-alpha and TNF-RII. “This suggested that all the markers we looked at—with the exception of these two—actually had a robust response to surgery,” Dr. Cleven said.
Of note, the postoperative rise in both ST2 and IL-8 was significantly higher in patients who suffered complications than in their counterparts who remained free of complications. By comparison, there was no significant increase in any of the anti-inflammatory biomarkers in patients who suffered complications. The area under the receiver operating characteristic curve for ST2 and IL-8 was 0.67 (95% CI, 0.57-0.77; P<0.01) and 0.65 (95% CI, 0.53-0.77; P=0.02), respectively.
“We know that surgery produces an intense inflammatory response, as confirmed by our findings,” she explained. “Probably one of the more interesting findings of our study is that we didn’t see any significant increase in any of the inflammatory biomarkers in patients who developed a complication, suggesting that there may be factors at play that might prevent this protective response in these patients.”
ST2 and IL-8 Are Culprits
The study is certainly not the first to find an association between ST2, IL-8 and postoperative complications. “We know, based on studies that have been done in the past, that ST2 has been a significant predictor of mortality due to cardiovascular disease, and might be able to predict outcomes in patients suffering an acute MI,” Dr. Cleven said. “We also know that IL-8 has been implicated in the development of ARDS [acute respiratory distress syndrome] and multiorgan failure in trauma patients, and has also been shown to be predictive in postoperative atrial fibrillation in cardiac surgery,” she added.
Despite these results, the researchers recognized the need for more work. “Although we looked at a composite outcome of complications, it would be interesting to look at each one more closely in this population, as this can have potential for clinical interventions and potential postoperative monitoring in these patients,” she said.
Harry B. Burke, MD, PhD, professor of medicine at Uniformed Services University of the Health Sciences, in Bethesda, Md., also saw the need for continued research, given the study’s limitations of small numbers and heterogeneity of procedures and clinical events. Nevertheless, Dr. Burke did not agree that patients who develop complications may have a dysregulated immune response to surgery. “An alternative explanation for the study findings is that the elevation of most of the biomarkers after surgery reduced their ability to predict postoperative clinical events,” he said.
“Another explanation,” Dr. Burke added, “is that some of the biomarkers were predictive for some of the surgeries and/or some of the clinical outcomes, but that the number of these surgeries and/or outcomes was too small to have a major impact on the results.”