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Biomarkers ID’d for Anesthesia-Related Neural Damage

Biomarkers ID’d for Anesthesia-Related Neural Damage

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Action Points

  • Plasma levels of neurofilament light (NFL) and tau, both biomarkers of neuronal injury, increased after general anesthesia and surgery in 30 older patients, with NFL levels continuing to rise 48 hours after surgery, but tau peaking at 6 hours.
  • Note that while anesthesia and surgery have been considered to act by a reversible mechanism that does not injure the brain, the increases in plasma NFL and tau suggest that neuronal injury has taken place.

Increasing levels of biomarkers for neuronal injury were seen in surgical patients receiving general anesthesia, a team of international researchers found, providing objective support for what’s been dubbed “postoperative neurocognitive disorder.”

In 30 patients whose average age was 69 — most of whom were undergoing joint arthroplasty — both plasma neurofilament light (NFL) and tau increased after anesthesia and surgery. NFL levels continued to increase 48 hours after surgery, but tau peaked at 6 hours, reported Brendan Silbert, MB, BS, of St. Vincent’s Health in Fitzroy, Australia, and co-authors.

“For more than 170 years, anesthesia and surgery have been considered to act by a reversible mechanism that does not injure the brain,” the team wrote in JAMA Neurology. “The increases in plasma NFL and tau identified in this study indicate that this may not be the case. The measurement of an increase in neurological biomarkers after anesthesia and surgery suggests a neuronal injury has taken place.”

NFL, a marker of central nervous system axonal injury, has been shown to predict the severity of neuronal injury in multiple sclerosis, Alzheimer’s disease, and other disorders. Increased levels of tau also indicate neuronal damage.

The findings are the combined results of the Cerebrospinal Fluid and Preclinical Alzheimer Cognitive Trajectory (CAPACITY) and the Assessment and Review of Cognition, Alzheimer Disease, and Inflammation in Elderly Patients after Hospital Intervention (ARCADIAN) studies. The research took place from January 2014 to August 2015.

ARCADIAN (n= 17) and CAPACITY (n=13) also included follow-up cognitive testing after surgery. That analysis has not been completed and is not part of the current report.

Both studies recruited patients age 60 and older who were undergoing surgery with general anesthesia of either a volatile agent (sevoflurane or desflurane) or an intravenous anesthesia (propofol), chosen by the anesthesiologist.

Hip and knee arthroplasty patients usually received general anesthesia and spinal anesthesia (bupivacaine). Knee arthroplasty patients also may have received femoral nerve or sciatic nerve blocks (ropivicaine).

The average age of patients in the studies was 69.1, and 59% were female. Of the 30 participants, 23 had major lower limb surgery with general anesthesia and spinal and/or perineural blockade (17 hip arthroplasty, five knee arthroplasty, and one vascular surgery). The remaining seven patients had major cavity surgery (six had cardiac surgery, and one had esophagogastrectomy with an epidural).

In both studies, the researchers sampled the patients’ blood before surgery and at 6, 24, and 48 hours after surgical incision.

At each measurement from baseline, plasma NFL levels increased, from a combined baseline mean of 22.3 pg/mL to a maximal combined mean of 35.1 pg/mL 48 hours after surgery — an increase of 67% (95% CI 45%-89%; P<0.001).

Plasma tau levels also increased from baseline, from a combined baseline mean of 3.1 pg/mL to a maximal combined mean of 10.8 pg/mL at 6 hours post-surgery, representing a peak increase of 257% (95% CI 154%-361%; P<0.001). Tau levels began to decline after 6 hours, but remained elevated after 48 hours.

These responses occurred regardless of the anesthetic technique or type of surgery.

The difference in time course for tau — which had a rapid rise that peaked at 6 hours — and NFL — which increased slowly but continuously through 48 hours — is unclear, the researchers noted.

“It is likely owing to differential mechanisms of release from damaged neurons, different routes of clearance from the brain to the blood (via either cerebrospinal fluid or the lymphatic system), different metabolism, or different degradation in the bloodstream, or combinations thereof.”

These incremental time courses closely match the results of other studies of patients with acute brain injuries, they added.

Writing in an accompanying editorial, Mervyn Maze, MB, ChB, chair of Anesthesia and Perioperative Care at the University of California San Francisco, and colleagues said that with this report, Silbert et al “have begun to bring some order to the imprecise field of postoperative neurocognitive disorder.”

“The clinical manifestations of postoperative cognitive decline run the gamut from delirium (there are listed criteria in the Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] for this form of ‘acute brain failure’) to a more indolent, diagnostically imprecise form of cognitive disorder,” the editorial stated. “Both ends of the spectrum can result in long-term consequences, such as dementia and increased mortality.”

Silbert and colleagues explained that while anesthesia historically has been seen as the main cause of cognitive decline, surgery itself may be part of the problem. The two often accompany each other, making it difficult to separate surgical inflammation and stress from the effects of anesthesia.

These findings come at a time when there is concern about the effects of anesthesia and surgery in both elderly and very young patients, the team added. In December 2016, the FDA issued a Drug Safety Communication warning that general anesthesia and sedation drugs may affect brain development of children in utero and those under the age of 3.

“We strongly encourage others to repeat these assays to confirm or refute these findings,” the researchers wrote. “Additionally, and more urgently, these neurological biomarkers should be assessed in children in order to help resolve the current controversy surrounding neurological outcomes in infants.”

The research was supported by the National Health and Medical Research Council of Australia, the Australian and New Zealand College of Anesthetists, the Swedish Research Council Formas, the European Research Council, the Swedish State Support for Clinical Research, the Swedish Alzheimer’s Foundation, the Swedish Brain Foundation, and LUA/ALF-medel Vastra Gotalandsregionen.

Silbert and co-authors reported having no conflicts of interest.

Editorialist Maze is co-founder of a company, NeuroproteXeon, which intends to develop a drug-device combination to treat acute ongoing neurological injury; no other co-authors disclosed potential conflicts.


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