The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial

Abstract

BackgroundSome degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting.Methods and designThis is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress.DiscussionThe PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial.Trial registrationThe PANACEA trial has been registered with the Therapeutic Goods Administration, and the Australian New Zealand Clinical Trials Registry: ACTRN12614000411640; registered on 15 April 2014. Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1529-4) contains supplementary material, which is available to authorized users.

Postoperative cognitive dysfunction and dementia: what we need to know and do

“…92 Another area of ongoing research is the use of antioxidants, and a randomized controlled trial using N-acetylcysteine is underway. 93 With such a limited evidence base, one strategy for managing patients at risk or concerned about developing POCD would be to extrapolate from efforts to reduce the incidence of postoperative delirium. Guidelines 2 94 already exist for this, and would be expected to yield some benefit for the earlier stages of POCD.…”

Investigating the Usability and Acute Effects of a Bedside Video Console to Prefrontal Cortical Activity Alterations: A Preclinical Study in Healthy Elderly

“…This seeming discrepancy might be explained due to the ability of the aging brain to compensate for structural atrophy by amending recruitment patterns that support functioning and maintain cognitive functions (Deary et al, 2009 ; Grady, 2012 ; Eggenberger et al, 2016 ). Deterioration of the mental learning processes may affect a variety of cognitive domains, such as psycho-motor skills, (working-) memory, and executive functions (Skvarc et al, 2016 ). Executive functions are “higher-order aspects of cognition that are strongly dependent upon the integrity of the prefrontal cortex” (Lipnicki et al, 2009 ).…”

“…Furthermore, cognitive decline may appear after surgery in 25% of the elderly population. Oxidative stress and adjacent neuro-inflammation of the brain are associated with cognitive decline, e.g., in post-operative delirium (Skvarc et al, 2016 ), however, the mechanisms of cognitive decline following surgery cannot be explained exactly for all elderly. The burden of post-operative cognitive deterioration is arduous, given the increased length of hospital sojourning, including prolonged stay on intensive care unit(s), and reduced functional performance; factors that not only have strong effects on the subjective way patients perceive the quality of their life, but also have an impact on the healthcare systems by increasing costs of care (Cropsey et al, 2015 ).…”

Cognitive Dysfunction after Surgery: An Emergent Problem

“…Skvarc et al undertook a promising study in order to evaluate the effect of orally supplemented N-Acetyl cysteine on the day before and four days after surgery. The drug suppresses or reduces the cognitive impairment [40].…”