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.
Highlights
Some 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
The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (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
Postoperative cognitive dysfunction (POCD) refers to dysfunction in postoperative cognitive performance relative to presurgical performance; the exact threshold delineating when cognitive decline can be classified as POCD varies considerably within the literature [4]
Summary
A single-centre, randomised, double-blind, placebocontrolled clinical trial. A total of 370 participants are randomised into either a placebo or treatment (NAC) group in a 1:1 ratio. An examination of the available research utilising the CBB provides an estimated effect size of cognitive change in comparison to healthy controls, MCI, and Alzheimer’s disease participants. Assuming an alpha level of 0.05, power of 80 %, and a pre and postsurgical score correlation of 0.5, a sample size of 370 participants will have 80 % power to detect a minimum absolute effect size of 0.255 using an analysis of covariance (ANCOVA) model This sample size includes approximately equal representation across stratification by age and surgery type for intervention. By treating the presence of POCD in a participant as an outcome level, it will be possible to examine the relative contributions of each independent variable to POCD (e.g. varying treatment effects for differing levels of demographics) This approach can be expanded to further examine other participant outcomes, such as the presence of delirium, mood dysfunction, or a significant change in quality of life. If data appears to be missing in a way that is not random (Missing Not At Random, MNAR), this data can be examined for potential biases or patterns statistically, and missing values can be estimated using monotonistic methods
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