Spinal Anesthesia with Targeted Sedation based on Bispectral Index Values Compared with General Anesthesia with Masked Bispectral Index Values to Reduce Delirium: The SHARP Randomized Controlled Trial.

BACKGROUND: Reducing depth of anesthesia and anesthetic exposure may help prevent delirium, but trials have been conflicting. Most studies were conducted under general anesthesia or in cognitively impaired patients. It is unclear whether reducing depth of anesthesia beyond levels consistent with general anesthesia reduces delirium in cognitively intact patients. The authors' objective was to determine whether a bundled approach to reduce anesthetic agent exposure as determined by Bispectral Index (BIS) values (spinal anesthesia with targeted sedation based on BIS values) compared with general anesthesia (masked BIS) reduces delirium. METHODS: Important eligibility criteria for this parallel-arm randomized trial were patients 65 yr or greater undergoing lumbar spine fusion. The intervention group received spinal anesthesia with targeted sedation to BIS greater than 60 to 70. The control group received general anesthesia (masked BIS). The primary outcome was delirium using the Confusion Assessment Method daily through postoperative day 3, with blinded assessment. RESULTS: The median age of 217 patients in the analysis was 72 (interquartile range, 69 to 77). The median BIS value in the spinal anesthesia with targeted sedation based on BIS values group was 62 (interquartile range, 53 to 70) and in the general anesthesia with masked BIS values group was 45 (interquartile range, 41 to 50; P < 0.001). Incident delirium was not different in the spinal anesthesia with targeted sedation based on BIS values group (25.2% [28 of 111] vs. the general anesthesia with masked BIS values group (18.9% [20 of 106]; P = 0.259; relative risk, 1.22 [95% CI, 0.85 to 1.76]). In prespecified subgroup analyses, the effect of anesthetic strategy differed according to the Mini-Mental State Examination, but not the Charlson Comorbidity Index or age. Two strokes occurred among patients receiving spinal anesthesia and one death among patients receiving general anesthesia. CONCLUSIONS: Spinal anesthesia with targeted sedation based on BIS values compared with general anesthesia with masked BIS values did not reduce delirium after lumbar fusion.

Shaping anesthetic techniques to reduce post-operative delirium (SHARP) study: a protocol for a prospective pragmatic randomized controlled trial to evaluate spinal anesthesia with targeted sedation compared with general anesthesia in older adults undergoing lumbar spine fusion surgery.

BACKGROUND: Postoperative delirium is common in older adults, especially in those patients undergoing spine surgery, in whom it is estimated to occur in > 30% of patients. Although previously thought to be transient, it is now recognized that delirium is associated with both short- and long-term complications. Optimizing the depth of anesthesia may represent a modifiable strategy for delirium prevention. However, previous studies have generally not focused on reducing the depth of anesthesia beyond levels consistent with general anesthesia. Additionally, the results of prior studies have been conflicting. The primary aim of this study is to determine whether reduced depth of anesthesia using spinal anesthesia reduces the incidence of delirium after lumbar fusion surgery compared with general anesthesia. METHODS: This single-center randomized controlled trial is enrolling 218 older adults undergoing lumbar fusion surgery. Patients are randomized to reduced depth of anesthesia in the context of spinal anesthesia with targeted sedation using processed electroencephalogram monitoring versus general anesthesia without processed electroencephalogram monitoring. All patients are evaluated for delirium using the Confusion Assessment Method for 3 days after surgery or until discharge and undergo assessments of cognition, function, health-related quality of life, and pain at 3- and 12-months after surgery. The primary outcome is any occurrence of delirium. The main secondary outcome is change in the Mini-Mental Status Examination (or telephone equivalent) at 3-months after surgery. DISCUSSION: Delirium is an important complication after surgery in older adults. The results of this study will examine whether reduced depth of anesthesia using spinal anesthesia with targeted depth of sedation represents a modifiable intervention to reduce the incidence of delirium and other long-term outcomes. The results of this study will be presented at national meetings and published in peer-reviewed journals with the goal of improving perioperative outcomes for older adults. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03133845. This study was submitted to Clinicaltrials.gov on October 23, 2015; however, it was not formally registered until April 28, 2017 due to formatting requirements from the registry, so the formal registration is retrospective.

Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation.

The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1ß by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1ß, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1ß in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.