Ignite Creation Date:
2024-05-06 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 1:55 PM
Study NCT ID:
NCT04732000
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-11-22
First Post:
2021-01-26
Brief Title:
Oxidative Stress and Surgical Recovery
Sponsor:
Stanford University
Organization:
Stanford University
Study Overview
Official Title:
Oxidative Stress and Surgical Recovery
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Chronic pain functional impairment and slow rates of recovery are key issues for patients after surgery and trauma No preventative strategy in current use unequivocally modifies these rates and few novel approaches have been tested Furthermore persistent postsurgical pain is a major route to chronic opioid use opioid use disorder and regrettably opioid overdose Most strategies designed to limit chronic pain or enhance functional recovery after surgery are directed at modulating peripheral and central nervous system activity and do not strongly modify the underlying tissue pathophysiology or fundamental systemic responses Strategies limiting oxidative stress in the perioperative period on the other hand might limit tissue damage organ dysfunction and immune system activation
N-acetyl cysteine NAC is an antioxidant well-studied in the perioperative period it is very safe relatively inexpensive and widely available The central hypothesis is therefore that perioperative administration of NAC will reduce perioperative oxidative stress limit immune system activation and improve key indices of surgical recovery Although the planned work will not comprehensively address this hypothesis it will identify the most useful tools and help the researchers estimate the required sample sizes for more definitive externally funded efforts
N-acetyl cysteine NAC is an antioxidant well-studied in the perioperative period it is very safe relatively inexpensive and widely available The central hypothesis is therefore that perioperative administration of NAC will reduce perioperative oxidative stress limit immune system activation and improve key indices of surgical recovery Although the planned work will not comprehensively address this hypothesis it will identify the most useful tools and help the researchers estimate the required sample sizes for more definitive externally funded efforts
Detailed Description:
This is a randomized double-blind placebo controlled interventional pilot study in 20 patients undergoing first-time total hip arthroplasty THA for chronic osteoarthritis at Stanford Medicine The researchers will screen enroll and collect biologic and behavioral data from 20 participants as outlined in previous observational and interventional clinical studies undertaken in close collaboration with the Department of Orthopedic Surgery In particular standard operating procedures for screening recruiting laboratory assessments and clinical data collection are in place including eligibility screening via EPIC EHR ahead of patients preoperative visit coordinated recruitment and consenting during the pre-surgery visit including study- related laboratory work further preoperative assessments after the visit eg remote completion of questionnaires and direct import of results into REDCap and real-time tracking of the data collection and storage process eg including phoneemail reminders if data are missing
Repeated assessments of pain physical function and analgesic medication will be made before surgery daily on postoperative days 1-3 and then twice a week in post-op weeks 1 - 6 Delirium will be measured days 1-3 while in-hospital Additional data will include demographics age BMI sex race and ethnicity surgicalanesthesia data eg duration and medicalmedication history
Peripheral blood samples will be collected before surgery and 1hr and 24hr after surgery based on our prior study showing that monocyte activation including STAT3 CREB and NFkB signaling responses in CD14CD16- monocytes early after surgery strongly correlates with delayed pain resolution and functional impairment Exhaled breath samples will be collected intraoperatively prior to incision and at wound closure as well as at 1 and 24 hours after surgery
N-Acetylcysteine infusion A loading dose of 50 mgkg will be started as a 1-hour infusion before surgical incision and will be followed by a maintenance dose of 50 mgkg administered over 4 hours This is a standard dosing paradigm that is safe when used intraoperatively and rarely causes significant adverse effects mainly allergic reactions
Surgery and anesthesia Participants will undergo unilateral hip arthroplasty performed by three surgeons using the same approach The anesthetic and perioperative management of patients is standardized and follows ERAS-based recommendations
Measures Well-validated instruments will be used to assess pain pain interference and function of the affected and operated joint including the Western Ontario and McMaster Universities Osteoarthritis Index WOMAC adapted for patients undergoing lower extremity joint surgery the Brief Pain Inventory BPI and the Surgical Recovery Scale SRS Opioid consumption will be quantified as intravenous hydromorphone equivalents milligramday using widely accepted opioid conversion tables
Sample analysis Blood and plasma will be collected and processed for analysis with mass cytometry as previously described A 39-parameter human CyTOF antibody panel will be applied that will allow the simultaneous analysis of 1 all major immune cell phenotypes 2 endogenous intracellular signaling responses including the pSTAT3 pCREB and pNF-kB signal and 3 intracellular markers of reactive aldehydes ie 4-HNE and MDA signal
Breath samples will be analyzed for aldehydes including formaldehyde crotenaldehyde and benzaldehyde using mass spectroscopy in the laboratory of Dr Gross
Plasma samples will be analyzed for free MDA and 4- HNE in baseline 1 and 24-hour plasma samples in the laboratory of Dr Clark
Analysis and modeling of outcome data Self-reported outcomes will be analyzed using the validated models associated with each outcome to extract a quantified and normalized number associated with recovery The 60Htz actigraphy data will first be mined for patterns associated with daily activities eg step counts and intensity levels Next a baseline will be established using the data collected during and prior to surgery for each variable All variables will be normalized to this baseline to account for patient-specific effects Finally a multivariate linear model with days passed since surgery as the response variable will be used to model the entire actigraphy dataset The area under the respective recovery curve of each patient according to this model will be used as an objective recovery outcome In our preliminary studies data not shown this outcome has been found to be correlated with several aspects of the immune system
Analysis and modeling of CyTOF data The large number of data points millions of cells per patient and measured variables tens of signaling pathways in hundreds of cell types pose unique computational challenges that cannot be addressed using traditional bioinformatics tools The researchers will develop a Bayesian framework that will combine a priori knowledge of the immune system with state-of-the-art mass cytometry profiling to build a predictive model of innate and adaptive immune cell signaling responses for each of the recovery outcomes
Repeated assessments of pain physical function and analgesic medication will be made before surgery daily on postoperative days 1-3 and then twice a week in post-op weeks 1 - 6 Delirium will be measured days 1-3 while in-hospital Additional data will include demographics age BMI sex race and ethnicity surgicalanesthesia data eg duration and medicalmedication history
Peripheral blood samples will be collected before surgery and 1hr and 24hr after surgery based on our prior study showing that monocyte activation including STAT3 CREB and NFkB signaling responses in CD14CD16- monocytes early after surgery strongly correlates with delayed pain resolution and functional impairment Exhaled breath samples will be collected intraoperatively prior to incision and at wound closure as well as at 1 and 24 hours after surgery
N-Acetylcysteine infusion A loading dose of 50 mgkg will be started as a 1-hour infusion before surgical incision and will be followed by a maintenance dose of 50 mgkg administered over 4 hours This is a standard dosing paradigm that is safe when used intraoperatively and rarely causes significant adverse effects mainly allergic reactions
Surgery and anesthesia Participants will undergo unilateral hip arthroplasty performed by three surgeons using the same approach The anesthetic and perioperative management of patients is standardized and follows ERAS-based recommendations
Measures Well-validated instruments will be used to assess pain pain interference and function of the affected and operated joint including the Western Ontario and McMaster Universities Osteoarthritis Index WOMAC adapted for patients undergoing lower extremity joint surgery the Brief Pain Inventory BPI and the Surgical Recovery Scale SRS Opioid consumption will be quantified as intravenous hydromorphone equivalents milligramday using widely accepted opioid conversion tables
Sample analysis Blood and plasma will be collected and processed for analysis with mass cytometry as previously described A 39-parameter human CyTOF antibody panel will be applied that will allow the simultaneous analysis of 1 all major immune cell phenotypes 2 endogenous intracellular signaling responses including the pSTAT3 pCREB and pNF-kB signal and 3 intracellular markers of reactive aldehydes ie 4-HNE and MDA signal
Breath samples will be analyzed for aldehydes including formaldehyde crotenaldehyde and benzaldehyde using mass spectroscopy in the laboratory of Dr Gross
Plasma samples will be analyzed for free MDA and 4- HNE in baseline 1 and 24-hour plasma samples in the laboratory of Dr Clark
Analysis and modeling of outcome data Self-reported outcomes will be analyzed using the validated models associated with each outcome to extract a quantified and normalized number associated with recovery The 60Htz actigraphy data will first be mined for patterns associated with daily activities eg step counts and intensity levels Next a baseline will be established using the data collected during and prior to surgery for each variable All variables will be normalized to this baseline to account for patient-specific effects Finally a multivariate linear model with days passed since surgery as the response variable will be used to model the entire actigraphy dataset The area under the respective recovery curve of each patient according to this model will be used as an objective recovery outcome In our preliminary studies data not shown this outcome has been found to be correlated with several aspects of the immune system
Analysis and modeling of CyTOF data The large number of data points millions of cells per patient and measured variables tens of signaling pathways in hundreds of cell types pose unique computational challenges that cannot be addressed using traditional bioinformatics tools The researchers will develop a Bayesian framework that will combine a priori knowledge of the immune system with state-of-the-art mass cytometry profiling to build a predictive model of innate and adaptive immune cell signaling responses for each of the recovery outcomes
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None