Oxidative Stress and Surgical Recovery

NCT04732000 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 59401
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Surgical Recovery; Pain, Postoperative

Outcome Measures

Primary Outcomes (2)

• Phosphorylation of STAT-3 in MDSC (Myeloid-derived Suppressor Cells)

  STAT3 phosphorylation in MDSC cells is measured in all MDSC cells before (T0) and one day after surgery (T1) using mass cytometry. The median phosphorylation in this cell population is then determined for each time point. The change in phosphorylation is expressed as the arc sinh ratio of these two medians (ratio = arc sinh \[median pSTAT3-T1/median pSTAT3-T0\]).

  Measurements will be made in samples collected before and 24 hours after surgery.

• Brief Pain Inventory Pain Score

  The Brief Pain Inventory was used to measure pain and pain interference following surgery. BPI Pain Composite Score was derived from worst pain, least pain, average pain, and pain right now subscale scores. BPI Pain Interference Composite Score (representing how pain interferes with daily life) was derived from general activity, mood, walking ability, normal work, relationships with others, sleep, and enjoyment of life subscale scores. Each composite score is the median value of the combined median values for each participant of the respective subscale scores (range for subscale and overall scores: 0 to 10, higher scores indicate more severe pain/pain interference).

  post-operative week 6

Secondary Outcomes (1)

• Pain Score

  Baseline through post-op day 1 (composite scores over 24 hours following surgery)

Study Arms (2)

N-acetyl cysteine

ACTIVE COMPARATOR

N-acetyl cysteine will be administered as follows: A loading dose of 50 mg/kg will be started as a 1-hour infusion before surgical incision, and will be followed by a maintenance dose of 50 mg/kg administered over 4 hours.

Drug: N-acetyl cysteine

Normal Saline

PLACEBO COMPARATOR

Normal will be administered as follows: A normal saline infusion will administered at a rate and duration to mimic the N-acetyl cysteine administration.

Other: Normal Saline

Interventions

N-acetyl cysteine DRUG

Intravenous infusion started during the clinically indicated surgery at a rate of 50mg/kg over 1 hour followed by 50mg/kg over 3 hours. This will be an accumulated total of 100 mg/kg over 4 hours.

Also known as: NAC

N-acetyl cysteine

Normal Saline OTHER

Intravenous infusion at a time and rate to mimic the active treatment. The infusion will be given over 4 hours beginning during the clinically indicated surgery

Also known as: NS

Normal Saline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Over 18
• Male of female
• Planning to undergo primary total hip arthroplasty
• Fluent in English
• Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures

You may not qualify if:

• Infectious disease within the last month
• Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
• Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake \> 30 mg)
• Major surgery within the last 3 months or minor surgery within the last month.
• History of substance abuse (e.g., alcoholism, drug dependency)
• Pregnancy
• Autoimmune disease interfering with data interpretation (e.g. lupus)
• Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function
• Active malignancy
• Participation in another clinical trial of an investigational drug or device within the last month that, in the investigator's opinion, would create an increased risk to the participant or compromise the integrity of the study
• Other conditions compromising a participant's safety or the integrity of the study

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Related Publications (11)

• Kim DH, Pearson-Chauhan KM, McCarthy RJ, Buvanendran A. Predictive Factors for Developing Chronic Pain After Total Knee Arthroplasty. J Arthroplasty. 2018 Nov;33(11):3372-3378. doi: 10.1016/j.arth.2018.07.028. Epub 2018 Aug 4.

  PMID: 30143334 BACKGROUND

• Zambelli VO, Gross ER, Chen CH, Gutierrez VP, Cury Y, Mochly-Rosen D. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain. Sci Transl Med. 2014 Aug 27;6(251):251ra118. doi: 10.1126/scitranslmed.3009539.

  PMID: 25163478 BACKGROUND

• Guo TZ, Wei T, Huang TT, Kingery WS, Clark JD. Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain. 2018 Oct;19(10):1147-1156. doi: 10.1016/j.jpain.2018.04.006. Epub 2018 Apr 30.

  PMID: 29715519 BACKGROUND

• Gaudilliere B, Fragiadakis GK, Bruggner RV, Nicolau M, Finck R, Tingle M, Silva J, Ganio EA, Yeh CG, Maloney WJ, Huddleston JI, Goodman SB, Davis MM, Bendall SC, Fantl WJ, Angst MS, Nolan GP. Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med. 2014 Sep 24;6(255):255ra131. doi: 10.1126/scitranslmed.3009701.

  PMID: 25253674 BACKGROUND

• Geiger-Maor A, Levi I, Even-Ram S, Smith Y, Bowdish DM, Nussbaum G, Rachmilewitz J. Cells exposed to sublethal oxidative stress selectively attract monocytes/macrophages via scavenger receptors and MyD88-mediated signaling. J Immunol. 2012 Feb 1;188(3):1234-44. doi: 10.4049/jimmunol.1101740. Epub 2012 Jan 4.

  PMID: 22219328 BACKGROUND

• Aghaeepour N, Kin C, Ganio EA, Jensen KP, Gaudilliere DK, Tingle M, Tsai A, Lancero HL, Choisy B, McNeil LS, Okada R, Shelton AA, Nolan GP, Angst MS, Gaudilliere BL. Deep Immune Profiling of an Arginine-Enriched Nutritional Intervention in Patients Undergoing Surgery. J Immunol. 2017 Sep 15;199(6):2171-2180. doi: 10.4049/jimmunol.1700421. Epub 2017 Aug 9.

  PMID: 28794234 BACKGROUND

• Fragiadakis GK, Gaudilliere B, Ganio EA, Aghaeepour N, Tingle M, Nolan GP, Angst MS. Patient-specific Immune States before Surgery Are Strong Correlates of Surgical Recovery. Anesthesiology. 2015 Dec;123(6):1241-55. doi: 10.1097/ALN.0000000000000887.

  PMID: 26655308 BACKGROUND

• Pereira JEG, El Dib R, Braz LG, Escudero J, Hayes J, Johnston BC. N-acetylcysteine use among patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized trials. PLoS One. 2019 May 9;14(5):e0213862. doi: 10.1371/journal.pone.0213862. eCollection 2019.

  PMID: 31071081 BACKGROUND

• Kapstad H, Rokne B, Stavem K. Psychometric properties of the Brief Pain Inventory among patients with osteoarthritis undergoing total hip replacement surgery. Health Qual Life Outcomes. 2010 Dec 9;8:148. doi: 10.1186/1477-7525-8-148.

  PMID: 21143926 BACKGROUND

• Baca Q, Marti F, Poblete B, Gaudilliere B, Aghaeepour N, Angst MS. Predicting Acute Pain After Surgery: A Multivariate Analysis. Ann Surg. 2021 Feb 1;273(2):289-298. doi: 10.1097/SLA.0000000000003400.

  PMID: 31188202 BACKGROUND

• Aghaeepour N, Finak G; FlowCAP Consortium; DREAM Consortium; Hoos H, Mosmann TR, Brinkman R, Gottardo R, Scheuermann RH. Critical assessment of automated flow cytometry data analysis techniques. Nat Methods. 2013 Mar;10(3):228-38. doi: 10.1038/nmeth.2365. Epub 2013 Feb 10.

  PMID: 23396282 BACKGROUND

MeSH Terms

Conditions

Pain, Postoperative

Interventions

Acetylcysteine; Saline Solution

Condition Hierarchy (Ancestors)

Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pain; Neurologic Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Professor of Anesthesia
• Organization: Stanford University

ang@stanford.edu

650-723-6412

Study Officials

• Martin S Angst, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Anesthesia

Study Record Dates

• First Submitted: January 26, 2021
• First Posted: February 1, 2021
• Study Start: July 1, 2021
• Primary Completion: March 1, 2023
• Study Completion: March 1, 2023
• Last Updated: April 30, 2025
• Results First Posted: April 30, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)