Effect of Low-Dose Versus High-Dose Alpha-Lipoic Acid on Oxidative Stress, Inflammation, and Clinical Outcomes in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory lung disease characterized by persistent airflow limitation and enhanced oxidative stress. Acute exacerbations of COPD (AECOPD) significantly increase morbidity, accelerate lung function decline, and worsen clinical outcomes. Oxidative stress plays a central role in AECOPD pathophysiology by amplifying inflammation through mediators such as IL-8 and TNF-α, leading to airway injury and impaired gas exchange. Alpha Lipoic Acid (ALA) is a potent antioxidant and anti-inflammatory agent that scavenges reactive oxygen species, regenerates endogenous antioxidants, and modulates redox-sensitive inflammatory pathways. Although preclinical evidence supports its protective role in respiratory diseases, no randomized clinical trial has evaluated ALA in AECOPD or compared different dosing strategies. Aim This study aims to evaluate and compare the effects of low-dose (600 mg/day) versus high-dose (1200 mg/day) ALA on oxidative stress markers, inflammatory biomarkers, clinical recovery, pulmonary oxygenation, gas exchange, and safety in patients with AECOPD. Methods This is a prospective, double-blind, randomized controlled trial conducted in the ICU at El Matareya Teaching Hospital. Adult patients (40-70 years) with confirmed COPD and frequent exacerbations were randomized (1:1:1) into three groups: Group A: Standard therapy + placebo Group B: Standard therapy + 600 mg/day oral ALA Group C: Standard therapy + 1200 mg/day oral ALA All patients received guideline-based AECOPD management according to GOLD recommendations, including bronchodilators, systemic corticosteroids, antibiotics (when indicated), oxygen therapy, and ventilatory support as needed. Assessments Baseline and Day 10 evaluations included: Primary Outcomes: Oxidative stress marker: Malondialdehyde (MDA) Inflammatory markers: Interleukin-8 (IL-8) and C-reactive protein (CRP) Secondary Outcomes: Time to clinical stability ICU and hospital length of stay Need for non-invasive or invasive ventilation Early relapse (14 days) and 30-day readmission Gas Exchange: ABGs (pH, PaO₂, PaCO₂, P/F ratio) Patient-Reported Outcomes: COPD Assessment Test (CAT) and mMRC dyspnea scale Safety: Monitoring for adverse effects including gastrointestinal symptoms, hypoglycemia, dizziness, and hypersensitivity reactions.

Acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are characterized by a sudden amplification of airway inflammation and oxidative stress, leading to worsening airflow limitation, impaired gas exchange, and increased healthcare utilization. Oxidative stress plays a central mechanistic role in exacerbation pathophysiology through excessive production of reactive oxygen species, depletion of endogenous antioxidant reserves, activation of redox-sensitive transcription factors, and upregulation of pro-inflammatory cytokines such as interleukin-8. These processes contribute to neutrophilic airway infiltration, epithelial injury, mucus hypersecretion, and deterioration of pulmonary function. Alpha lipoic acid (ALA) is an endogenous mitochondrial cofactor with potent antioxidant and anti-inflammatory properties. In its reduced and oxidized forms, ALA participates in redox cycling, directly scavenges reactive oxygen species, regenerates intracellular antioxidants including glutathione, and modulates redox-sensitive inflammatory signaling pathways. Preclinical investigations have demonstrated protective pulmonary effects of ALA in experimental models of oxidative lung injury, including smoke-induced damage and inflammatory airway disease. However, its clinical efficacy during acute exacerbations of COPD has not been evaluated in a randomized controlled setting. This study is designed as a prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial to evaluate the adjunctive use of ALA during hospitalization for acute exacerbations of COPD. Participants will be randomly assigned in a 1:1:1 ratio to receive placebo, low-dose ALA (600 mg daily), or high-dose ALA (1200 mg daily) for 10 days in addition to standard-of-care therapy consistent with current GOLD recommendations. The intervention duration was selected to correspond with the typical treatment window for systemic corticosteroids in AECOPD and to capture early biochemical and clinical responses. The study is structured to examine dose-response relationships by directly comparing two ALA dosing regimens against placebo under identical standard therapy conditions. Randomization will be computer-generated, and allocation concealment will be ensured using identical capsules to maintain blinding of participants, clinicians, and outcome assessors. Laboratory analyses of oxidative and inflammatory biomarkers will be performed using standardized and validated methods. The primary objective is to determine whether adjunctive ALA reduces systemic oxidative stress and inflammatory burden over the acute treatment period. Secondary objectives include evaluation of clinical stabilization parameters, respiratory gas exchange indices, symptom burden, healthcare utilization outcomes, and safety. Time to clinical stability will be assessed using predefined physiological criteria to provide an objective measure of recovery dynamics. The study incorporates structured safety monitoring, including surveillance for gastrointestinal intolerance, hypoglycemia, neurological symptoms, and hypersensitivity reactions, given the known pharmacological profile of ALA. All adverse events will be documented and assessed for severity and relatedness. The sample size was calculated to detect clinically meaningful differences in oxidative stress markers among the three treatment arms while accounting for multiple comparisons and maintaining 90% statistical power. Statistical analysis will follow an intention-to-treat framework with appropriate adjustments for multiple testing. By targeting the oxidative-inflammatory axis during acute exacerbations, this trial seeks to generate the first randomized clinical evidence regarding dose-dependent effects of alpha lipoic acid as adjunctive therapy in hospitalized AECOPD patients. The findings may inform future antioxidant-based therapeutic strategies aimed at improving biochemical and clinical recovery in this high-risk population.