Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial

Abstract

Objective: To evaluate the impact of N-acetyl-cysteine (NAC) on amputation stump perfusion and healing in patients with critical limb-threatening ischemia (CLTI).

Background: Patients with CLTI are at increased risk of poor amputation site healing leading to increased procedure-associated morbidity.

Methods: In a pilot, double-blind, placebo-controlled, randomized controlled trial, patients with CLTI undergoing major elective lower extremity amputation were randomized 1:1 to intravenous NAC (1200 mg twice-daily) or placebo for up to 5 days postoperatively. Primary outcomes were change in stump perfusion at postoperative day 3 (POD3) and POD5, and healing at POD30. Stumps were serially evaluated for wound healing, and tissue perfusion was evaluated using noninvasive laser-assisted fluorescent angiography.

Results: Thirty-three patients were randomized to NAC (n = 16) or placebo (n = 17). Thirty-one patients were eligible for intent-to-treat analysis (NAC14; placebo17). Twenty patients (NAC7; placebo13) had amputation stump perfusion defects at POD0 and were considered high-risk for poor healing. Intent-to-treat analysis revealed no significant differences between treatment groups. Subgroup analysis of high-risk patients revealed differences in stump perfusion defect size (NAC-0.53-fold, placebo +0.71-fold; 95% confidence interval -2.11 to-0.35; P < 0.05) and healing (NAC [100%], placebo [46%]; P < 0.01) between study treatments.

Conclusions: Postoperative NAC administration may improve amputation stump perfusion and healing in patients with CLTI and tissue perfusion defects at the time of amputation. Intraoperative laser-assisted fluorescent angiogra-phy may help surgeons identify high-risk patients with stump perfusion defects and provide early adjunctive interventions. Future studies can further explore the therapeutic benefits of NAC in the healing and perfusion of other surgical operative sites in high-risk individuals.

Trial registration: clinicaltrials.gov, Identifier: NCT03253328.

Figure 1.

Flowchart of Patient Disposition at 30 Days Abbreviations: NAC, N-acetyl Cysteine; LAFA, Laser-Assisted-Fluorescence-Angiography

Figure 2.

Amputation stump healing, and fold change in postoperative dynamic and static perfusion ‘intent to treat’ patient subgroup A-C: The change in LAFA-derived dynamic parameters: T_PI, R_in, T_d50% D: The change in LAFA-derived static parameters for within 1cm of the suture line E: The change in LAFA-derived static parameters for the entire stump. Data were reported as a fold change from baseline on POD3 and 5 (0–3 and 0–5, respectively) and from POD3 to 5 (3–5).

Figure 3.

Perfusion defects at POD3 and 5 in the ‘high-risk’ subgroup A: Evolution of perfusion defects in amputation stumps of representative patients randomized to either NAC or placebo treatment groups. Green regions of interest (ROIs) represent areas of amputation stump poor perfusion. B: Fold change in perfusion defect (% area of the total stump surface) in postoperative periods 0–3, 0–5, and 3–5 in ‘high-risk’ patient subgroup. C: Significant improvement in amputation stump healing in patients randomized to NAC group.

Figure 4.

Representative longitudinal amputation stumps assessments from patients randomized to NAC and placebo treatment groups.

Figure 5.

Assessment of serum and plasma thiol and cysteine metabolites in study patients at POD0 and 5. A: The change in serum cysteine concentration on POD0 and 5 in patients randomized to NAC and placebo treatment groups. B: The change in plasma thiol concentration on POD0 and 5 in patients randomized to NAC and placebo treatment groups. C: The change in plasma thiol concentration on POD0 and 5 in all patients.