Department of Anesthesiology, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
Department of Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
Mol Pain. 2024 Jan-Dec;20:17448069241259535. doi: 10.1177/17448069241259535.
Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1β and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1β, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.
亚甲蓝（MB）已被证明可降低心脏手术后血管扩张患者的死亡率和发病率。尽管 MB 被认为是安全的，但已有 MB 外渗导致皮肤毒性的报道。在这项研究中，我们试图描述 MB 诱导的皮肤毒性并研究其潜在机制。为了诱导 MB 诱导的皮肤毒性，我们向足底后爪注射 200μL 生理盐水（载体）或 1%、0.1%或 0.01% MB 溶液，测量爪肿胀、皮肤组织学变化以及热和机械性痛觉过敏。与生理盐水相比，注射 1%，而不是 0.1%或 0.01% MB，可导致明显的爪肿胀。注射 1% MB 可产生热痛觉过敏，但不会产生机械性痛觉过敏。注射 0.1%或 0.01% MB 后，疼痛行为无变化。RNAseq 的全转录组分析鉴定出 117 个差异表达基因（111 个上调，6 个下调）。通路分析显示白细胞数量增加，脂质增加，髓样细胞和吞噬细胞凋亡减少，IL-1β和 Fos 作为两个主要调控枢纽被激活。qPCR 显示 IL-6 mRNA 增加了 16 倍。因此，我们使用一种新型的 MB 诱导皮肤毒性大鼠模型，表明 1% MB 渗入皮肤组织会引起剂量依赖性的促炎反应，突出了 IL-6、IL-1β 和 Fos 的潜在作用。因此，麻醉师应通过外周静脉导管静脉内给予稀释的 MB。应通过中心静脉导管给予较高浓度的 MB（1%），以最大限度地降低皮肤毒性的风险。
