Fomepizole <i>versus</i> ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak
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<i>Context.</i> Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. <i>Objective.</i> During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. <i>Methods.</i> The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case–control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. <i>Results.</i> Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (<i>p</i> < 0.001) and late-presenting (>12 h; <i>p</i> = 0.028) patients received fomepizole more often than ethanol, as reflected in the higher number of fomepizole-treated patients being intubated (<i>p</i> = 0.009). No association was found between the type of antidote and the survival in either the case series (<i>p</i> = 0.205) or the quasi-control groups (<i>p</i> = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9–39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3–10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2–22) days in the fomepizole group and 4 (range, 1–33) days in the ethanol group (<i>p</i> = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (<i>n</i> = 100), nor the case–control groups (<i>n</i> = 50)). <i>Conclusions.</i> This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness.
研究背景 全球范围内曾多次报告大规模或群体性甲醇中毒事件。由于开展随机对照试验（randomized controlled trial）存在技术难度，目前尚不明确乙醇与甲吡唑（fomepizole）作为甲醇中毒解毒剂的相对临床疗效。 研究目的 2012至2014年捷克共和国发生群体性甲醇中毒暴发事件期间，本研究对比两种解毒剂对患者健康后遗症发生率及死亡率的影响。 研究方法 本研究采用横断面病例系列（cross-sectional case series）与拟病例对照研究（quasi-case–control study）设计。纳入入院时确诊为甲醇中毒的患者作为研究对象。确诊标准如下：（1）存在近期饮用违禁酒类的病史，且血清甲醇浓度高于6.2毫摩尔每升（mmol/L，即20毫克每分升mg/dL）；或（2）存在甲醇中毒病史或临床怀疑甲醇中毒，且血清甲醇浓度高于检测限，同时满足以下至少2项指标异常：酸碱度（pH）＜7.3、血清碳酸氢盐＜20毫摩尔每升、阴离子间隙（AG）≥20毫摩尔每升。甲吡唑给药方案为：以15毫克每千克体重的负荷剂量（bolus dose）经静脉（i.v.）稀释于等渗生理盐水中静脉注射，随后每12小时给予10毫克每千克体重（血液透析（hemodialysis）期间改为每4小时一次）。乙醇给药方式包括：以10%乙醇溶液（溶于5%葡萄糖溶液）静脉给药，以及口服（per os）给予20%乙醇溶液的负荷剂量。采用多元回归（multivariate regression）分析明确解毒剂对临床结局的影响。此外，针对回顾性拟病例对照研究，我们选取了接受乙醇治疗的对照组患者，该组患者在中毒严重程度及其他关键参数方面均经过严格匹配，以控制混杂因素。 研究结果 本研究共纳入100例确诊甲醇中毒的住院患者：其中25例接受甲吡唑治疗，68例接受乙醇治疗，另有7例未接受任何解毒剂治疗。酸中毒程度更严重（p＜0.001）且就诊时间较晚（＞12小时，p=0.028）的患者更倾向于接受甲吡唑治疗，这一趋势在接受气管插管的甲吡唑治疗患者比例更高（p=0.009）中得到体现。在病例系列分析中，未发现解毒剂类型与生存率存在显著关联（p=0.205）；在经过严格匹配以最小化分配混杂的拟对照研究组中，同样未观察到此类关联（p=0.705）。多元回归分析显示，入院时血清乙醇阳性（比值比（odds ratio, OR）=10.8，95%置信区间（confidence interval, CI）：2.9~39.9）与动脉血酸碱度（OR=3.7，95%CI：1.3~10.5）是影响患者生存率的唯一独立变量。甲吡唑组患者的重症监护病房（intensive care unit, ICU）中位住院时长为6天（范围：2~22天），乙醇组为4天（范围：1~33天，p=0.131）。两组患者的中毒清除治疗手段使用率无显著差异（无论是在全部100例患者队列中，还是在50例病例对照研究亚组中）。 研究结论 本项针对甲醇中毒解毒剂的研究未发现两种药物临床疗效存在差异的证据。尽管乙醇通常被认为并发症发生率更高，但本研究提示两种解毒剂疗效相近，临床不应仅基于疗效因素而避免使用乙醇。
