N-乙酰半胱氨酸对偏二甲基肼和四氧化二氮吸入性肺损伤的保护作用

目的观察N-乙酰半胱氨酸(NAC)对大剂量火箭液体推进剂偏二甲基肼(UDMH)和四氧化二氮(N2O4)吸入性急性肺损伤(ALI)的保护性作用.方法42只大鼠随机平均分为对照组、毒物暴露组(暴露组)和毒物暴露+NAC治疗组(NAC干预组).制模动物在静式染毒柜中染毒,UDMH和N2O4质量浓度分别为0.98 mg/L和0.19 mg/L,均染毒10 min.NAC干预组染毒后立即经尾静脉注射NAC150 mg/kg,3 h后再次补充50 mg/kg NAC腹腔注射;另两组均以等量生理盐水代替.各组动物均于实验后6 h测定肺组织湿/干质量比(W/D)、支气管肺泡灌洗液(BALF)蛋白含量和乳酸脱氢酶(LDH)活性、肺组织超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)和血浆丙二醛(MDA),并观察动物一般情况及组织病理学变化.结果与对照组相比,暴露组大鼠肺W/D、BALF中蛋白和LDH以及血浆MDA等均明显增加,而肺组织SOD、GSH-Px活性则明显降低;NAC干预组上述指标均有不同程度改善.暴露组大鼠有明显憋喘症状,病理学表现为明显的肺泡内渗出和肺间质水肿;而NAC干预组上述改变明显减轻.肺W/D与肺组织SOD和GSH-Px活性均呈显著负相关,相关系数r分别为-0.662和-0.707(P均＜0.01).结论NAC对大剂量UDMH和N2O4吸入性ALI有保护性治疗作用,其作用机制可能与其抗氧化和防治脂质过氧化损伤有关.     

不同时间给予猪肺表面活性物质对大鼠油酸型急性肺损伤疗效的影响

目的 探讨不同时间给予猪肺表面活性物质(PPS)混悬液对油酸致大鼠急性肺损伤(ALI)的治疗作用.方法 将48只SD大鼠随机分为假手术组、模型组、0.5 h PPS治疗组和2 h PPS治疗组.假手术组仅行气管和颈动脉插管手术操作,其余各组大鼠静脉注入油酸诱发ALI;0.5 h PPS治疗组和2 h PPS治疗组分别于油酸注入后0.5 h和2 h经气道均滴入100 mg/kg和150 mg/kg两个剂量的PPS,实验过程中计数大鼠呼吸频率,测定动脉血气指标;于实验4 h计算大鼠存活率后处死动物,观察肺组织病理学改变,并检测肺系数及支气管肺泡灌洗液(BALF)中总蛋白(TP)含量和血浆中肿瘤坏死因子-α(TNF-α)浓度.结果 与模型组比较,0.5 h给予PPS 100 mg/kg和150 mg/kg以及2 h给予PPS 150 mg/kg治疗都能显著降低大鼠的呼吸频率,提高动脉血氧分压(PaO2)及大鼠存活率,降低肺毛细血管通透性及肺出血、肺水肿发生率,降低血浆中TNF-α和BALF中TP含量(P均＜0.05).而2 h给予100 mg/kg PPS的治疗作用不明显.结论 早期气道内滴入≥100 mg/kg的PPS,能明显改善油酸型ALI大鼠的呼吸功能、减轻肺损伤;晚期较大剂量的PPS(150 mg/kg)才有治疗作用.     

片仔癀肝宝对慢性肝损伤凋亡的影响

目的:探讨片仔癀肝宝(肝宝)对CCl4诱导大鼠慢性肝损伤凋亡的影响。方法:60只SD大鼠随机分为正常对照组、模型组、西利宾胺组、肝宝低剂量组、肝宝中剂量组、肝宝高剂量组,每组10只。除正常对照组外,SD大鼠腹腔注射50%CCl4橄榄油溶液1 ml/kg,2次/周,连续8周。于造模第四周开始给药,设正常对照组(生理盐水)、模型组(生理盐水)、阳性药对照组(西利宾胺,50 mg/kg),肝宝低剂量组(150 mg/kg)、肝宝中剂量组(300 mg/kg)、肝宝高剂量组(600 mg/kg),1次/d,连续4周。于末次给药24 h后,HE染色观察肝宝对肝组织病理学的影响,TUNEL法观察肝组织凋亡情况,比色法检测Caspase-3和Caspase-9的变化,western blot检测肝宝对Bax和Bcl-2蛋白表达的影响。结果:HE染色发现,各用药组均可不同程度缓解CCl4诱导的肝损伤;肝宝抑制肝细胞凋亡;降低Caspase-3和Caspase-9的活力;下调Bax表达,上调Bcl-2表达。结论:片仔癀肝宝可以抑制CCl4诱导的肝细胞凋亡。     

N-乙酰半胱氨酸对百草枯中毒大鼠肺组织细胞凋亡及Fas/FasL的影响

目的 探讨百草枯( paraquat,PQ)中毒所致大鼠急性肺损伤时N-乙酰半胱氨酸( N-acetylcysteine,NAC)对肺组织的细胞凋亡和Fa/FasL表达的影响.方法 将SD大鼠随机(随机数字法)分为对照组、PQ染毒组和NAC治疗组,每组15只.复制PQ染毒大鼠急性肺损伤模型,腹腔注入2％百草枯液( 25 mg/ kg);NAC治疗组为0.5h后对PQ染毒大鼠,再腹腔注射NAC (200 mg/kg)进行干预;对照组腹腔注射等量生理盐水.利用原位缺口末端标记(TUNEL)法检测肺组织细胞凋亡率,采用逆转录-聚合酶链反应(RT-PCR)和蛋白质印迹(Western blot)方法分别检测肺组织Fas/FasL mRNA和蛋白的表达.结果 PQ组和对照组相比细胞凋亡率和Fas/FasL系统表达差异均具有统计学意义(P＜0.05);NAC治疗组细胞凋亡率和fas/fasL表达明显降低,和PQ组相比差异均有统计学意义(P＜0.05).结论 NAC可能通过抑制Fas/FasL系统活化抑制百草枯中毒大鼠肺组织细胞凋亡.     

猪百草枯急性中毒灌胃模型的建立与研究

目的:建立更接近和符合百草枯中毒临床实际情况的家猪百草枯急性中毒灌胃模型,以满足针对洗胃、血液灌流等治疗开展疗效观察的模型需求。方法:小型雌性家猪镇静麻醉、气管插管及心电监护后,分别以生理盐水(对照组)、30mg/kg、60mg/kg、120mg/kg(百草枯染毒组)的剂量经胃管给予浓度为40%的百草枯原液。持续监测生命体征,留取0、2、4、6、8、12、24h,血浆标本采用液相色谱质谱连用法检测血浆百草枯浓度,留取给药前和给药后24h血液标本送检血气分析、血常规、肝肾功能及电解质,于24h处死、收获动物并留取组织样本。结果:预实验发现百草枯30mg/kg染毒剂量下,2周内动物无明显的脏器功能损伤;120mg/kg染毒剂量下,动物在12h内因循环衰竭而死亡。百草枯60mg/kg剂量组染毒后,与对照组相比动物在24h存活率为66.67%,血药浓度提示灌胃模型的血浆百草枯峰浓度为(5.12±2.38)μg/ml,染毒组的生命体征、肝肾功能电解质、乳酸水平等与对照组相比均差异有统计学意义,氧分压在24h有下降趋势但差异无统计学意义。60mg/kg染毒组动物组织病理检查发现,肺组织急性炎症明显,肺泡腔内大量中性粒细胞及炎性渗出,肾小管上皮细胞水肿,部分坏死。结论:小型家猪可应用于百草枯急性中毒的灌胃模型。适合实验的百草枯染毒剂量是60mg/kg。     

N-乙酰半胱氨酸对肝缺血再灌注损伤的抗氧化作用

目的探讨N-乙酰半胱氨酸（NAC）对肝缺血再灌注损伤的抗氧化作用。方法40例需肝门阻断行肝脏手术病人随机分为观察组和对照组，每组20例。观察组切皮后采用静脉泵持续静脉输注NAC120mg／kg直至肝门阻断开放即刻泵完；肝门阻断开放后3h采用静脉泵持续静脉输注NAC10mg／（kg·h）直至术毕。对照组切皮后采用静脉泵持续静脉输注生理盐水60mL直至肝门阻断开放即刻泵完；肝门阻断开放后3h采用静脉泵持续静脉输注生理盐水15mL直至术毕。2组病人分别于肝门阻断前（T0）、肝门阻断后30min（T1），肝门阻断开放后1（T2）、6（T2）、24（T4）h抽静脉血检测血浆丙二醛（MDA）水平及超氧化物歧化酶（SOD）的活性。结果2组病人肝门阻断时间、术中出血量及手术时间比较差异均无统计学意义（均P〉0．05），观察组T3、T4血浆MDA水平均低于对照组（均P〈0．05），对照组T2-T4血浆SOD活性均低于观察组（均P〈0．05）。结论术中肝门阻断前后静脉泵持续静脉输注NAC对肝缺血再灌注损伤有一定抗氧化作用。     

阿替普酶治疗不同时间窗发病急性脑梗死疗效观察

目的观察不同剂量阿替谱酶(rt-PA)治疗不同时间窗发病急性脑梗死的疗效观察。方法选择2019年1月至12月于发病<4.5 h行rt-PA静脉溶栓治疗的急性脑梗死患者122例,对其资料进行回顾性分析。按照发病时间窗、rt-PA剂量不同分为4组,发病至用药时间<3 h为Ⅰ组,rt-PA剂量0.6mg/kg(Ⅰa组),0.9 mg/kg(Ⅰb组);发病至用药3~4.5 h为Ⅱ组,rt-PA剂量0.6 mg/kg(Ⅱa组),0.9 mg/kg(Ⅱb组)。比较4组患者间溶栓治疗后2h、24 h、7 d神经功能缺损量表(NIHSS)评分改善情况。结果Ⅰa组与Ⅱa组比较,溶栓后2h、24h、7d NIIHSS改善程度较后者明显(P<0.05);Ⅰb组与Ⅱb组比较,溶栓后2 h NIHSS改善程度较后者明显(P<0.05)。Ⅰ组与型组比较,2h、24 h、7 d症状程度明显改善(P<0.05)。结论超早期应用rt-PA,治疗时间窗越短,早期疗效越佳。     

地塞米松对黄磷吸入致急性肺损伤大鼠的治疗作用

目的 探讨不同剂量地塞米松在不同时期干预对急性黄磷及其化合物吸入致急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)的治疗作用.方法 模拟黄磷厂工人中毒环境,自行设计大鼠染毒装置制备黄磷中毒动物模型.将80只SD大鼠随机分为对照组,模型组,地塞米松早期高、低剂量治疗组(分别于制模后0、4、8 h腹腔注射地塞米松5 mg/kg或1 mg/kg),地塞米松中期高、低剂量治疗组(分别于制模后12、16、20 h腹腔注射地塞米松5 mg/kg或1 mg/kg).采用酶联免疫吸附法测定制模成功后6、24、48 h血清白细胞介素-1β(IL-1β)的水平;观察48 h时肺组织病理改变.结果 模型大鼠血清IL-1β明显升高,病理组织学显示透明膜形成及大量炎性细胞浸润等.治疗组各项指标均减轻,其中早期高剂量组<中期高剂量组≈中期低剂量组<早期低剂量组(P<0.05或P<0.01).结论 早期给予大剂量地塞米松可通过抑制过度炎症反应,抑制IL-1β高水平表达,减轻肺损伤;中期治疗两组效果相当,早期低剂量组效果最差.     

超高浓度甲氨蝶呤中毒抢救成功1例并文献复习

患儿因确诊急性淋巴细胞白血病（B系 高危）5月余,为进行巩固阶段化疗再次住院。按照治疗方案给予大剂量甲氨蝶呤（HDMTX ）5 g/m2化疗,解救药物亚叶酸钙剂量按照首剂甲氨蝶呤起第43小时(即满42小时)进行解救,亚叶酸钙每次用量为15 mg/m2,48小时甲氨蝶呤血药浓度：32 μmol/L。考虑甲氨蝶呤中毒,暂停所有化疗,按照甲氨蝶呤(MTX)中毒方案予大剂量亚叶酸钙解救,并加强补液水化、碱化,强迫利尿等处理, 72小时甲氨蝶呤血药浓度16.9 μmol/L;继续予大剂量亚叶酸钙、水化、碱化。患儿腹痛无改善,第82小时起行连续性肾脏替代治疗（CRRT）。96小时甲氨蝶呤血药浓度仍达到7.2 μmol/L ,考虑CRRT效果不佳,故于MTX后124小时开始行血浆置换,血浆置换后继续行CRRT。第120小时,甲氨蝶呤血药浓度下降到3.8 μmol/L。中毒第7天即148小时,为加快解毒再次行血浆置换。第192小时甲氨蝶呤血药浓度下降到0.52 μmol/L。     

异环磷酰胺引起肾小管功能缺陷

异环磷酰胺(IFF)大剂量(150mg/kg/d)可致肾毒性反应.小剂量(1.25g/m~2/d)引起肾小管功能缺陷未见报道,本文报告4例如下:病人和方法:4例系反复发作的恶性淋巴瘤患者曾接受化疗.IFF治疗前全血细胞计数(CBC)、血生化、肝、肾功能和尿液检查等均正常,无糖尿病.     

Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management

The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of acetaminophen. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of acetaminophen alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care. The panel's recommendations follow. These recommendations are provided in chronological order of likely clinical use. The grade of recommendation is provided in parentheses. 1) The initial history obtained by the specialist in poison information should include the patient's age and intent (Grade B), the specific formulation and dose of acetaminophen, the ingestion pattern (single or multiple), duration of ingestion (Grade B), and concomitant medications that might have been ingested (Grade D). 2) Any patient with stated or suspected self-harm or who is the recipient of a potentially malicious administration of acetaminophen should be referred to an emergency department immediately regardless of the amount ingested. This referral should be guided by local poison center procedures (Grade D). 3) Activated charcoal can be considered if local poison center policies support its prehospital use, a toxic dose of acetaminophen has been taken, and fewer than 2 hours have elapsed since the ingestion (Grade A). Gastrointestinal decontamination could be particularly important if acetylcysteine cannot be administered within 8 hours of ingestion. Acute, single, unintentional ingestion of acetaminophen: 1) Any patient with signs consistent with acetaminophen poisoning (e.g., repeated vomiting, abdominal tenderness in the right upper quadrant or mental status changes) should be referred to an emergency department for evaluation (Grade D). 2) Patients less than 6 years of age should be referred to an emergency department if the estimated acute ingestion amount is unknown or is 200 mg/kg or more. Patients can be observed at home if the dose ingested is less than 200 mg/kg (Grade B). 3) Patients 6 years of age or older should be referred to an emergency department if they have ingested at least 10 g or 200 mg/kg (whichever is lower) or when the amount ingested is unknown (Grade D). 4) Patients referred to an emergency department should arrive in time to have a stat serum acetaminophen concentration determined at 4 hours after ingestion or as soon as possible thereafter. If the time of ingestion is unknown, the patient should be referred to an emergency department immediately (Grade D). 5) If the initial contact with the poison center occurs more than 36 hours after the ingestion and the patient is well, the patient does not require further evaluation for acetaminophen toxicity (Grade D). Repeated supratherapeutic ingestion of acetaminophen (RSTI): 1) Patients under 6 years of age should be referred to an emergency department immediately if they have ingested: a) 200 mg/kg or more over a single 24-hour period, or b) 150 mg/kg or more per 24-hour period for the preceding 48 hours, or c) 100 mg/kg or more per 24-hour period for the preceding 72 hours or longer (Grade C). 2) Patients 6 years of age or older should be referred to an emergency department if they have ingested: a) at least 10 g or 200 mg/kg (whichever is less) over a single 24-hour period, or b) at least 6 g or 150 mg/kg (whichever is less) per 24-hour period for the preceding 48 hours or longer. In patients with conditions purported to increase susceptibility to acetaminophen toxicity (alcoholism, isoniazid use, prolonged fasting), the dose of acetaminophen considered as RSTI should be greater than 4 g or 100 mg/kg (whichever is less) per day (Grade D). 3) Gastrointestinal decontamination is not needed (Grade D). Other recommendations: 1) The out-of-hospital management of extended-release acetaminophen or multi-drug combination products containing acetaminophen is the same as an ingestion of acetaminophen alone (Grade D). However, the effects of other drugs might require referral to an emergency department in accordance with the poison center's normal triage criteria. 2) The use of cimetidine as an antidote is not recommended (Grade A).     

Cimetidine as an alternative to N-acetylcysteine in patients with paracetamol poisoning

A 20 year old woman attended the emergency department of Wollongong Hospital 11 hours after a toxic ingestion of paracetamol. After developing a significant anaphylactoid reaction to N-acetylcysteine (NAC), she was treated with cimetidine 40mg/kg intravenously as an alternative. This therapy may be an option when NAC cannot be used.     

Intoxication par le paracétamol : quoi de neuf ?

Acetaminophen is one of the most common causes of poisoning worldwide often leading to fatalities. The objectives of this paper were to: 1) review the mechanisms and predictive factors of acetaminophen poisoning; and 2) present the most recent clinical studies aiming at improving its management. Acetaminophen overdose is responsible for a dosedependent toxic hepatitis resulting in liver necrosis. According to the French guidelines, treatment with N-acetylcysteine (NAC) should be decided based on the interpretation of plasma acetaminophen concentration in relation to the time of ingestion using a nomogram with a line starting at 150 mg/l at h4 as threshold for treatment. New protocols of NAC infusion have been studied to simplify its administration and limit its potential side effects. Indications and modalities of NAC administration remain a matter of intense debate. Investigations aim at reaching the best equilibrium between the necessity to treat all patients at risk of liver toxicity and the wish to minimize the treatment costs and side effects. New biomarkers assessed in studies focused at understanding the mechanisms of acetaminophen-related toxicity have been suggested to identify poisoned patients who are at risk of liver toxicity and allow their treatment on time. These new prognosticators should be soon available at the bedside.     

Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

Objectives:  Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N -acetylcysteine (NAC) therapy after deliberate acetaminophen overdose.
Methods:  This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC.
Results:  There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi-square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the "200-line" and was independent of the interval between ingestion and assessment.
Conclusions:  Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion.     

Acetaminophen/diphenhydramine overdose in profound hypothermia

Background. There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting. Case report. A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10–37 U/L) and 104 IU/L (ref 12–78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2). Discussion. Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed. Conclusions. Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.     

Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics

Context: Early onset acidosis from mitochondrial toxicity can be observed in massive acetaminophen poisoning prior to the development of hepatotoxicity. In this context, the efficacy of acetylcysteine to reverse mitochondrial toxicity remains unclear and hemodialysis may offer prompt correction of acidosis. Unfortunately, toxicokinetics of acetaminophen and acetylcysteine during extracorporeal treatments hemodialysis have seldom been described.

Case details: An 18-year-old woman presented to the emergency department 60?minutes after ingestion of 100?g of acetaminophen, and unknown amounts of ibuprofen and ethanol. Initial assessment revealed an agitated patient. Her mental status worsened and she required intubation for airway protection. Investigations showed metabolic acidosis with lactate peaking at 8.6?mmol/L. Liver and coagulation profiles remained normal. Acetaminophen concentration peaked at 981?μg/ml (6496?μmol/L). Pending hemodialysis, the patient received 100?g of activated charcoal and an acetylcysteine infusion at 150?mg/kg over 1?hour, followed by 12.5?mg/kg/h for 4?hours. During hemodialysis, the infusion was maintained at 12.5?mg/kg/h to compensate for expected removal before it was decreased to 6.25?mg/kg for 20?hours after hemodialysis. The patient rapidly improved during hemodialysis and was discharged 48?hours post-admission.

Toxicokinetics: The acetaminophen elimination half-life was 5.2?hours prior to hemodialysis, 1.9-hours during hemodialysis and 3.6?hours post hemodialysis. The acetaminophen and acetylcysteine clearances by A-V gradient during hemodialysis were 160.4?ml/min and 190.3?ml/min, respectively. Hemodialysis removed a total of 20.6?g of acetaminophen and 17.9?g of acetylcysteine.

Conclusion: This study confirms the high dialyzability of both acetaminophen and acetylcysteine. Hemodialysis appears to be a beneficial therapeutic option in cases of massive acetaminophen ingestion with coma and lactic acidosis. Additionally, these results suggest that the infusion rate of acetylcysteine must be more than double during hemodialysis to compensate for its ongoing removal and provide similar plasma concentrations to the usual acetylcysteine regimen.     

A patient-tailored N-acetylcysteine protocol for acute acetaminophen intoxication

BACKGROUND: Hepatotoxicity as a result of acetaminophen(APAP) intoxication has become an important problem, but early intervention with N-acetylcysteine (NAC) is effective in preventing hepatic injury. Two NAC regimens are currently approved for acute APAP intoxication: NAC administered orally every 4 hours for 72 hours, and NAC administered intravenously for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP. However, clinical observations suggest that a variable treatment duration may be more appropriate than use of these predetermined, fixed-duration protocols. OBJECTIVES: This study investigated the tolerability and efficacy of a patient-tailored NAC protocol for acute APAP intoxication by comparing the incidence of hepatotoxicity in patients receiving this protocol and in historical controls receiving 1 of 2 fixed-duration protocols: oral NAC for 72 hours and intravenous NAC for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP. METHODS: This was a retrospective case series study that included all patients admitted through the emergency department (ED) of the National Taiwan University Hospital with a diagnosis of APAP intoxication between October 1997 and October 2002. According to the patient-tailored protocol, which had been used in the ED since 1997, patients with a serum APAP concentration above the limit for possible risk based on a modified Rumack-Matthew nomogram received oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours. NAC treatment was discontinued when the APAP concentration was <10 mg/L and serum aspartate aminotransferase (AST) was <40 IU/L. For the purposes of assessing clinical outcomes, patients were divided into 3 groups based on duration of treatment: the short-course group (/=73 hours). The primary outcome measure was development of hepatotoxicity, defined as a serum AST or alanine aminotransferase concentration >1000 IU/L. RESULTS: Twenty-seven patients were included in the study, 17 in the short-course group, 4 in the intermediate-course group, and 6 in the long-course group. The mean (SD) durations of NAC treatment in the respective groups were 22.1 (5.5) hours, 45.0 (8.2) hours, and 97.3 (33.2) hours. All 6 patients (22%) in the long-course group had hepatotoxicity (peak AST range, 1083-9770 IU/L); their treatment duration ranged from 80 to 164 hours. No patients in the short- or intermediate-course group had evidence of hepatotoxicity. One woman in the long-course group in whom initiation of NAC treatment was delayed by 28 hours died of fulminant hepatic failure. The overall incidence of hepatotoxicity was similar to that in the historical controls. CONCLUSIONS: In this retrospective case series inpatients who received patient-tailored NAC therapy for acute APAP intoxication, the incidence of hepatotoxicity was low and comparable to that in historical controls who received treatment with 1 of 2 fixed-duration regimens. Use of this protocol may have the potential to shorten hospital stays without increasing the risk to patients. However, the sample size was small, and the findings require confirmation in prospective clinical trials.     

Massive acetaminophen ingestion with early metabolic acidosis and coma: treatment with IV NAC and continuous venovenous hemodiafiltration

Context.?We report the extraction of acetaminophen by continuous venovenous hemodiafiltration (CVVHD) during treatment of an acute ingestion of 200 g with a peak recorded serum acetaminophen level of 1,614 mg/L (10,652 μmol/L).?Case details.?The patient presented with early onset of coma, metabolic acidosis, and hypotension in the absence of significant hepatic injury. In addition to N-acetylcysteine (NAC) therapy, CVVHD was performed to manage the acid–base disturbance. Flow rate, effluent volume, and serum and effluent drug concentrations were obtained at hourly intervals. During 16 h of CVVHD the acetaminophen level dropped from 1,212 to 247 mg/L.?Discussion.?The average clearance of acetaminophen by CVVHD was 2.53 L/h, with removal of 24 g of acetaminophen over 16 h. As NAC is effective in preventing hepatic injury after acute acetaminophen overdose, the role of dialysis or CVVHD is limited.     

An analysis of N-acetylcysteine treatment for acetaminophen overdose using a systems model of drug-induced liver injury

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V(max) for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.     

Massive levothyroxine ingestion in a pediatric patient: case report and discussion

We describe the course of a toddler who ingested a massive amount of levothyroxine and review treatment options for such overdoses. A 2?-year-old boy presented shortly after an ingestion of up to 7.6 mg of levothyroxine (potentially as much as 700 μg/kg). He was initially asymptomatic, treated with oral charcoal 1 g/kg, and discharged home from the emergency department after a few hours. He returned approximately 24 hours later with a temperature of 38.5°C, heart rate of 163 beats per minute, respiratory rate of 30 breaths per minute, and blood pressure of 136/70 mm Hg. He had a slightly decreased appetite and no signs or symptoms of infection. He was admitted to hospital and treated with oral acetaminophen. The initial free thyroxine (T4) was > 100 pmol/L and free triiodothyronine (T3) was 35.3 pmol/L. The patient had desquamation of the palms and soles, hair loss, and irritability during the month following the ingestion. Resolution of the elevated free T4 occurred by 12 days post-ingestion and normalization of the thyroid-stimulating hormone by 7 weeks post-ingestion. There were no long-term sequelae. Levothyroxine overdose can result in significant complications, including seizures and arrhythmias, both of which should be monitored for. However, as our case illustrates, massive ingestion of levothyroxine in children typically follows a benign course.