不同剂量N-乙酰半胱氨酸治疗重症肝病患者的临床安全性研究

Study on clinical safety of different doses of N-acetylcysteine in treatment of patients with severe liver diseases

目的:观察不同剂量N-乙酰半胱氨酸(NAC)治疗重症肝病患者所致不良反应,探讨其安全使用。方法:2006年2月至2008年1月在我院应用NAC治疗的各种类型重症肝病患者173例纳入研究。173例患者分为3个剂量组:大剂量组(25例)、小剂量组(66例)及剂量增加组(82例)。大剂量组男16例,女9例,平均年龄(42.3±3.6)岁。小剂量组男42例,女24例,平均年龄(41.6±4.8)岁。剂量增加组男51例,女31例,平均年龄(45.2±5.2)岁。给药方法如下:大剂量组患者给予NAC8g溶于10%葡萄糖注射液250ml中静脉滴注,1次/d;小剂量组患者给予NAC4g溶于10%葡萄糖注射液250ml中静脉滴注,1次/d,同时给予法莫替丁20mg口服,2次/d,10%葡萄糖酸钙10ml加入50%葡萄糖注射液20ml中缓慢静脉推注;剂量增加组患者给予NAC起始剂量4g/d静脉滴注;如无不良反应,自第4天起剂量增至8g/d,给药方法及其他用药同小剂量组。所有患者至少观察2周。结果:大剂量组25例患者中16例(64%)出现不良反应,包括皮肤反应(9例,36%)、胸闷和头晕(2例,8%)、消化道反应(3例,12%)、过敏性休克(1例,4%),双下肢活动障碍(1例,4%)。该组中发生不良反应患者和未发生不良反应患者的终末期肝病(MELD)评分分别为(11.26±5.47)分和(18.38±5.71)分,差异有统计学意义(P<0.05),提示发生不良反应患者病情较轻。小剂量组66例患者中2例(3.03%)出现不良反应,其中皮疹1例和上腹部不适1例。小剂量组不良反应发生率显著低于大剂量组,差异有统计学意义(P<0.001)。皮疹患者和上腹部不适患者的MELD评分分别为11.38分和10.29分。剂量增加组有4例(4.88%)在用药3d内发生不良反应,其余78例中有7例(8.97%)在用药4d后出现不良反应,其发生率高于小剂量组而低于大剂量组(均P<0.001)。78例中,MELD评分>15者31例,发生胃肠反应和皮疹各1例;MELD评分<15者47例,发生胃肠道反应3例,头皮水肿和皮疹各1例。两者差异有统计学意义(P<0.001)。所有患者出现的不良反应经停药、对症处理后消失。结论:NAC小剂量或逐渐增加剂量与口服法莫替丁及静脉推注10%葡萄糖酸钙联用是一种较为安全的治疗重症肝病的方法,但对病情较轻的重症肝病患者用药时应加强监测以避免或减少不良反应的发生。

Objective： To observe the adverse reactions caused by different doses of N-acetylcysteine （NAC） in treatment of patients with severe liver diseases for an approach to the drug safe use. Methods： Between February 2006 and January 2008, 173 patients with various patterns of severe liver diseases in our hospital were enrolled in the study. One hundred and seventy-three patients were divided into 3 groups： the high-dose group （25 cases）, the low-dose group （66 cases） , and the dose-escalation group （82 cases）. The high-dose group comprised 16 men and 9 women with average age （42.3 ± 3.6） years. The low-dose group comprised 42 men and 24 women with average age （41.6 ±4.8） years. The dose-escalation group comprised 51 men and 31 women with average age （45.2 ± 5.2） years. The drug administration was as follows： the patients in the high-dose group were administered an IV infusion of NAC 8 g dissolved in 10% glucose 250 ml once daily; the patients in the low-dose group were administered NAC 4 g dissolved in 10% glucose 250 ml once daily, while oral famotidine 20 mg twice daily and slowly IV push of 10% calcium gluconate 10 ml mixed with 50% glucose 20 ml were given. The patients in the dose-escalation group received an initial dose of IV NAC 4 g/d, and if no adverse reaction occurred, the dose of NAC was increased to 8 g/d on day 4. The administration and other medications were the same as those in the low-dose group. All patients were observed at least two weeks. Results： In the high-dose group, adverse reactions occurred in 16 cases （64%） of 25 patients including 9 cases （36%） of skin disorders, 2 cases （8%） of chest distress and dizziness, 3 cases （12%） of gastrointestinal disorders, one case （4%） of anaphylactic shock, and one case （4%） of lower limbs dyskinesia. The Model for End-Stage Liver Disease （MELD） scores to the patients experiencing adverse reactions and the patients no experiencing adverse reactions in the high-dose group were 11.26 ± 5.47 and 18.38 ± 5.71, respectively. The difference was statistically significant （P 〈 0.05 ）. It indicated that the condition of patients experiencing adverse reactions was mild. In the low-dose group, adverse reactions occurred in 2 cases （ 3.03% ） of 66 patients including 1 case of rash, and 1 case of upper abdominal discomfort. The incidence of adverse reactions in the low-dose group was lower than that in the high-dose group. The difference was statistically significant （P 〈 0.001 ）. The MELD scores in the patients experiencing rash and the patients experiencing upper abdominal discomfort were 11.38 and 10.29, respectively. In the dose-escalation group, 4 patients（4.88% ） developed adverse reactions within 3 days of treatment; seven（8.97% ） of other 78 patients developed adverse reactions in more than 4 days of treatment, and the incidence was higher than the low-dose group and lower than the high-dose group （ all P 〈0.001 ）. Of the 78 patients, 31 patients＇ MELD score was 〉 15, and one case of gastrointestinal disorders and one case of skin rash occurred; 47 patients＇ MELD score was 〈 15, and 3 case of gastrointestinal disorder, one case of scalp swelling and one case of skin rash occurred. The difference between both of them was statistically significant （P 〈 0.001 ）. The patients＇ adverse reactions disappeared after discontinuation of the drug and symptomatic treatment. Conclusion： Low-dose or dose-escalation NAC combined with oral famotidine and IV calcium gluconate 10% is a safe regimen in treatment of severe liver diseases, but relatively mild cases of severe liver diseases should be closely monitored during treatment in order to avoid or decrease adverse reaction occurring.