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Volume 39 Issue 6
Nov.  2021
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ZHANG Jingming, LU Wenjie, ZHOU Shuqin, ZHAO Jian, WAN Honghong, ZHUANG Yugang. Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 566-568. doi: 10.12206/j.issn.1006-0111.202103017
Citation: ZHANG Jingming, LU Wenjie, ZHOU Shuqin, ZHAO Jian, WAN Honghong, ZHUANG Yugang. Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 566-568. doi: 10.12206/j.issn.1006-0111.202103017

Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning

doi: 10.12206/j.issn.1006-0111.202103017
  • Received Date: 2021-01-17
  • Rev Recd Date: 2021-08-30
  • Available Online: 2021-12-27
  • Publish Date: 2021-11-25
  •   Objective  To explore the role of clinical pharmacists in the treatment of drug poisoning by analyzing the clinical pharmacist's participation in the treatment of a patient with sodium valproate poisoning.   Methods  Clinical pharmacists measured the plasma concentration of sodium valproate to inform the doctor to diagnose illnesses. At the initial stage when the concentration is high, to eliminate the free drug by continuous venous-venous hemodialysis-filtration (CVVHDF). Then, the combined drug was cleared by hemoperfusion (HP).   Results  The blood concentration dropped by half at the first CVVHDF and decreased obviously after two HPs. After stable observation in five days’ course of disease, the blood concentration was maintained at a low level and the patient was cured and discharged.   Conclusion  The implementation of the blood purification program under the monitoring of the blood drug concentration with the participation of pharmacists is helpful for the rescue of drug overdose and is worthy of promotion.
  • [1] LÖSCHER W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy[J]. CNS Drugs,2002,16(10):669-694.
    [2] FERREY A E, GEULAYOV G, CASEY D, et al. Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning[J]. BMC Psychiatry,2018,18(1):399.
    [3] 喻东山, 李广录, 汪春运. 丙戊酸钠的不良反应研究新进展[J]. 国际神经病学神经外科学杂志, 2005, 32(4):319-321.
    [4] DUPUIS R E, LICHTMAN S N, POLLACK G M. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites[J]. Drug Saf,1990,5(1):65-71.
    [5] 孙利伟, 闫红月. 荧光偏振免疫法测定丙戊酸钠血清药物浓度[J]. 中国实用医药, 2010, 5(29):127-128.
    [6] 黄凤娇, 李继洪, 唐敦立, 等. 丙戊酸钠与双丙戊酸钠的毒性比较[J]. 中国药物警戒, 2012, 9(1):7-9.
    [7] 中国医师协会急诊医师分会, 中国毒理学会中毒与救治专业委员会. 急性中毒诊断与治疗中国专家共识[J]. 中华急诊医学杂志, 2016, 25(11):1361-1375.
    [8] 戈文兰, 王广基, 孙建国, 等. 丙戊酸钠缓释片及其人体生物利用度的研究[J]. 中国药科大学学报, 2000, 31(6):422.
    [9] GHANNOUM M, LALIBERTÉ M, NOLIN T D, et al. Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup[J]. Clin Toxicol (Phila),2015,53(5):454-465.
    [10] MOINHO R, DIAS A, ESTANQUEIRO P, et al. Overdose with antiepileptic drugs: the efficacy of extracorporeal removal techniques[J]. BMJ Case Rep,2014,2014:bcr2014207761.
    [11] DORÉ M, SAN JUAN A E, FRENETTE A J, et al. Clinical importance of monitoring unbound valproic acid concentration in patients with hypoalbuminemia[J]. Pharmacotherapy,2017,37(8):900-907.
    [12] 史道华, 邓婕, 连秋燕. 血浆蛋白含量与丙戊酸游离药物浓度的相关性[J]. 中国临床药理学杂志, 2014, 30(3):188-189,201.
    [13] 史纳. 醒脑静与门冬氨酸鸟氨酸联合用药方案治疗肝性脑病的临床研究[J]. 中国现代药物应用, 2020, 14(16):156-158.
    [14] 曹芳, 张广文, 闫亚平. 乳果糖口服溶液联合注射用门冬氨酸鸟氨酸治疗肝性脑病的临床效果及对神经毒性物质、炎症因子水平的影响[J]. 临床医学研究与实践, 2020, 5(36):14-16.
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Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning

doi: 10.12206/j.issn.1006-0111.202103017

Abstract:   Objective  To explore the role of clinical pharmacists in the treatment of drug poisoning by analyzing the clinical pharmacist's participation in the treatment of a patient with sodium valproate poisoning.   Methods  Clinical pharmacists measured the plasma concentration of sodium valproate to inform the doctor to diagnose illnesses. At the initial stage when the concentration is high, to eliminate the free drug by continuous venous-venous hemodialysis-filtration (CVVHDF). Then, the combined drug was cleared by hemoperfusion (HP).   Results  The blood concentration dropped by half at the first CVVHDF and decreased obviously after two HPs. After stable observation in five days’ course of disease, the blood concentration was maintained at a low level and the patient was cured and discharged.   Conclusion  The implementation of the blood purification program under the monitoring of the blood drug concentration with the participation of pharmacists is helpful for the rescue of drug overdose and is worthy of promotion.

ZHANG Jingming, LU Wenjie, ZHOU Shuqin, ZHAO Jian, WAN Honghong, ZHUANG Yugang. Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 566-568. doi: 10.12206/j.issn.1006-0111.202103017
Citation: ZHANG Jingming, LU Wenjie, ZHOU Shuqin, ZHAO Jian, WAN Honghong, ZHUANG Yugang. Analysis of clinical pharmacists participating in the treatment of a case of sodium valproate poisoning[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 566-568. doi: 10.12206/j.issn.1006-0111.202103017
  • 丙戊酸钠是一种临床常用的抗癫痫药物,用于治疗全身和部分发作类型的癫痫,同时,丙戊酸钠也可用于治疗与双向情感障碍相关的躁狂发作[1]。丙戊酸钠中毒可能偶然发生,也可能是有意而为之,尤其是对有自残意图的患者[2]。急性丙戊酸钠中毒通常表现为中枢神经系统抑制、肝酶升高、血氨升高和电解质紊乱,如高钠血症等。严重过量使用丙戊酸钠的患者可出现低血压、心动过速、呼吸抑制、代谢性酸中毒、脑水肿等,如果不积极治疗,可进展为昏迷甚至死亡[3]。本文报道一例丙戊酸钠中毒患者的救治过程,为临床救治药物中毒患者中如何发挥临床药师的作用提供参考。

    • 患者,女性,22岁,身高165 cm,体重55 kg。因“服用丙戊酸钠缓释片(0.5 g/片)60片4 h”入院。入院前4 h患者因情绪激动自服丙戊酸钠缓释片(0.5g/片)60片(准确计数)后依次出现少语,乏力,嗜睡,但无明显呕吐。

      患者自2年前被诊断为双向情感障碍,长期服用抗抑郁药帕罗西汀20mg qd、丙戊酸钠缓释片0.5g qn,规律服药。否认高血压、糖尿病、心脏病、肝炎等慢性疾病,否认食物药物过敏史、无吸烟史,偶有饮酒。

      急诊查体:血压145/91 mmHg,心率127次/min,体温37.4℃,呼吸频率20次/min,双肺呼吸音粗,未及明显干湿啰音。心律齐,腹软,未及明显包块,无明显肌紧张。四肢肌力正常,病理征未引出。

      实验室检查:C反应蛋白2.47 mg/L,白细胞6.82×109/L,血小板388×109/L,淋巴细胞百分比0.52%,谷丙转氨酶12.7 U/L,结合胆红素2.0 μmol/L,血氨24 μmol/L,白蛋白41 g/L,血红蛋白133 g/L,血总淀粉酶106.8 U/L,血钾3.3 mmol/L,血肌酐63 μmol/L,乳酸3.8 mmol/L,尿隐血1+。肺部CT:两肺下叶炎症。

      急查丙戊酸钠血药浓度307.8 mg/L。立即予以洗胃催吐,洗胃容量为20 000 ml,无明显药物碎屑洗出。同时给与纳洛酮促醒、呋塞米利尿、谷胱甘肽、异甘草酸镁保肝、奥美拉唑抑酸护胃等对症支持治疗后,转入ICU继续治疗。入院诊断:急性丙戊酸钠中毒,肺部感染,双向情感障碍。

    • 患者转入时嗜睡乏力,鼻导管吸氧。有文献报道,如果急性摄入丙戊酸钠超过200 mg/kg或血药浓度大于180 mg /L的患者,常导致中枢神经系统功能障碍,可能发生震颤、躁动、脑水肿等神经功能损伤[4]。考虑到患者丙戊酸钠血药浓度较高,临床医生开放中心静脉通路,行连续静脉-静脉透析-滤过治疗(CVVHDF),处理前急查丙戊酸钠血药浓度317.4 mg/L,CVVHDF模式,血流速度160 ml/min,脱水速度110 ml/h,透析液2000 ml/h。首次CVVHDF后,立即查丙戊酸钠血药浓度150.3 mg/L,仍然偏高,CVVHDF后约8 h查血药浓度为260.9 mg/L,药师建议行CVVHDF联合血液灌注加速药物的清除。

      入院第2天,患者神志清,精神软,乏力状,气平,心律齐,血氨67 μmol/L,血红蛋白110 g/L,白蛋白34.8 g/L,余未见明显异常,针对血氨升高,使用注射用门冬氨酸鸟氨酸10 g qd,继续补液、护胃、保肝等治疗。并行血液灌流治疗3 h,低分子肝素体外抗凝,血流速度160 ml/min。血液灌流后查丙戊酸钠血药浓度97.7 mg/L。第3天,查丙戊酸钠血药浓度227.8 mg/L,血氨116.5 μmol/L,白蛋白28 g/L,总蛋白56 g/L,临床药师建议补充人血白蛋白,血总淀粉酶139.9 U/L,关注胰腺炎可能。患者诉入院以来没有大便,腹部听诊器检查提示肠鸣音较弱,临床药师结合患者血氨较高,建议医生使用乳果糖口服液,20 ml tid。患者精神状态可,神志清,精神软,考虑到患者服用丙戊酸钠剂量过大,组织器官可能存在药物蓄积,故继续行CVVHDF联合血液灌流治疗,方法同前。治疗后,测丙戊酸钠血药浓度73.5 mg/L。第4天,查血药浓度65 mg/L,血氨96 μmol/L,入院第5天血药浓度41 mg/L,血氨28 μmol/L,精神状态可,神志清,嗜睡情况明显好转,转出ICU。在住院期间,除白蛋白短暂降低,血氨升高外,肝肾功能未见明显异常,予以出院。

    • 近年来急诊各种药物过量患者呈现上升趋势,服用药物也越来越复杂。临床上能开展的血药浓度监测较少。而近年来开展的丙戊酸钠血药浓度监测逐渐应用于临床。目前测定丙戊酸钠血药浓度采用荧光免疫法,具有简便、快速,临床实用性强等特点[5]

      丙戊酸钠口服生物利用度接近100%,血浆蛋白结合率较高,血药浓度50 mg/L时蛋白结合率约为94%,血药浓度100 mg/L时,蛋白结合率为80%~85%,主要分布在细胞外液和肝、肾、肠、脑等组织,大部分经肝脏代谢,包括与葡萄糖醛酸共价结合和β氧化酶氧化等过程,后大部分经肾脏排泄。丙戊酸钠为小分子化合物,水溶性较强,蛋白结合率高,考虑到患者吞服丙戊酸钠缓释片剂量过大,且血药浓度较高,文献报道急性摄入丙戊酸钠过多,血药浓度大于180 mg/L常导致患者中枢神经系统功能障碍,如震颤、躁动、脑水肿等神经功能损伤,丙戊酸钠组织器官药物浓度高可能损伤肝、脑、肾等多种重要器官[4]。有文献报道大鼠口服丙戊酸钠半数致死量折算到人的半数致死量为0.13~0.16 g/kg[6],按照患者60 kg计算,半数致死剂量约为8~10 g,极限致死剂量为15 g左右,该患者服用丙戊酸钠缓释片总量达到30 g,具有积极抢救的意义。

      过量服用丙戊酸钠虽无特效解毒剂,但亦无洗胃禁忌证。专家共识认为,对无特效解毒剂的急性重度中毒患者,即使已超过6 h仍可考虑洗胃[7],丙戊酸钠缓释片服药10 h可溶出80%左右[8],其说明书亦指出洗胃治疗在药物摄入后10~12 h内仍然有效果,故临床药师认为对该患者进行洗胃处理很合理且必要。

      丙戊酸钠为强碱弱酸盐,水中溶解后呈弱碱性,pH7.5~9.0,加强利尿可促进丙戊酸钠的排出。临床药师结合丙戊酸钠理化性质、药动学特点,建议采用连续肾脏替代治疗(CRRT)和血液灌流相结合的方法清除药物。文献表明,血液透析和血液灌流可以加快丙戊酸的消除。在一项病例研究中,血液透析使丙戊酸半衰期从治疗前13 h减少到治疗后1.7 h,并在治疗4 h内表现出显著的临床改善[9]。当血清丙戊酸钠浓度降至50 ~ 100 mg /L (350 ~ 700 mmol/L)时,可停止体外治疗。

      在本例中,临床医生紧急开放中心静脉通路,行CVVHDF治疗,快速稳定降低患者血液中游离态丙戊酸钠浓度。经10 h CVVHDF治疗,丙戊酸钠血药浓度从317 mg/L降低至150 mg/L,8 h后血药浓度又反跳至261 mg/L。血液净化一次后丙戊酸钠血药浓度可能出现反跳现象[10],缘于组织器官药物浓度依然较大,药物重新分布导致血药浓度再次上升。临床药师考虑到丙戊酸钠蛋白结合率高,而CRRT主要用于高水溶性、小分子、低蛋白结合率的毒物清除,对结合态丙戊酸钠清除效果不佳,故建议在CRRT基础上联合血液灌流治疗,血液灌流主要用于高蛋白结合率、高脂溶性、相对分子质量较大的毒物,树脂灌流器对蛋白结合和脂溶性分子清除较好,经3 h血液灌流,丙戊酸钠血药浓度从261 mg/L降低至97.7 mg/L,清除效果较显著。在体内,丙戊酸钠以游离状态与相应受体结合产生药效,因丙戊酸钠血浆蛋白结合率高,血浆蛋白含量的改变可以显著影响游离丙戊酸钠浓度,进而影响药效或产生毒性不良反应[11]。有研究证实等量丙戊酸钠随血浆蛋白的增加,游离丙戊酸钠血药浓度呈下降趋势[12],当患者血浆白蛋白降低时适当补充白蛋白可以减小丙戊酸钠的毒副作用。

      丙戊酸钠导致的血氨升高及相关的高氨血症性脑病时有报道[4],可表现为精神错乱、癫痫发作、嗜睡等,可进展为昏迷甚至死亡,临床应密切关注患者血氨变化。患者入院第二天血氨升高,达67 μmol/L,使用注射用门冬氨酸鸟氨酸10 g qd。本药可提供尿素和谷氨酰胺合成的底物,谷氨酰胺是氨的解毒产物,同时也是氨的储存及运输形式;鸟氨酸涉及尿素循环的活化和氨的解毒全过程;门冬氨酸参与肝细胞内核酸的合成,以利于修复被损伤的肝细胞[13]。入院第三天患者诉入院以来无大便,且血氨升至116.5 μmol/L,故临床药师建议口服乳果糖,乳果糖为渗透性轻泻剂,在小肠内不被水解吸收,其渗透性使水和电解质保留于肠腔,本药在结肠内被细菌分解成乳酸、醋酸,使肠内渗透压进一步升高,粪便容量增大,刺激肠蠕动,产生导泄作用。结肠内生成的乳酸和醋酸可以使肠腔pH值降低,形成不利于分解蛋白质的细菌生存、繁殖的酸性内环境,从而减少氨的产生,酸性环境还可使NH3转变为NH4+,解离状态的NH4+脂溶性小,肠道难以吸收而随粪便排出,当结肠内pH值从7.0降至5.0时,结肠黏膜不仅不吸收氨入血,反而从血液中向结肠排出氨[14]。乳果糖在治疗便秘的同时可以降低血氨。

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