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J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (2): 158-169    DOI: 10.3785/j.issn.1008-9292.2020.03.01
    
Pharmaceutical care for severe and critically ill patients with COVID-19
JIANG Saiping1(),LI Lu1,RU Renping2,ZHANG Chunhong3,RAO Yuefeng1,LIN Bin4,WANG Rongrong1,CHEN Na1,WANG Xiaojuan1,CAI Hongliu1,SHENG Jifang1,ZHOU Jianying1,LU Xiaoyang1,*(),QIU Yunqing1,*()
1. The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
2. Hangzhou Xixi Hospital, Hangzhou 310023, China
3. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China
4. Changxing Hospital, the Second Affiliated Hospital, Zhejiang University School of Medicine, Changxing 313100, Zhejiang Province, China
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Abstract  

Severe and critically ill patients with coronavirus disease 2019 (COVID-19) were usually with underlying diseases, which led to the problems of complicated drug use, potential drug-drug interactions and medication errors in special patients. Based on Diagnosis and treatment of novel coronavirus pneumonia (trial version 6), and Management of COVID-19: the Zhejiang experience, we summarized the experience in the use of antiviral drugs, corticosteroids, vascular active drugs, antibacterial, probiotics, nutrition support schemes in severe and critically ill COVID-19 patients. It is also suggested to focus on medication management for evaluation of drug efficacy and duration of treatment, prevention and treatment of adverse drug reactions, identification of potential drug-drug interactions, individualized medication monitoring based on biosafety protection, and medication administration for special patients.



Key wordsCoronavirus disease 2019      Severe acute respiratory syndrome coronavirus 2      Novel coronavirus infection      Critical illness      Safety management      Drug utilization     
Received: 23 February 2020      Published: 06 March 2020
CLC:  R969.3  
Corresponding Authors: LU Xiaoyang,QIU Yunqing     E-mail: j5145@zju.edu.cn;luxiaoyang@zju.edu.cn;qiuyq@zju.edu.cn
Cite this article:

JIANG Saiping,LI Lu,RU Renping,ZHANG Chunhong,RAO Yuefeng,LIN Bin,WANG Rongrong,CHEN Na,WANG Xiaojuan,CAI Hongliu,SHENG Jifang,ZHOU Jianying,LU Xiaoyang,QIU Yunqing. Pharmaceutical care for severe and critically ill patients with COVID-19. J Zhejiang Univ (Med Sci), 2020, 49(2): 158-169.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.03.01     OR     http://www.zjujournals.com/med/Y2020/V49/I2/158


2019冠状病毒病(COVID-19)重型、危重型患者用药管理经验

2019冠状病毒病(COVID-19)重型、危重型患者往往合并基础疾病,用药种类复杂,存在潜在的药物相互作用、特殊人群用药等问题。本文依据《新型冠状病毒肺炎诊疗方案(试行第六版)》,基于《2019冠状病毒病(COVID-19)诊疗浙江经验》,总结重型、危重型患者选择抗病毒药物、糖皮质激素、血管活性药物、抗菌药物、微生态制剂、营养支持方案等经验,建议针对药物疗效和疗程评估、药物不良反应防治、潜在药物相互作用识别、基于生物安全防护的个体化用药监测以及特殊人群给药等进行重点用药管理,以期为COVID-19患者临床药物选择和用药管理提供参考。


关键词: 2019冠状病毒病,  严重急性呼吸综合征冠状病毒2,  新型冠状病毒感染,  危重病,  安全管理,  药物利用 
药物名称 可能作用机制 代谢途径和代谢酶 给药方案
  ACE2:血管紧张素转换酶2.
α干扰素(雾化) 抑制病毒RNA与蛋白合成,诱导细胞产生抗病毒蛋白 每次500万U,2次/d,雾化(建议在负压病房进行)
利巴韦林 抑制病毒RNA多聚酶和mRNA鸟苷转移酶等 肝脏 500 mg,2~3次/d,静脉输注,疗程不超过10 d
洛匹那韦/利托那韦 抑制病毒3CLpro蛋白酶活性 肝脏,CYP3A 400 mg/100 mg,2次/d,口服,疗程不超过10 d
达芦那韦/考比司他 可能与洛匹那韦/利托那韦相同 肝脏,CYP3A 800 mg/150 mg,1次/d,口服,随餐同服
阿比多尔 抑制病毒的脂膜与宿主细胞的融合 肝脏,CYP3A4 200 mg,3次/d,口服,疗程不超过10 d
法匹拉韦 活性代谢产物抑制病毒基因组复制和转录 肝脏,前体药物 首剂1600 mg,1次/12 h,维持剂量600 mg,1次/12 h,口服
磷酸氯喹 抑制冠状病毒与人体细胞ACE2受体结合及免疫调节等 肝脏 适用于18~65周岁患者:>50 kg,500 mg,2次/d,口服;≤50 kg,500 mg,口服,第1~2天,2次/d,第3~7天,1次/d,疗程不超过7 d
Tab 1 Mechanism, metabolism and dosage regimens of antiviral agents for COVID-19[1, 2, 11-14]
药物名称 受 体 心脏兴
奋强度
作用血管强度作用时间
收 缩 舒 张
  “—”无相关资料.
去甲肾上腺素 α 一般 1~2 min
肾上腺素 α β 中等 1~2 h (皮下注射)
异丙肾上腺素 β1 β2 不到1 h
多巴胺 D α β 中等 一般 中等 5~10 min
多巴酚丁胺 β1 中等 约10 min
间羟胺 α 一般 中等 20 min
Tab 2 Mechanism, effect time and dosage regimens of vasoactive agents for COVID-19
分类 代表药物 药动学 PK/PD特性 临床PK/PD靶目标 给药方案(静脉用药)
  PK/PD:药动学/药效学;AUC:药时曲线下面积;MIC:最低抑菌浓度;Cmax:峰浓度;T>MIC:药物浓度高于MIC的时间.
喹诺酮类 莫西沙星 半衰期为12 h,肝肾排泄 浓度依赖型 AUC0-24/MIC:125~250 Cmax/MIC≥8 400 mg,1次/d
酶复合制剂 哌拉西林/他唑巴坦 半衰期为0.7~1.2 h,原形肾脏排泄 时间依赖型 40%~50% T>MIC 4.5 g,3~4次/d(根据感染严重程度及药敏结果调整方案)
头孢哌酮/舒巴坦(1:1) 头孢哌酮半衰期为1.7 h,75%胆道排泄;舒巴坦半衰期为1 h,原形肾脏排泄 时间依赖型 45%~100% T>MIC 2 g,3~4次/d(根据感染严重程度及药敏结果调整方案)
头孢他啶/阿维巴坦(4:1) 半衰期为2~3 h,大部分以原形肾脏排泄 时间依赖型 45%~100% T>MIC 2.5 g,1次/8 h
碳青霉烯类 亚胺培南 半衰期为1 h,原形肾脏排泄 时间依赖型 75% T>MIC ≤4 g/d,2次/d以上,根据感染严重程度及药敏结果调整方案
美罗培南 半衰期为1 h,原形肾脏排泄 时间依赖型 75% T>MIC ≤6 g/d,2次/d以上,根据感染严重程度及药敏结果调整方案
糖肽类 万古霉素 半衰期为4~6 h,原形肾脏排泄 时间-浓度依赖型 AUC0-24/MIC≥400 1 g,2次/d,根据血药浓度监测调整方案
恶唑烷酮类 利奈唑胺 半衰期为5 h,65%非肾脏途径清除,其余原形肾脏排泄 时间-浓度依赖型 AUC0-24/MIC≥85 85%T>MIC 600 mg,2次/d,必要时根据血药浓度监测调整方案
环脂肽类 达托霉素 半衰期约为8 h,原形肾脏排泄 浓度依赖型 Cmax/MIC:59~94
AUC0-24/MIC:388~537
6~10 mg/kg,1次/d
三唑类 伏立康唑 半衰期约为6 h,肝脏CYP2C19、CYP2C9等代谢 时间-浓度依赖型 AUC0-24/MIC≥20 负荷剂量:6 mg/kg,1次/12 h(第1天);维持剂量:4 mg/kg,2次/d,根据血药浓度监测调整方案
棘白菌素类 卡泊芬净 半衰期为9~11 h,肝脏代谢 浓度依赖型 Cmax/MIC>10 负荷剂量:70 mg,1次/d(第1天);维持剂量:50 mg,1次/d
Tab 3 Pharmaceutical characteristics and dosage regimens of therapeutic drugs for secondary infections in severe and critical ill COVID-19 patients[15-18]
药物名称 成 分 剂型、规格及用量用法
  CFU:菌落形成单位.
地衣芽孢杆菌活菌地衣芽孢杆菌胶囊剂、颗粒剂0.25 g(含2.5亿活菌)
成人:每次0.5 g,3次/d,首剂加倍
儿童:每次0.25 g,3次/d,首剂加倍
吞咽困难者可打开胶囊将药粉倒出加入少量温开水后服用
双歧杆菌活菌 双歧杆菌 胶囊剂0.35 g(含0.5亿活菌)
成人:每次0.35~0.7 g,2次/d
餐后服用
双歧杆菌乳杆菌三联活菌 长型双歧杆菌、保加利亚乳杆菌、嗜热链球菌 片剂0.5 g(每片含双歧杆菌活菌数应不低于0.5×107CFU,保加利亚乳杆菌和嗜热链球菌应不低于0.5×106CFU)
成人:每次2 g,2次/d或3次/d
餐后服用,温开水或温牛奶冲服
双歧杆菌三联活菌 长型双歧杆菌、嗜酸乳杆菌、粪肠球菌散剂1 g(含活菌数分别应不低于1.0×107CFU) 6岁及以上,每次2 g,3次/d
1~5岁,每次1 g,3次/d
0~1岁,每次0.5 g,3次/d
温水冲服
胶囊剂0.21 g(含活菌数分别应不低于1.0×107CFU)
成人:每次420~840 mg,2次/d或3次/d
儿童用药酌减
餐后半小时,婴幼儿服用可剥开胶囊倒出药粉,温开水或温牛奶送服
布拉氏酵母菌冻干布拉氏酵母菌菌粉0.25 g/袋(每1 g菌粉含活菌数分别应不低于1.3×109CFU)
成人:每次2袋,2次/d
3岁及以上儿童:每次1袋,2次/d
3岁以下儿童:每次1袋,1次/d
可将内容物倒入少量温水中,混合均匀后服下;可在任何时候服用,但最好不在进食时服用
复方嗜酸乳杆菌 中国株嗜酸乳杆菌、日本株嗜酸乳杆菌、粪链球菌、枯草杆菌 片剂0.5 g(每克含嗜酸乳杆菌107个)
口服,成人一次1~2片,3次/d
Tab 4 Dosage regimens and notes of intestinal microecological modulators for COVID-19 patients
药物 主要不良反应 监护要点
α干扰素 流感样症状,白细胞和血小板下降等 使用干扰素雾化吸入治疗易诱发气溶胶,建议在负压病房进行,不建议普通病房内开展雾化治疗
利巴韦林 骨髓抑制,引起溶血性贫血、白细胞下降等 使用前评估血细胞计数等,如引起严重白细胞下降及血色素下降,予停药,同时给予粒细胞集落刺激因子、促红细胞生长素等治疗
洛匹那韦/利托那韦 可引起腹泻、恶心、呕吐,肝酶与黄疸升高、血脂异常,乳酸增高等不良反应,停药后可恢复 如腹泻等不能耐受,可选择达芦那韦抗病毒治疗,肝酶及黄疸升高,给予降酶及退黄对症治疗
达芦那韦/考比司他 与洛匹那韦相似,但临床观察胃肠道耐受性高于洛匹那韦 使用过程密切监测肝功能,含磺胺成分,磺胺过敏者谨慎使用
阿比多尔 肝酶及黄疸升高,心率下降,与洛匹那韦联用时,发生率更高,停药后一般可恢复 使用过程密切监测肝功能,可引起心动过缓等不良反应,存在传导阻滞、心动过缓的患者谨慎使用
法匹拉韦 血尿酸升高、腹泻、中性粒细胞降低、休克、急性重型肝炎、急性肾损伤等; 重型患者可出现黄疸升高,尤见于老年或合并细胞因子风暴的患者 使用过程密切监测肝功能,尤其老年及危重型患者,注意监测血尿酸及血常规等指标
磷酸氯喹 可引起头晕、头痛、恶心、呕吐、腹泻、各种皮疹等,心博骤停是最严重不良反应,眼部病变是最主要不良反应 适用于18~65岁人群; 用药前行心电图检查,禁忌或相对禁忌用于心律失常(如传导阻滞)、慢性心脏病、视网膜疾病,以及听力减退或听力丧失等患者
甲泼尼龙可引起内分泌紊乱、血压升高、电解质紊乱、消化道溃疡、感染、肾上腺皮质功能减退等 治疗前完善结核感染T细胞斑点试验、乙型肝炎病毒和丙型肝炎病毒标志物等检测,避免在激素治疗过程中发生潜在感染被激活;根据情况应用质子泵抑制剂预防消化道溃疡及出血;监测血糖,一旦出现血糖升高,使用胰岛素皮下注射或强化胰岛素治疗;注意霉菌感染的风险,必要时给予碳酸氢钠含漱液、抗真菌药物等治疗
Tab 5 Main adverse reactions and pharmaceutical notes of antiviral drugs and glucocorticoids for COVID-19 patients[13, 19-22]
Fig 1 Bio-safety protection in therapeutic drug monitoring for COVID-19 patients
药物名称 采血时间点 治疗浓度范围 样品保藏条件 注意事项
  “—”无相关资料;TDM:治疗药物监测;MRSA:耐甲氧西林金黄色葡萄球菌.
洛匹那韦/利托那韦(峰)给药后30 min内
(谷)给药前30 min内
洛匹那韦:(谷)>1 μg/mL
(峰) < 8.2 μg/mL
疗效相关的血药浓度监测可只监测洛匹那韦;高浓度的利托那韦与神经和胃肠道不良反应相关
亚胺培南 当日给药前10 min内 1~8 μg/mL 室温半小时,冷藏1 h,冷冻1 h,须立即送检 β-内酰胺类抗生素为时间依赖型抗生素,2019冠状病毒病患者继发细菌感染时,须结合病原学检测的最低抑菌浓度值解读血药浓度监测结果,进而调整用药方案
美罗培南 当日给药前10 min内 1~16 μg/mL 室温2 h,冷藏3 d,冷冻10 d
哌拉西林/舒巴坦 当日给药前10 min内 16~64 μg/mL
万古霉素 当日给药前30 min内 10~20 mg/L(重症MRSA感染时推荐15~20 mg/L) 室温1 d,冷藏3 d,冷冻14 d 须常规监测血药浓度,同时密切关注患者的肾功能
利奈唑胺 当日给药前30 min内 2~7 μg/mL 室温1 h,冷藏2 h,冷冻3 d,需立即送检 肾功能不全患者和透析患者须加强监测利奈唑胺血药浓度
伏立康唑 当日给药前30 min内 1~5.5 μg/mL 室温14 d,冷藏14 d,冷冻14 d 须考虑药物相互作用对伏立康唑血药浓度的影响;监测患者肝功能
Tab 6 Therapeutic drug monitoring for COVID-19 patients[23-24]
药物名称 可能的相互作用 联合用药禁忌
  “—”无相关资料;TDM:治疗药物监测;AUC:药时曲线下面积.
洛匹那韦/利托那韦①与CYP3A代谢的药物(如二氢吡啶、钙通道阻滞剂、HMG-CoA还原酶抑制剂、免疫抑制剂和PDE5抑制剂)联合使用可导致药物的血浆浓度升高,尤其要注意临床症状及治疗药物监测;
②导致利伐沙班AUC增加153%,阿托伐他汀AUC增加5.9倍,咪达唑仑AUC增加13倍
严禁与胺碘酮(致命性心律失常)、喹硫平(严重昏迷)、辛伐他汀(横纹肌溶解)等联合使用
达芦那韦/考比司他 ①与主要经由CYP3A和/或CYP2D6代谢的药物联合用药时可导致此类药物血浆浓度升高;
②药物相互作用参考洛匹那韦/利托那韦
参考洛匹那韦/利托那韦
阿比多尔 与CYP3A4及UGT1A9底物、抑制剂和诱导剂之间可能存在药物相互作用
利巴韦林 ①与齐多夫定联合使用可导致药物毒性增加;
②与核苷反转录酶抑制剂联合使用可导致线粒体中毒(乳酸中毒、胰腺炎、肝衰竭)相关不良反应风险增加
法匹拉韦①茶碱可使法匹拉韦生物利用度上升;
②可使乙酰氨基酚生物利用度上升到1.79倍;
③与吡嗪酰胺联合使用可使血液中尿酸水平升高;
④与瑞格列奈联合使用会导致瑞格列奈血药浓度升高,不良反应发生率增加
磷酸氯喹 严禁与莫西沙星、阿奇霉素、胺碘酮等可能导致Q-T间期延长的药物合用
Tab 7 Interactions between antiviral drugs and drugs for common underlying diseases in patients with COVID-19[25-27]
药物名称 妊娠妇女 机械通气患者 肝功能不全患者 肾功能不全患者 肾脏替代治疗者 体外膜氧合器治疗者
  “—”无相关资料;TDM:治疗药物监测;CrCL:肌酐清除率.
洛匹那韦/利托那韦 选择片剂 选择口服液 重度肝功能不全禁用 无须调整 无须调整 增加剂量
α干扰素(雾化) 禁用 避免使用超声雾化 肝硬化失代偿期禁用 无须调整 无须调整 无须调整
利巴韦林 禁用 无须调整 慎用 CrCL<50 mL/min避免使用 血液透析:按1/2原剂量给药
连续性肾脏替代治疗:无须调整
无须调整
磷酸氯喹 禁用 无须调整 慎用 慎用 血液透析部分清除
阿比多尔 无须调整 慎用 重度肾功能不全慎用
达芦那韦/考比司他 慎用 不可碾碎 重度肝功能不全禁用 无须调整 无须调整 增加剂量
法匹拉韦 禁用 无须调整 减少剂量 无须调整
甲泼尼龙 慎用 无须调整 无须调整 无须调整 血液透析可清除
微生态制剂 避免使用布拉氏酵母菌 无须调整 无须调整 无须调整 无须调整 无须调整
莫西沙星 禁用 无须调整 肝功能损伤(Child Pugh C)和转氨酶升高大于5倍正常值上限者禁用 无须调整 无须调整
头孢呋辛 可用 无须调整 无须调整CrCL 10~20 mL/min:750 mg,1次/12 h;
CrCL < 10 mL/min:750 mg,1次/d
血液透析后加用750 mg
连续性肾脏替代治疗:
1.5 g,1次/12 h
哌拉西林/他唑巴坦慎用无须调整无须调整CrCL 20~40 mL/min:4.5 g,1次/8 h;
CrCL < 20 mL/min:4.5 g,1次/12 h
血液透析:医院获得性肺炎最大剂量2.25 g,1次/8 h,透析后加用0.75 g
连续性肾脏替代治疗:2.25~4.5 g,1次/6 h
无须调整
头孢哌酮/舒巴坦慎用无须调整重度肝功能不全者头孢哌酮日剂量 < 2 gCrCL 15~30 mL/min:舒巴坦最高剂量为0.5 g,1次/12 h;
CrCL < 15 mL/min:舒巴坦最高剂量为0.5 g,1次/12 h
血液透析:血透结束后给药
连续性肾脏替代治疗:1g,1次/8 h
头孢他啶/阿维巴坦慎用无须调整无须调整CrCL 31~50 mL/min:1.25 g,1次/8 h;
CrCL 16~30 mL/min:0.94 g,1次/12 h;
CrCL 6~15 mL/min:0.94 g,1次/d;
CrCL≤5 mL/min:0.94 g,1次/48 h
血液透析:血透结束后适当追加药物剂量
连续性肾脏替代治疗:2.5 g,1次/8 h
亚胺培南/西司他丁慎用无须调整无须调整CrCL 41~70 mL/min:原剂量的2/3~3/4
CrCL 21~40 mL/min:原剂量的1/2
CrCL 6~20 mL/min:原剂量的1/4~1/2
血液透析:CrCL≤5 mL/min患者进行血液透析时参考CrCL 6~20 mL/min未行血液透析时剂量,血液透析后使用;
连续性肾脏替代治疗:0.5~1 g,1次/6 h
谷浓度个体差异大
万古霉素慎用无须调整无须调整CrCL 20~50 mL/min:0.5 g,1次/12~24 h;
CrCL10~19 mL/min:0.5 g,1次/24~48 h;
CrCL < 10 mL/min:0.5g,1次/48~96 h;
根据TDM调整
血液透析:500 mg,1次/48~96 h,高通量透析后需补充剂量,根据TDM调整;
连续性肾脏替代治疗:初始给予15~20 mg/kg剂量,后续根据TDM调整
可能需要增加剂量,建议根据TDM调整
利奈唑胺 慎用 无须调整 无需调整,建议监测血药浓度 无需调整,建议监测血药浓度 无需调整,建议监测血药浓度 无须调整
达托霉素 可用 无须调整 无须调整 CrCL<30 mL/min:6 mg/kg,1次/48 h 血透:CrCL<30 mL/min:6 mg/kg,1次/48 h
连续性肾脏替代治疗:6~8 mg/kg,1次/d
无须调整
伏立康唑 避免使用 无须调整 肝硬化Child Pugh A与B,负荷剂量不变,维持剂量减半,Child Pugh C缺少研究注射剂CrCL<50 mL/ min权衡利弊使用无须调整 浓度升高,可能需要减少剂量
卡泊芬净 慎用 无须调整 Child Pugh评分7~9负荷剂量不变,维持剂量每日35 mg 无须调整 无须调整 无须调整
Tab 8 Drug therapy recommendation in special populations of severe and critical ill COVID-19 patients[11, 28-31]
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