中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 周佳
患儿,男,9岁,体质量45 kg。患儿于入院10 d前,玩耍时摔伤后出现左髋疼痛,行走受限,左髋疼痛持续不好转,并逐渐加重,1 d后无法行走,并出现发热,至当地医院按“左髋滑膜炎”治疗。具体药物不详,效果欠佳,左髋疼痛加重,伴发热反复发作,体温波动于约38.4 ℃,遂来我院就诊,拟“左髋关节感染性病变”收治入院。患儿既往无药物食物过敏史,无家族过敏史。2017年3月24日行左髋切开引流术、病变活检术、关节清理术。
术后分泌物培养结果显示耐甲氧西林金黄色葡萄球菌,给予替考拉宁(商品名:他格适,Sanofi-aventis S.p.A.,批号:A5471)400 mg,qd+0.9%氯化钠注射液250 mL,静脉滴注,抗感染治疗。输注前8 d,临床情况平稳。第9天患儿输注替考拉宁(浓度1.6 mg·mL-1,滴速约2 mL·min-1)约5 min后突发呼吸困难、口唇发绀并心率增快,立即停止替考拉宁输液,给予吸氧,并急诊应用地塞米松5 mg后症状缓解。药师会诊,确认了当时替考拉宁之前配置浓度及输液速度正常,查看患儿当日用药医嘱仅替考拉宁(其他辅助治疗药物包括骨瓜提取物注射液、复合辅酶已于昨日停用),考虑替考拉宁变态反应不能排除,临床停用替考拉宁,换用利奈唑胺注射液(商品名:斯沃,Fresenius Kabi Norge AS,Norway,批号15C26U59)450 mg,q8h,静脉滴注治疗。输注前两剂过程中未见异常情况,第3剂输注过程中患儿胸腹部出现皮疹,高出皮肤表面,呈现团块样,10 min后未经特殊处理,皮疹自行好转。在利奈唑胺第4剂(浓度2 mg·mL-1,滴速约2 mL·min-1)输注2~3 min后患儿发生呼吸困难,心率增快,临床予以吸氧后转重症监护室(ICU),入ICU待患儿症状缓解后,继续予输注利奈唑胺抗感染,在原先正常滴速的基础上进一步减慢滴速,当日临床情况平稳。次日ICU主任查房后,停用利奈唑胺,换用万古霉素(商品名:稳可信,Lilly S.A.,批号:C542011)450 mg,q6h+0.9%氯化钠注射液200 mL治疗,正常滴速情况下(配置浓度2.25 mg·mL-1,滴速1.5 mL·min-1)开始输注2~3 min后再次出现呼吸困难、口唇发绀伴心率增快,给予吸氧后症状缓解。药师会诊,与院内药品不良反应监测部门核实了近期未收到临床其他患儿使用以上3种同批号药物发生类似不良反应报告,考虑目前用药为治疗必需,结合入科后曾通过减慢利奈唑胺滴速使当日输液平稳完成,故建议临床在严密监护前提下,将万古霉素输注速度减慢到单剂大于5 h,同时滴注前加用抗过敏药物氯雷他定片10 mg,qd,口服。之后在缓慢输注万古霉素过程中,未再出现不适症状,顺利治疗1周后出院回当地继续治疗。
患儿左髋关节耐甲氧西林金黄色葡萄球菌感染,可供选择的治疗药物主要有糖肽类(万古霉素、替考拉宁)和 唑烷酮类(利奈唑胺)。由上述病程可见,患儿最初使用的药物是替考拉宁,输注前8 d,临床情况平稳。第9天患儿输注替考拉宁约5 min后出现了呼吸困难、心率增快的症状。已有报道显示[1],替考拉宁在临床使用中的不良反应主要包括变态反应、红人综合征、发热、畏寒、寒战、肾毒性、血液学异常等,其中发生时间最短为输液约1 h,最长为用药后第9天,本患儿最初不良反应发生的时间与文献报道相吻合。替考拉宁所致的不良反应中,全身性损害占2/3,主要包括过敏性休克和红人综合征等[1]。过敏性休克常发生在首次输液过程中,红人综合征在机体首次接触该药时即可出现,也可发生于用药数天后。红人综合征严格意义上不是变态反应,而属于“类过敏反应”,即一种症状表现与变态反应相似,但发生机制不同,无需提前致敏且不经免疫介导,首次接触即可发生的药物不良反应[2]。
继替考拉宁之后患儿改用利奈唑胺,在使用利奈唑胺的过程中先出现了皮疹,后出现呼吸困难,心率增快。类似的不良反应也有相关报道[3]。既往报道显示1例老年患者使用利奈唑胺2 d后全身出现散在小红丘疹伴瘙痒不适,当日输注利奈唑胺过程中出现面部及全身皮肤潮红、烦躁、大汗等症状,心率增快,血压升高。停止输注利奈唑胺并对症处理后心率、血压恢复正常,但丘疹及瘙痒症状至次日才逐渐消失。本例发生皮疹十几分钟后自行消退,当出现呼吸困难心率增快经对症处理缓解后,医生曾再次使用利奈唑胺,通过将正常输注速度进一步减慢,前述症状未再出现。
由病程可见,临床将正常输注速度进一步减慢(利奈唑胺和万古霉素)之后未再发生类似变态反应相关症状。从该患儿病情转归看,一系列反应符合“类过敏反应”。虽然临床未尝试通过减慢替考拉宁的输注速度来观察患儿的不良反应是否会消失,但是考虑到替考拉宁和万古霉素同属于糖肽类,在结构上有相似之处,因此病程最初患儿对替考拉宁的临床反应很可能也是和输注速度相关的类过敏反应。从症状上来说,过敏反应和类过敏反应都可以出现皮疹、呼吸困难及心动过速等表现,两者很难从症状上区分。但是从后续转归上可以区别。两者的区别在于变态反应是通过IgE介导,而后者不经过免疫反应直接作用于肥大细胞及嗜碱性粒细胞,导致组胺大量释放所致[4]。如果是IgE介导的变态反应,其和滴速不相关,一定要切断过敏原,否则还是会继续发生变态反应症状。而类过敏反应通过调整输注速度或预防性使用抗组胺药物是可以减少甚至避免发生[5,6,7]。
为减少类过敏反应,相关成人研究建议万古霉素输注速度每分钟不要超过10 mg或配置浓度不超过5 mg·mL-1至少滴注1h [5],由于儿童与成人给药剂量差异,笔者认为后者标准更适于儿童参考。基于目前国内外对于如何判别类过敏反应和过敏反应尚无明确临床标准,当万古霉素常规输注速率下仍发生过敏样反应,尤其是不同于典型红人综合征表现时[8],药师建议临床改用其他替代药物。若特殊情况下,高度怀疑为万古霉素类过敏反应史,且无法获得合适替代药物或必须使用万古霉素时,药师建议可尝试在常规速率下进一步减慢滴速,并在给药前预防性使用抗组胺药物[5,9-10],但前提是具备有良好的应急抢救措施。本患儿替考拉宁、利奈唑胺和万古霉素三药先后致类过敏反应,临床选药困难,故后期病程中尝试在严密监护下缓慢输注万古霉素(浓度2.25 mg·mL-1,单次滴注时间≥5 h)并且加用抗组胺药物。在减慢滴速输注后,组胺产生量减少,而组胺在体内会迅速被代谢经尿排出,本身产生速度减慢又被快速代谢,从而大剂量组胺引起支气管收缩继发呼吸困难以及心动过速等临床症状就不再出现。
The authors have declared that no competing interests exist.
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替考拉宁是糖肽类抗生素，临床上主要用于治疗对青霉素或头孢菌素耐药的革兰阳性菌所致的各种感染。其在临床使用中的不良反应主要包括过敏反应、红人综合征、发热、畏寒、寒战、肾毒性、血液学异常等。临床医务人员应加强对替考拉宁的合理使用，避免或减少其所致的ADR发生。
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Background: Nonallergic drug hypersensitivities, also referred to as pseudoallergic or anaphylactoid reactions, have clinical manifestations that are often indistinguishable from allergic reactions. Methods: We performed a PubMed search using the terms ‘drug allergy, drug hypersensitivity, pseudoallergies, anaphylaxis and nonallergic drug reactions’ and reviewed 511 publications dated between 1970 and 2012. A total of 160 papers that were relevant to the most common nonallergic drug hypersensitivity reactions were selected for discussion. Results: Nonallergic drug hypersensitivities do not involve either IgE-mediated (type 1) or delayed (type 4) hypersensitivity. Nonallergic hypersensitivities are commonly referred to as pseudoallergic or idiosyncratic reactions. The common nonallergic drug hypersensitivities are secondary to chemotherapeutic drugs, radiocontrast agents, vancomycin, nonsteroidal anti-inflammatory agents, local anesthetic reactions and opiates. Protocols for skin testing of radiocontrast, nonsteroidal anti-inflammatory agents, local anesthetics and chemotherapeutic agents have been developed, though most have not been validated or standardized. Other diagnostic tests include in vitro-specific IgE tests, and the current ‘gold’ standard is usually an oral challenge or bronchoprovocation test. In the case of aspirin, even though it is not believed to be IgE-mediated, a ‘desensitization’ protocol has been developed and utilized successfully, although the mechanism of this desensitization is unclear. Conclusions: Diagnostic methods exist to distinguish allergic from nonallergic drug hypersensitivity reactions. The best option in nonallergic drug hypersensitivity is avoidance. If that is not possible, premedication protocols have been developed, although the success of premedication varies amongst drugs and patients.
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Two regimens for infusing vancomycin over 1 h (500 mg every 6 h for five doses or 1000 mg every 12 h for three doses) were used in 11 volunteers. Subjects received both regimens one week apart; the regimen used first for each subject was randomized. Nine receiving the 1000-mg dose experienced the "red-man (neck)" syndrome; none had the reaction while receiving the 500-mg dose (P = .002). Plasma histamine concentration, measured every 10 min during the first infusion of each regimen, increased in most subjects given 1000mg doses; there was only a slight change in histamine levels after 500-mg doses. There was a significant relation between histamine release and reaction severity; frequency and severity of the reaction declined with subsequent doses. We conclude that the red-man syndrome occurs frequently in normal adults who receive 1000 mg of vancomycin over 1 h, that vancomycin causes an infusion rate-dependent increase in plasma histamine concentration, and that the increase in plasma histamine concentration is correlated with the severity of the reaction.
[本文引用:3]
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The use of lower osmolality radiocontrast media (RCM) has been associated with satisfactory radiographic opacification and a reduced incidence of severe reactions. The higher cost without clearly established benefit of these media have limited their use. This investigation assessed the incidence of immediate generalized reactions (IGRs) to repeated RCM IGRs in pretreated high-risk patients who received iopamidol or iohexol during 200 procedures (181 intravascular). All patients had experienced a previous IGR to a conventional RCM. Pretreatment consisted of prednisone, 50 mg, 13, 7, and 1 hour before the procedure and diphenhydramine, 50 mg, 1 hour before the procedure in 140 intravascular infusions. Ephedrine, 25 mg, 1 hour before the infusion was added to prednisone-diphenhydramine in 41 cases. Only one (0.7%) urticarial reaction occurred in 141 procedures with prednisone-diphenhydramine. No repeated IGR occurred with the three-drug regimen. The reaction rate after pretreatment with prednisone-diphenhydramine or prednisone-diphenhydramine-ephedrine and use of conventional contrast media during 800 intravascular procedures was 9.1%, and with pretreatment and lower osmolality contrast media in 181 intravascular infusions, it was 0.5% (chi 2 = 14.35; p less than 0.001). Lower osmolality contrast media should be the contrast media of choice for patients with a prior IGR to conventional contrast media. In addition, patients should receive prednisone-diphenhydramine-ephedrine or prednisone-diphenhydramine prophylaxis.
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DOI:10.1186/cc1871
URL
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The red man syndrome (RMS) is the most common toxicity of vancomycin therapy. A prospective trial to investigate the frequency, causation, and possible prophylaxis of this syndrome was conducted. Thirty-three patients were observed during their first two doses (1 g/60 min) of vancomycin. Before dose 1, they were randomized to double-blinded pretreatment with either diphenhydramine (50 mg) or placebo. Patients were examined frequently, and histamine levels were obtained at 0, 30, and 60 min during dose 1. Those with first-dose reactions were rerandomized for pretreatment and had histamine levels drawn during a second infusion. Of 17 patients with placebo pretreatment, 8 (47%) had RMS. None of the 16 pretreated with diphenhydramine had a first-dose reaction (P = .003). Three of the eight first-dose reactors had a second-dose RMS reaction; in one of these three, it was more severe than the dose 1 RMS despite diphenhydramine pretreatment. RMS events were associated with elevated plasma histamine; this was especially true of severe reactions.
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Rapid infusion of vancomycin causes histamine-mediated side effects, hypotension, and rash, known as "red man syndrome." In this prospective, randomized, double-blind, placebo-controlled study, we examined the ability of oral antihistamines to attenuate three clinical end points: rash, hypotension, and vancomycin discontinuation, and we compared these findings with those of a similar study using IV antihistamines. Patients (ASA physical status I-III) who required vancomycin prophylaxis for elective arthroplasty received either oral antihistamines (diphenhydramine < or = 1 mg/kg and cimetidine < or = 4 mg/kg, n = 20) or placebo (n = 10) 1 h before rapid vancomycin infusion (1 g over 10 min). The vancomycin infusion was discontinued if the mean arterial blood pressure decreased by > or = 20% or if itching was intolerable for the patient. Clinically significant hypotension developed in no treated patients, compared with five (50%) patients in the placebo group (P = 0.001). Rapid infusion was stopped for one treated patient (5%) and for five (50%) patients in the placebo group (P = 0.004). Incidence (P = 0.011) and severity of rash (P = 0.015) were also reduced in treated patients. Peak histamine levels were increased but were similar for patients in both groups (mean +/- SD, 1.9+/-2.5 vs 1.6+/-2.4 ng/mL; P = 0.75). Oral antihistamines were as effective as IV antihistamines. In conclusion, oral H1 and H2 antihistamine pretreatment is a practical, safe, and inexpensive option to attenuate histamine-mediated side effects associated with rapid vancomycin infusion. Clinicians often must administer vancomycin faster than the 1-h recommended time, which can cause "red man syndrome" (rash, itching, hypotension). Our randomized, double-blind, placebo-controlled study showed that oral H1 and H2 antihistamine pretreatment significantly reduced the histamine-related side effects of rapid vancomycin infusion.
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