程林 梁再明 劉職瑞 喻明潔 夏培元

中圖分類號 R591.1;R969.3;R978.5 文獻(xiàn)標(biāo)志碼 A 文章編號 1001-0408（2021）20-2520-05

DOI 10.6039/j.issn.1001-0408.2021.20.14

摘 要 目的：探討伏立康唑致神經(jīng)系統(tǒng)不良反應(yīng)的臨床特征及不良反應(yīng)發(fā)生前的低血鉀和低血鈉發(fā)生情況。方法：回顧性分析2018年1月-2020年11月我院收治的411例使用伏立康唑治療的患者資料，包括基本資料（性別、年齡、體質(zhì)量、感染類型、基礎(chǔ)疾病、致病真菌類型以及伏立康唑的給藥方式、維持劑量、血藥濃度等），發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)患者的基本情況（性別、年齡、感染類型、基礎(chǔ)疾病、聯(lián)合用藥情況、發(fā)生時(shí)間、臨床表現(xiàn)等）及其發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)前3天內(nèi)的血鉀、血鈉和肝功能指標(biāo)[谷丙轉(zhuǎn)氨酶（ALT）、谷草轉(zhuǎn)氨酶（AST）、γ-谷氨酰轉(zhuǎn)肽酶（γ-GT）、堿性磷酸酶（ALP）、總膽紅素、直接膽紅素]水平，并分析神經(jīng)系統(tǒng)不良反應(yīng)與伏立康唑谷濃度、血鉀、血鈉水平的關(guān)系。結(jié)果：411例患者中，有31例患者（7.54%）出現(xiàn)了神經(jīng)系統(tǒng)不良反應(yīng)，男性患者占比（64.52%）高于女性（35.48%），以50歲及以上人群（74.20%）為主，肺部感染（96.77%）為主要感染類型。在31例發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)的患者中，有26例患者（83.87%）為給藥1～7 d后出現(xiàn)神經(jīng)系統(tǒng)不良反應(yīng);30例患者（96.77%）為靜脈滴注給藥。伏立康唑谷濃度>5.0 μg/mL患者（8.99%）的神經(jīng)系統(tǒng)不良反應(yīng)發(fā)生率顯著高于谷濃度≤5.0 μg/mL患者（3.42%，χ 2=4.91，P=0.027）。臨床表現(xiàn)主要為幻覺（32.35%）、煩躁（32.35%）、睡眠差（17.65%）等。在30例檢測相關(guān)指標(biāo)的患者發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)的前3天內(nèi)，有16例患者（53.33%）出現(xiàn)低血鉀，12例患者（40.00%）出現(xiàn)低血鈉，均顯著高于未發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)患者的低血鉀發(fā)生率（24.74%，P=0.001）和低血鈉發(fā)生率（12.89%，P<0.001）;分別有8、10、7、13、7、10例患者出現(xiàn)ALT、AST、ALP、γ-GT、總膽紅素和直接膽紅素升高。31例發(fā)生神經(jīng)系統(tǒng)不良反應(yīng)的患者經(jīng)減少劑量或停用伏立康唑后，其相關(guān)癥狀均減輕或消失。結(jié)論：伏立康唑致神經(jīng)系統(tǒng)不良反應(yīng)多發(fā)生在給藥后1～7 d，以靜脈滴注給藥為主，多發(fā)生于男性和50歲及以上人群：神經(jīng)系統(tǒng)不良反應(yīng)的發(fā)生可能與伏立康唑谷濃度有關(guān)，且神經(jīng)系統(tǒng)不良反應(yīng)發(fā)生前大多數(shù)患者出現(xiàn)了低血鉀或低血鈉。

關(guān)鍵詞 伏立康唑;神經(jīng)系統(tǒng)不良反應(yīng);谷濃度;低血鉀;低血鈉

Clinical Characteristics of Voriconazole-induced Neurological ADR and the Occurrence of Hypokalemia and Hyponatremia

CHENG Lin，LIANG Zaiming，LIU Zhirui，YU Mingjie，XIA Peiyuan（Dept. of Pharmacy， the First Affiliated Hospital of Army Medical University， Chongqing 400038， China）

ABSTRACT? ?OBJECTIVE： To explore the clinical characteristics of voriconazole-induced neurological ADR and the occurrence of hypokalemia and hyponatremia before ADR. METHODS： The medical records of 411 patients receiving voriconazole therapy， who admitted to our hospital from January 2018 to November 2020， were retrospectively analyzed. The general information of all patients， including sex， age， body weight， type of infection， underlying disease， type of pathogenic fungal infection and? administration route of voriconazole， maintenance dose， blood drug concentration， were collected. The basic information of patients with neurological ADR， including sex， age， types of infection， underlying disease， drug combination， occurrence time and clinical manifestations， were collected. The levels of blood potassium， blood sodium and liver function indexes （ALT， AST， γ-GT， ALP， total bilirubin， direct bilirubin） within 3 days before the neurological ADR were also collected. The relationship of neurological ADR with voriconazole trough concentration， blood potassium and blood sodium levels was analyzed.? RESULTS： Among 411 patients， 31 （7.54%） patients suffered from neurological ADR， which were higher in male （64.52%） than in female （35.48%）， mainly in patients aged 50 and over （74.20%）. The major infection type was lung infection （96.77%）. Among 31 patients with neurological ADR， 26 patients suffered from neurological ADR after 1-7 days after voriconazole administration， accounting for 83.87%. Thirty patients received intravenous drip， accounting for 96.77%. The incidence of neurological ADR in patients with voriconazole trough concentration>5.0 μg/mL （8.99%） was significantly higher than that in patients with trough concentration≤5.0 μg/mL （3.42%， χ 2=4.91， P=0.027）. The clinical manifestations of the patients were mainly hallucinations （32.35%）， irritability （32.35%） and poor sleep （17.65%）， etc. Within 3 days before 30 patients， receiving related indexes test， suffered from neurological ADR， 16 patients （53.33%） had hypokalemia and 12 patients （40.00%） had hyponatremia， which were significantly higher than the incidence of hypokalemia （24.74%，P=0.001） and hyponatremia （12.89%，P<0.001） in those without neurological ADR. There were 8， 10， 7， 13， 7 and 10 patients with ALT， AST， ALP， γ-GT， total bilirubin and direct bilirubin increased. In 31 patients with neurological ADR， the neurological ADR were relieved or disappeared after reducing the dosage or discontinuing voriconazole. CONCLUSIONS： The neurological ADR of voriconazole mostly occurs 1-7 days after voriconazole administration， mainly by intravenous drip， mostly in male and people aged 50 and over. The occurrence of neurological ADR may be related to trough concentration of voriconazole， and most patients suffer from hypokalemia or hyponatremia before the occurrence of ADR.