伏立康唑致神經系統不良反應的臨床特征及低血鉀和低血鈉發生情況

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 文獻標志碼 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系統不良反應的臨床特征及不良反應發生前的低血鉀和低血鈉發生情況。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、體質量、感染類型、基礎疾病、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），發生神經系統不良反應患者的基本情況（性別、年齡、感染類型、基礎疾病、聯合用藥情況、發生時間、臨床表現等）及其發生神經系統不良反應前3天內的血鉀、血鈉和肝功能指標[谷丙轉氨酶（ALT）、谷草轉氨酶（AST）、γ-谷氨酰轉肽酶（γ-GT）、堿性磷酸酶（ALP）、總膽紅素、直接膽紅素]水平，并分析神經系統不良反應與伏立康唑谷濃度、血鉀、血鈉水平的關系。結果：411例患者中，有31例患者（7.54%）出現了神經系統不良反應，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例發生神經系統不良反應的患者中，有26例患者（83.87%）為給藥1～7 d后出現神經系統不良反應;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%）的神經系統不良反應發生率顯著高于谷濃度≤5.0 μg/mL患者（3.42%，χ 2=4.91，P=0.027）。臨床表現主要為幻覺（32.35%）、煩躁（32.35%）、睡眠差（17.65%）等。在30例檢測相關指標的患者發生神經系統不良反應的前3天內，有16例患者（53.33%）出現低血鉀，12例患者（40.00%）出現低血鈉，均顯著高于未發生神經系統不良反應患者的低血鉀發生率（24.74%，P=0.001）和低血鈉發生率（12.89%，P<0.001）;分別有8、10、7、13、7、10例患者出現ALT、AST、ALP、γ-GT、總膽紅素和直接膽紅素升高。31例發生神經系統不良反應的患者經減少劑量或停用伏立康唑后，其相關癥狀均減輕或消失。結論：伏立康唑致神經系統不良反應多發生在給藥后1～7 d，以靜脈滴注給藥為主，多發生于男性和50歲及以上人群：神經系統不良反應的發生可能與伏立康唑谷濃度有關，且神經系統不良反應發生前大多數患者出現了低血鉀或低血鈉。

關鍵詞 伏立康唑;神經系統不良反應;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.