Background

Hyperammonaemia is frequent in Intensive Care Unit patients. Some drugs have been described as associated with this condition, but there are no large-scale studies investigating this topic and most descriptions only consist of case-reports.

Methods

We performed a disproportionality analysis using VigiBase, the World Health Organization Pharmacovigilance Database, using the information component (IC). The IC compares observed and expected values to find associations between drugs and hyperammonaemia using disproportionate Bayesian reporting. An IC_0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. The main demographic and clinical features, confounding factors, and severity of cases have been recorded.

Results

We identified 71 drugs with a disproportionate reporting in 2924 cases of hyperammonaemia. Most of the suspected drugs could be categorised into 4 main therapeutic classes: oncologic drugs, anti-epileptic drugs, immunosuppressants and psychiatric drugs. The drugs most frequently involved were valproic acid, fluorouracil, topiramate, oxaliplatin and asparaginase. In addition to these molecules known to be responsible for hyperammonaemia, our study reported 60 drugs not previously identified as responsible for hyperammonaemia. These include recently marketed molecules including anti-epileptics such as cannabidiol, immunosuppressants such as basiliximab, and anti-angiogenics agents such as tyrosine kinase inhibitors (sunitinib, sorafenib, regorafenib, lenvatinib) and monoclonal antibodies (bevacizumab, ramucirumab). The severity of cases varies depending on the drug class involved and high mortality rates are present when hyperammonaemia occurs in patients receiving immunosuppressant and oncologic drugs.

Conclusions

This study constitutes the first large-scale study on drug-associated hyperammonaemia. This description may prove useful for clinicians in patients’ care as well as for trial design.

Graphical Abstract

中文翻译：

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药物相关性高氨血症：世界卫生组织药物警戒数据库的贝叶斯分析

背景

高氨血症在重症监护病房患者中很常见。一些药物被描述为与这种情况有关，但没有大规模的研究调查这个主题，大多数描述只包括病例报告。

方法

我们使用信息组件 (IC) 使用世界卫生组织药物警戒数据库 VigiBase 进行了不成比例分析。IC 使用不成比例的贝叶斯报告比较观察值和预期值，以发现药物和高氨血症之间的关联。IC _0.25（IC 95% 可信区间的下限）> 0 被认为具有统计学意义。记录了病例的主要人口统计学和临床​​特征、混杂因素和严重程度。

结果

我们在 2924 例高氨血症病例中确定了 71 种药物报告不成比例。大多数可疑药物可分为4个主要治疗类别：肿瘤药物、抗癫痫药物、免疫抑制剂和精神药物。最常涉及的药物是丙戊酸、氟尿嘧啶、托吡酯、奥沙利铂和天冬酰胺酶。除了这些已知导致高氨血症的分子外，我们的研究还报告了 60 种以前未被确定为导致高氨血症的药物。这些包括最近上市的分子，包括抗癫痫药（如大麻二酚）、免疫抑制剂（如巴西利昔单抗）和抗血管生成药物（如酪氨酸激酶抑制剂（舒尼替尼、索拉非尼、瑞戈非尼、乐伐替尼）和单克隆抗体（贝伐单抗、雷莫芦单抗））。

结论

这项研究构成了第一个关于药物相关高氨血症的大规模研究。这种描述可能对临床医生在患者护理以及试验设计方面有用。

图形概要