How to monitor thiopental administration in the intensive care unit for refectory status epilepticus or intracranial hypertension?,Critical Care

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How to monitor thiopental administration in the intensive care unit for refectory status epilepticus or intracranial hypertension?
Critical Care ( IF 15.1 ) Pub Date : 2021-12-17 , DOI: 10.1186/s13054-021-03851-8
Erika Dabricot ₁ , Inès Seqat ₂ , Frédéric Dailler ₁ , Sylvain Rheims _{2,

3} , Sebastien Boulogne _{2,

3} , Baptiste Balança _{1,

3}

Affiliation

Thiopental continuous administration can be used as a rescue therapy for refractory status epilepticus (SE) or intracranial hypertension (IH). It induces an electroencephalographic (EEG) slowing up to a burst suppression state. The subsequent reduction in the cerebral metabolic demand and blood flow also allows decreasing the intracranial pressure (ICP) [1]. The continuous administration is usually guided both by thiopental serum concentration, to avoid accumulation, and efficacy on seizures or ICP. Thiopental side effects (hemodynamic dysfunction or immunosuppression) can occur at concentrations of 30–70 mg/ml [2, 3]. Conversely, the relation between serum concentrations and efficacy is less robust. In healthy subjects during anesthesia and in brain-injured patients, there is a great variability in the concentration needed to reach the same EEG changes [4, 5], with an overlap between the therapeutic and toxic ranges. The digitalization of the EEG signal provides quantitative indexes at the bedside and may allow tailoring sedative administration in the intensive care unit (ICU). For instance, the suppression ratio (SR) provides a metric of the depth of sedation during general anesthesia [5]. Since the target of thiopental sedation is to reach a discontinuous EEG activity (i.e., SR ≥ 10%); the aim of the herein study was to evaluate the relationship between the thiopental concentration and the SR in patients with a refractory SE or IH.

We conducted a retrospective study (2013–2020) in adult patients sedated with thiopental and monitored with a continuous EEG, in the neurological ICU of the Hospices Civils de Lyon (France). We analyzed EEG signals of 2 h windows around the serum measurements (1 h before and after). Suppression periods were defined by an EEG amplitude < 10 µV for ≥ 400 ms [6] and was calculated on 2 s epochs on the central derivation with the best signal (Fz-Cz or adjacent; BRAIN-QUICK, Micromed). We took the mean SR of the 2 h. The relation between concentration and duration of thiopental administration and the SR was analyzed with a linear mixed effect model with the R software (lme4 library). The diagnostic accuracy of thiopental concentration to predict a discontinuous EEG was analyzed with a receiver operating characteristic curve (ROC, pROC library). Data are presented as their median and interquartile range.

We included 30 patients, 47% (n = 14/30) had a refractory SE. They were 39.5 years old [27.5–55.5], 30% (n = 9) were female, and 37% had a potent thiopental adverse effect (sepsis: n = 5; hemodynamic instability: n = 6). The median concentration of thiopental (n = 95 samples) was 16.5 mg/ml [8.5–23.1], with a median administration rate of 2.1 mg/kg/h [1.3–2.9]. At the blood sampling time, 45.3% (n = 43/95) of the EEG were discontinuous with heterogeneous SR decay time (Fig. 1). 74% of the EEG from patients with a SE did not have epileptic discharges and 68% of patients with an IH had an ICP < 25 mmHg. The ICP value was not significantly associated with the thiopental concentration. There was a significant association between thiopental concentration and SR, which was not dependent on the indication (SE or IH). However, for a given thiopental concentration, the level of SR was highly variable and thiopental concentration could not predict a discontinuous EEG (AUC of the ROC = 0.59 95%CI [0.47; 0.71], Fig. 2). Other sedative agents were also administered in 20 patients but did not significantly influence SR; their withdraw led to a SR decrease in 4 cases.

The main limitation of the herein study is its retrospective design. Given the heterogeneity of the EEG changes for a given thiopental administration, we would argue to have a continuous SR monitoring when using barbiturate to reach a discontinuous activity. The concomitant monitoring of electrophysiological data and serum concentration might help tailor the individual administration and monitor the effect of thiopental on brain activity. Such strategy will need to be evaluated in a prospective trial.

The datasets used during the current study are available from the corresponding author on reasonable request.

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Author notes

Erika Dabricot and Inès Seqat have contributed equally to this work.

Affiliations

Department of Neurological Anesthesiology and Intensive Care, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, Groupement Hospitalier Est, 59 Boulevard Pinel, 69500, Bron, Lyon, France
Erika Dabricot, Frédéric Dailler & Baptiste Balança
Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Lyon 1 University, Lyon, France
Inès Seqat, Sylvain Rheims & Sebastien Boulogne
Lyon’s Neuroscience Research Center, INSERM U1028/CNRS UMR 5292, Lyon 1 University, Lyon, France
Sylvain Rheims, Sebastien Boulogne & Baptiste Balança

Authors

Erika DabricotView author publications
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Inès SeqatView author publications
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Frédéric DaillerView author publications
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Sylvain RheimsView author publications
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Sebastien BoulogneView author publications
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Baptiste BalançaView author publications
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Contributions

BB, ED, IS and SB conceived and design the study. ED collected the data from digital medical records. IS and SB reviewed electrophysiological data. BB analyzed the data. BB, ED, IS and SB interpreted the data. ED and BB draft the article. All authors critically revised the article. All authors approved the final version to be published.

Corresponding author

Correspondence to Baptiste Balança.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the French Intensive Care Society (No. IRB 00010254-2021-032).

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Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Dabricot, E., Seqat, I., Dailler, F. et al. How to monitor thiopental administration in the intensive care unit for refectory status epilepticus or intracranial hypertension?. Crit Care 25, 439 (2021). https://doi.org/10.1186/s13054-021-03851-8

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Received: 27 October 2021
Accepted: 01 December 2021
Published: 17 December 2021
DOI: https://doi.org/10.1186/s13054-021-03851-8

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中文翻译：

如何监测重症监护病房中的硫喷妥钠给药是否存在食道性癫痫持续状态或颅内高压？

硫喷妥钠连续给药可用作难治性癫痫持续状态 (SE) 或颅内高压 (IH) 的抢救疗法。它诱导脑电图 (EEG) 减慢到爆发抑制状态。随后脑代谢需求和血流量的减少也可以降低颅内压 (ICP) [1]。连续给药通常以硫喷妥钠血清浓度为指导，以避免蓄积，以及对癫痫发作或 ICP 的疗效。硫喷妥钠的副作用（血流动力学功能障碍或免疫抑制）可在 30–70 mg/ml 的浓度下发生 [2, 3]。相反，血清浓度和疗效之间的关系不太可靠。在麻醉期间的健康受试者和脑损伤患者中，达到相同 EEG 变化所需的浓度存在很大差异 [4, 5]，治疗范围和毒性范围之间存在重叠。EEG 信号的数字化可在床边提供定量指标，并可能允许在重症监护病房 (ICU) 中定制镇静剂给药。例如，抑制比 (SR) 提供了一种衡量全身麻醉期间镇静深度的指标 [5]。由于硫喷妥钠镇静的目标是达到不连续的 EEG 活动（即 SR ≥ 10%）；本研究的目的是评估难治性 SE 或 IH 患者硫喷妥浓度与 SR 之间的关系。EEG 信号的数字化可在床边提供定量指标，并可能允许在重症监护病房 (ICU) 中定制镇静剂给药。例如，抑制比 (SR) 提供了一种衡量全身麻醉期间镇静深度的指标 [5]。由于硫喷妥钠镇静的目标是达到不连续的 EEG 活动（即 SR ≥ 10%）；本研究的目的是评估难治性 SE 或 IH 患者硫喷妥浓度与 SR 之间的关系。EEG 信号的数字化可在床边提供定量指标，并可能允许在重症监护病房 (ICU) 中定制镇静剂给药。例如，抑制比 (SR) 提供了一种衡量全身麻醉期间镇静深度的指标 [5]。由于硫喷妥钠镇静的目标是达到不连续的 EEG 活动（即 SR ≥ 10%）；本研究的目的是评估难治性 SE 或 IH 患者硫喷妥浓度与 SR 之间的关系。

我们对使用硫喷妥钠镇静并通过连续脑电图监测的成年患者进行了一项回顾性研究（2013-2020 年），该患者在里昂市民医院（法国）的神经 ICU 中进行。我们分析了血清测量周围 2 小时窗口的脑电图信号（前后 1 小时）。抑制周期由 EEG 幅度 < 10 µV ≥ 400 ms [6] 定义，并以最佳信号（Fz-Cz 或相邻；BRAIN-QUICK，Micromed）的中心推导的 2 s 时期计算。我们取了 2 小时的平均 SR。使用 R 软件（lme4 库）采用线性混合效应模型分析硫喷妥给药浓度和持续时间与 SR 之间的关系。用受试者工作特征曲线（ROC，pROC 库）分析硫喷妥钠浓度预测不连续 EEG 的诊断准确性。

我们纳入了 30 名患者，47% ( n = 14/30) 患有难治性 SE。他们是 39.5 岁 [27.5–55.5]，30% ( n = 9) 是女性，37% 有强烈的硫喷妥钠副作用（败血症：n = 5；血流动力学不稳定：n = 6）。硫喷妥钠（n = 95 个样品）的中位浓度为 16.5 mg/ml [8.5–23.1]，中位给药率为 2.1 mg/kg/h [1.3–2.9]。在采血时，45.3% ( n = 43/95）的脑电图不连续，具有异质 SR 衰减时间（图 1）。74% 的 SE 患者的 EEG 没有癫痫放电，68% 的 IH 患者的 ICP < 25 mmHg。ICP值与硫喷妥浓度没有显着相关性。硫喷妥钠浓度和 SR 之间存在显着关联，这不依赖于适应症（SE 或 IH）。然而，对于给定的硫喷妥浓度，SR 水平变化很大，并且硫喷妥浓度不能预测不连续的 EEG（ROC 的 AUC = 0.59 95%CI [0.47; 0.71]，图 2）。20 名患者还使用了其他镇静剂，但对 SR 没有显着影响；他们的退出导致 4 个病例的 SR 下降。

本研究的主要局限在于其回顾性设计。鉴于给定硫喷妥给药的脑电图变化的异质性，我们认为在使用巴比妥类药物达到不连续活动时进行连续的 SR 监测。同时监测电生理数据和血清浓度可能有助于调整个体给药并监测硫喷妥钠对大脑活动的影响。这种策略需要在前瞻性试验中进行评估。

当前研究期间使用的数据集可根据合理要求从相应作者处获得。

1.
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CAS 文章谷歌学术
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Huynh F, Mabasa VH, Ensom MHH。批判性评论：硫喷妥钠持续输注是否需要在重症监护人群中进行治疗药物监测？药物监测。2009；31：153–69。
CAS 文章谷歌学术
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Parviainen I、Uusaro A、Kälviäinen R、Kaukanen E、Mervaala E、Ruokonen E. 高剂量硫喷妥钠治疗重症监护病房难治性癫痫持续状态。神经病学。2002；59：1249–51。
CAS 文章谷歌学术
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Winer JW、Rosenwasser RH、Jimenez F. 脑电图活动以及血清和脑脊液戊巴比妥水平在确定巴比妥类昏迷期间的治疗终点时。神经外科。1991；29:739。
CAS 文章谷歌学术
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Bührer M, Maitre PO, Hung OR, Ebling WF, Shafer SL, Stanski DR. 硫喷妥钠药效学 I. 定义假稳态血清浓度-脑电图效应关系。麻醉学。1992；77:226-36。
文章谷歌学术
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Särkelä M、Mustola S、Seppänen T、Koskinen M、Lepola P、Suominen K 等。麻醉中爆发抑制的自动分析和监测。J临床监视器比较。2002；17：125-34。
文章谷歌学术

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作者笔记

Erika Dabricot 和 Inès Seqat 对这项工作做出了同样的贡献。

隶属关系

神经麻醉学和重症监护部，Hospices Civils de Lyon, Hôpital Pierre Wertheimer, Groupement Hospitalier Est, 59 Boulevard Pinel, 69500, Bron, Lyon, France
Erika Dabricot、Frédéric Dailler 和 Baptiste Balança
功能性神经病学和癫痫学系，Hospices Civils de Lyon 和 Lyon 1 大学，法国里昂
Inès Seqat、Sylvain Rheims 和 Sebastien Boulogne
里昂神经科学研究中心，INSERM U1028/CNRS UMR 5292，里昂第一大学，法国里昂
西尔万·兰斯、塞巴斯蒂安·布洛涅和巴蒂斯特·巴兰萨

作者

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贡献

BB、ED、IS 和 SB 构思并设计了这项研究。ED 从数字医疗记录中收集数据。IS 和 SB 审查了电生理数据。BB 分析了数据。BB、ED、IS 和 SB 对数据进行了解释。ED 和 BB 起草文章。所有作者都对文章进行了批判性修改。所有作者都批准了最终版本的出版。

通讯作者

给巴蒂斯特·巴兰萨的信函。

伦理批准和同意参与

该研究得到了法国重症监护协会伦理委员会的批准（编号 IRB 00010254-2021-032）。

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