A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS
A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS
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DOI：
10.1172/jci.insight.124039
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发表时间：
2018-12-06
期刊：
影响因子：
8
通讯作者：
Choi, Augustine M. K.
中科院分区：
文献类型：
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作者：
Fredenburgh, Laura E.;Perrella, Mark A.;Choi, Augustine M. K.
背景。急性呼吸窘迫综合征（ARDS）是一种死亡率高的常见病，目前尚无有效的药物治疗方法。低剂量吸入一氧化碳（iCO）在败血症和ards临床前模型中具有细胞保护作用。我们进行了一项I期剂量递增试验，以评估低剂量iCO给药败血症性ARDS患者的可行性和安全性。在两个队列中，12名参与者被随机分为iCO或安慰剂空气2:1。4名受试者分别给予iCO（队列1为100ppm，队列2为200ppm）或安慰剂90分钟，最多连续5天。主要结局包括羧酸血红蛋白（COHb）水平>= 10%的发生率、预先规定的给药相关不良事件（ae）和严重不良事件（sae）。次要终点包括预测COHb水平、生物标志物水平和临床结果的coburn - foster - kane （CFK）方程的准确性。没有参与者的COHb水平超过10%，也没有与用药相关的ae或与研究相关的sae。与安慰剂治疗组（1.97% +/- 0.39%）相比，co治疗组的COHb显著升高（3.48% +/- 0.7%[队列1]；4.9% +/- 0.28%[队列21]）。CFK方程在预测COHb水平方面非常准确，特别是在队列2中（R-2 = 0.9205; F < 0.0001）。与安慰剂治疗的受试者相比，ico治疗的受试者循环线粒体DNA水平降低。对于脓毒症诱导的ARDS患者，精确给药低剂量iCO是可行的，耐受性良好，并且似乎是安全的。预测和观察到的COHb之间的良好一致性应确保COHb水平在未来的疗效试验中保持在目标范围内。
BACKGROUND. Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS.METHODS. We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to S consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level >= 10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes.RESULTS. No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% +/- 0.7% [cohort 1]; 4.9% +/- 0.28% [cohort 21) compared with placebo-treated subjects (1.97% +/- 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R-2 = 0.9205; F < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects.CONCLUSION. Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials.