Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial

Acute acidaemia is frequently observed during critical illness. Sodium bicarbonate infusion for the treatment of severe metabolic acidaemia is a possible treatment option but remains controversial, as no studies to date have examined its effect on clinical outcomes. Therefore, we aimed to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients.

急性酸中毒常见于危重病患者。输注碳酸氢钠治疗严重酸中毒尽管是一种治疗选择，但仍存在争议，因为至今没有研究验证其对临床预后的影响。因此，我们旨在评价输注碳酸氢钠能否改善危重病患者预后。

We did a multicentre, open-label, randomised controlled, phase 3 trial. Local investigators screened eligible patients from 26 intensive care units (ICUs) in France. We included adult patients (aged ≥18 years) who were admitted within 48 h to the ICU with severe acidaemia (pH ≤7·20, PaCO₂ ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L) and with a total Sequential Organ Failure Assessment score of 4 or more or an arterial lactate concentration of 2 mmol/L or more. We randomly assigned patients (1:1), by stratified randomisation with minimisation via a restricted web platform, to receive either no sodium bicarbonate (control group) or 4·2% of intravenous sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7·30. Our protocol recommended that the volume of each infusion should be within the range of 125–250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion. Randomisation criteria were stratified among three prespecified strata: age, sepsis status, and the Acute Kidney Injury Network (AKIN) score. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7. All analyses were done on data from the intention-to-treat population, which included all patients who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02476253.

我们进行了一项多中心、开放、随机对照3期临床试验。法国26个ICU的研究者负责筛选符合条件的患者。我们纳入收入ICU不足48 h的成年患者（年龄≥ 18岁），患者合并严重酸中毒（pH ≤7·20，PaCO₂ ≤ 45 mmHg，碳酸氢根≤ 20 mmol/L）且SOFA评分≥ 4分或乳酸水平≥ 2 mmol/L。我们通过分层随机将患者按照1:1的比例分为无碳酸氢钠（对照组）或静脉输注4.2%碳酸氢钠（碳酸氢钠组）以维持动脉pH > 7.30。我们的方案推荐30分钟内输注容量125-250 ml，入选后24小时内最大输注量不超过1000 ml。根据预先确定的标准进行分层随机分组：年龄，全身性感染，及AKIN评分。主要预后指标为复合终点，包括28天全因死亡及第7天至少一个器官功能衰竭。针对意向治疗人群（纳入所有接受随机分组的患者）进行所有统计分析。研究在ClinicalTrials.gov注册，注册号 NCT02476253。

Between May 5, 2015, and May 7, 2017, we enrolled 389 patients into the intention-to-treat analysis in the overall population (194 in the control group and 195 in the bicarbonate group). The primary outcome occurred in 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate −5·5%, 95% CI −15·2 to 4·2; p=0·24). The Kaplan-Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group was not significant (46% [95% CI 40–54] vs 55% [49–63]; p=0·09. In the prespecified AKIN stratum of patients with a score of 2 or 3, the Kaplan-Meier method estimate of survival by day 28 between the control group and bicarbonate group was significant (63% [95% CI 52–72] vs 46% [35–55]; p=0·0283). Metabolic alkalosis, hypernatraemia, and hypocalcaemia were observed more frequently in the bicarbonate group than in the control group, with no life-threatening complications reported.

2015年5月5日至2017年5月7日之间，共有389名患者纳入意向治疗分析（对照组194名，碳酸氢钠组195名）。对照组194名患者中138名(71%)以及碳酸氢钠组195名患者中128名(66%)发生主要预后事件（绝对差异-5·5%，95% CI -15·2 to 4·2; p=0·24）。对照组与碳酸氢钠组患者28天生存概率的Kaplan-Meier分析并无差异 (46% [95% CI 40–54] vs 55% [49–63]; p=0·09)。在预先计划的AKIN 2-3级亚组，对照组与碳酸氢钠组患者28天生存概率的Kaplan-Meier分析存在显著差异 (63% [95% CI 52–72] vs 46% [35–55]; p=0·0283)。与对照组相比，碳酸氢钠组更常发生代谢性碱中毒、高钠血症及低钙血症，未报告致命性并发症。

In patients with severe metabolic acidaemia, sodium bicarbonate had no effect on the primary composite outcome. However, sodium bicarbonate decreased the primary composite outcome and day 28 mortality in the a-priori defined stratum of patients with acute kidney injury.

对于严重代谢性酸中毒患者，碳酸氢钠不影响主要复合预后终点。然而，对于预先确定的AKI亚组患者，碳酸氢钠减少主要复合预后指标和28天病死率。

French Ministry of Health and the Société Française d'Anesthésie Réanimation.