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Intravenous vitamin C in adults with sepsis in the intensive care unit: still LOV’IT?
Critical Care ( IF 8.8 ) Pub Date : 2022-07-30 , DOI: 10.1186/s13054-022-04106-w
Christian Stoppe 1 , Jean-Charles Preiser 2 , Daniel de Backer 3 , Gunnar Elke 4
Affiliation  

The recent results of the lessening organ dysfunction with vitamin C (LOVIT) randomized controlled trial (RCT) have challenged the potentially beneficial role and brought concerns on the safety of high-dose vitamin C in patients with sepsis. Septic patients admitted to the intensive care unit (ICU) received either high-dose vitamin C or placebo. As opposed to placebo, vitamin C was associated with an increased occurrence of the primary endpoint (persistent organ dysfunction plus death) [1]. While these results may suggest the end of the vitamin C story, several aspects suggest that LOVIT is just one piece of the puzzle and that the baby should not be thrown out with the bathwater.

Regarding LOVIT, it should be noted that although the primary endpoint was met, there were no differences in its individual components. Imbalances in baseline characteristics may have contributed to the observed differences. Patients in the intervention group had 10% higher lactate levels, were more often in shock and mechanically ventilated already at baseline. Thus, compared to placebo, patients receiving vitamin C appeared to be sicker, overall contributing to the higher risk of organ dysfunction.

The results of LOVIT differ from previous RCTs, where beneficial effects of vitamin C were observed: Vitamin C may restore vascular responsiveness to vasoactive agents, improve microcirculatory blood flow, preserve endothelial function, augment bacterial defense and prevent apoptosis.2 Due to its redox-potential and powerful antioxidant capacities, vitamin C may modify the inflammatory cascade and related organ dysfunctions [2]. Observational studies demonstrated low vitamin C levels to be associated with organ dysfunctions in septic patients [3, 4]. As humans are incapable to synthesize and store vitamin C, supplementation to replete vitamin C pool is imperative [5].

The clinical significance of high-dose vitamin C given as a "sepsis cocktail” with hydrocortisone and thiamine was popularized by Marik et al. [6]. This cocktail significantly reduced hospital mortality, time on vasopressor and organ injury. Consequently, numerous RCTs assessing the effects of IV vitamin C have been performed in critically ill patients followed by several systematic reviews and meta-analyses (SRMA) [7]. Some demonstrated benefits including lower mortality, less organ dysfunction and reduced duration on vasopressor support in those patients receiving high-dose vitamin C [7]. None of these trials showed evidence of harm of high-dose vitamin C in septic or non-septic critically ill patients [8], with exception of one study using a prolonged continuous infusion of vitamin C that indicated an increase in acute kidney injury (AKI) [9]. No evidence of increased AKI was observed in LOVIT.

The most recent updated SRMA demonstrated beneficial effects on 30-day and hospital mortality in 4366 patients, while a detrimental effect was observed at 90 days in an analysis including only a subset of 1722 patients and for which LOVIT contributed to 58% [10].

The LOVIT investigators could not provide an explanation for their findings. We offer further thoughts, which should carefully be considered for the interpretation of the received findings and planning of future studies (Table 1).

Table 1 Research questions regarding vitamin C supplementation in critically ill (septic) patients
Full size table

First, assuming a time dependent production and release of reactive oxygen species (ROS), the benefit of vitamin C may depend on the redox- and inflammation balance in the early acute inflammatory phase of sepsis [11]. Besides hyperinflammation with overwhelming release of ROS, patients with sepsis including SARS-CoV-2 commonly show a period of relative immunosuppression [12]. In the LOVIT trial, patients were excluded if > 24 h in the ICU; however, 13.3% of patients in the IVVC group already spent 49 h in another hospital’s ICU, so that the acute onset of sepsis may have occurred earlier. Thus, the initiation of the treatment may have been started too late being mainly delivered after the initial cytokine storm, and probably given here at relatively too high dose, potentially negating any biologically plausible antioxidant treatment benefits.

Second, in most of the trials, patients were included largely based on undifferentiated phenotypes, likely having a different mortality risk and also different treatment response [12, 13]. Thus, imbalances in sepsis phenotypes may have contributed to the heterogeneity in response to vitamin C in the different trials. Third, no surrogate markers of vitamin C were measured and the average vitamin C level (measured in a sub-cohort) was in the normal range, whereas patients with vitamin C deficiency are known to most likely to benefit from a supplementation. The absence of severe deficiencies, or biological surrogate markers that identify patients, which benefit from the intervention may provide explanations, why multiple RCTs have repeatedly failed to demonstrate clinical benefits.13 It has been hypothesized that not all patients show the same response to an intervention, so that the future concept of a personalized therapy should be adapted to interindividual “metabotypes” based on patient’s illness severity, level of inflammation and oxidative stress capacity (“sweet spot”), respectively [14].

So how do we get there? It is under current debate that we have to move beyond syndromic characterization of the underlying disease of critical illness and to develop disease models based on shared pathophysiological patterns [15]. While position papers and consensus conferences try to provide better guidance during times were several RCTs having failed to demonstrate beneficial effects, a combination of theoretical and practical considerations across key domains such as the patients' individual insult and biological response deserves more attention. Ongoing larger RCTs in different cohorts including COVID-19 (LOVIT-COVID, REMAP-CAP), burn (VICTORY), post-cardiac arrest (VITaCCA) and/or cardiac surgery patients (advanceCSX) may help to answer the question whether vitamin C treatment is effective in more specific patient cohorts.

Vitamin C—lov’it or not anymore? Most recent evidence does not support the routine administration of high-dose vitamin C in septic patients. Heterogeneity in outcome between various studies suggests that certain subsets of patients may benefit from vitamin C. Further trials will focus on a more personalized approaches to identify which critically ill patients respond positively to a certain intervention. These should also better define the optimal dose and duration of therapy, better assessment of the risk-to-benefit ratio, evaluate the underlying mechanism and consider which clinical outcomes are likely to be improved by the intervention.

Not applicable.

ICU:

Intensive care unit

LOVIT:

Lessening organ dysfunction with vitamin C

RCT:

Randomized controlled trial (RCTs)

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SRMA:

Systematic review and meta-analysis

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Authors and Affiliations

  1. Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Josef-Schneider-Straße 2, 97080, Wuerzburg, Germany

    Christian Stoppe

  2. Medical Direction, Erasme University Hospital, Universtié Libre de Bruxelles, Brussels, Belgium

    Jean-Charles Preiser

  3. Department of Intensive Care, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium

    Daniel de Backer

  4. Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 Haus 12, 24105, Kiel, Germany

    Gunnar Elke

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  2. Jean-Charles PreiserView author publications

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  3. Daniel de BackerView author publications

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  4. Gunnar ElkeView author publications

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Contributions

CS, JCP, DdB and GE substantially contributed to the designed, conception of this article and drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Christian Stoppe.

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Not applicable.

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All authors confirmed consent on publication of the present manuscript.

Competing interest

Dr. Stoppe reported that he has received consultant fees from Baxter Healthcare and Fresenius Kabi in the past. Dr. Preiser reported that he has received travel expenses, speaker and advisory honoraria from Baxter, Fresenius Kabi, Nestlé HealthScience and Nutricia Danone. Dr. Elke reported that he has received travel expenses, speaker and advisory honoraria from Fresenius Kabi. Dr. De Backer declares that he has no conflict of interest.

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Stoppe, C., Preiser, JC., de Backer, D. et al. Intravenous vitamin C in adults with sepsis in the intensive care unit: still LOV’IT?. Crit Care 26, 230 (2022). https://doi.org/10.1186/s13054-022-04106-w

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中文翻译：

重症监护室脓毒症成人静脉注射维生素 C：仍然喜欢吗？


维生素 C 减轻器官功能障碍 (LOVIT) 随机对照试验 (RCT) 的最新结果对维生素 C 的潜在有益作用提出了挑战，并引发了人们对大剂量维生素 C 在脓毒症患者中的安全性的担忧。入住重症监护病房 (ICU) 的脓毒症患者接受高剂量维生素 C 或安慰剂治疗。与安慰剂相反，维生素 C 与主要终点（持续性器官功能障碍加死亡）的发生率增加相关[1]。虽然这些结果可能预示着维生素 C 故事的终结，但从多个方面来看，LOVIT 只是拼图中的一小部分，不应将婴儿与洗澡水一起倒掉。


关于 LOVIT，值得注意的是，虽然达到了主要终点，但其各个组成部分没有差异。基线特征的不平衡可能导致了观察到的差异。干预组患者的乳酸水平高出 10%，更常处于休克状态，并且在基线时已经接受机械通气。因此，与安慰剂相比，接受维生素 C 的患者病情似乎更严重，总体上导致器官功能障碍的风险更高。


LOVIT 的结果与之前的随机对照试验不同，之前观察到了维生素 C 的有益作用：维生素 C 可以恢复血管对血管活性药物的反应性、改善微循环血流、保护内皮功能、增强细菌防御和防止细胞凋亡。 2由于其氧化还原电位和强大的抗氧化能力，维生素 C 可以改变炎症级联反应和相关器官功能障碍 [2]。观察性研究表明，低维生素 C 水平与脓毒症患者的器官功能障碍有关 [3, 4]。由于人类无法合成和储存维生素 C，补充维生素 C 库势在必行 [5]。


Marik 等人推广了高剂量维生素 C 与氢化可的松和硫胺素作为“脓毒症鸡尾酒”的临床意义。[6]。这种鸡尾酒显着降低了医院死亡率、血管加压药时间和器官损伤。因此，大量随机对照试验评估静脉注射维生素 C 的效果已在危重患者中进行，随后进行了多项系统评价和荟萃分析 (SRMA) [7]，其中一些显示的益处包括接受高剂量治疗的患者死亡率较低、器官功能障碍较少以及血管加压药物支持持续时间缩短。剂量维生素 C [7]，没有证据表明高剂量维生素 C 对脓毒症或非脓毒症危重患者有害 [8]，但一项使用长期连续输注维生素 C 的研究除外。 LOVIT 中没有观察到 AKI 增加的证据。


最近更新的 SRMA 证明对 4366 名患者的 30 天死亡率和住院死亡率有有益影响，而在仅包括 1722 名患者的一部分的分析中，在 90 天观察到有害影响，其中 LOVIT 占 58% [10]。


LOVIT 研究人员无法对他们的发现做出解释。我们提出了进一步的想法，在解释收到的研究结果和规划未来的研究时应仔细考虑这些想法（表 1）。


表 1 关于危重病（脓毒症）患者补充维生素 C 的研究问题
 全尺寸桌子


首先，假设活性氧 (ROS) 的产生和释放具有时间依赖性，维生素 C 的益处可能取决于败血症早期急性炎症阶段的氧化还原和炎症平衡 [11]。除了ROS大量释放引起的过度炎症外，包括SARS-CoV-2在内的脓毒症患者通常会表现出一段相对的免疫抑制期[12]。在 LOVIT 试验中，如果 > 24 小时在 ICU 中，则患者被排除；然而，IVVC组中13.3%的患者已经在另一家医院的ICU度过了49小时，因此败血症的急性发作可能更早发生。因此，治疗的开始可能太晚了，主要是在最初的细胞因子风暴之后进行的，并且可能以相对过高的剂量给予，可能会抵消任何生物学上合理的抗氧化治疗的益处。


其次，在大多数试验中，患者主要是根据未分化的表型被纳入的，可能具有不同的死亡风险和不同的治疗反应[12, 13]。因此，败血症表型的不平衡可能导致了不同试验中维生素 C 反应的异质性。第三，没有测量维生素 C 的替代标志物，平均维生素 C 水平（在子队列中测量）处于正常范围，而已知维生素 C 缺乏的患者最有可能从补充剂中受益。缺乏严重的缺陷或识别从干预中受益的患者的生物替代标志物可能可以解释为什么多项随机对照试验屡次未能证明临床益处​​。 13据推测，并非所有患者对干预措施都表现出相同的反应，因此个性化治疗的未来概念应根据患者的疾病严重程度、炎症水平和氧化应激能力（“甜蜜”）来适应个体间的“代谢型”。点”），分别[14]。


那么我们如何到达那里呢？当前的争论是，我们必须超越危重疾病基础疾病的症状特征，并根据共同的病理生理学模式开发疾病模型[15]。虽然立场文件和共识会议试图在多项随机对照试验未能证明有益效果的情况下提供更好的指导，但跨关键领域（例如患者的个人侮辱和生物反应）的理论和实践考虑的结合值得更多关注。在不同队列中正在进行的大型随机对照试验，包括 COVID-19 (LOVIT-COVID、REMAP-CAP)、烧伤 (VICTORY)、心脏骤停后 (VITaCCA) 和/或心脏手术患者 (advanceCSX) 可能有助于回答维生素 C 是否有效的问题治疗对更特定的患者群体有效。


维生素 C——喜欢还是不喜欢？最近的证据不支持脓毒症患者常规服用大剂量维生素 C。各种研究之间结果的异质性表明，某些患者亚群可能受益于维生素 C。进一步的试验将侧重于更加个性化的方法，以确定哪些危重患者对某种干预措施有积极反应。这些还应该更好地确定最佳剂量和治疗持续时间，更好地评估风险效益比，评估潜在机制并考虑干预措施可能改善哪些临床结果。

 不适用。

 重症监护病房：

 重症监护室

 洛维特：


用维生素 C 减轻器官功能障碍

 随机对照试验：


随机对照试验 (RCT)

 RNS：


活性氮物种

 活性氧：

 活性氧

 SRMA：


系统评价和荟萃分析


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    CAS 文章谷歌学术


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  9. Honore PM、Redant S、Djimafo P、Preseau T、Cismas BV、Kaefer K、Barreto Gutierrez L、Anane S、Attou R、Gallerani A、De Bels D。得出的结论是维生素 C 单一疗法未能显着降低感染性休克患者的死亡率：谨防潜在的混杂因素！重症监护医学。 2022；50：e611–2。 https://doi.org/10.1097/CCM.0000000000005516。


    文章 PubMed 谷歌学术


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     文章谷歌学术


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    CAS 文章 PubMed 谷歌学术

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 作者和单位


  1. 维尔茨堡大学医院麻醉科、重症监护、急诊和疼痛医学科，Josef-Schneider-Straße 2, 97080, 维尔茨堡, 德国

     克里斯蒂安·斯托普


  2. 比利时布鲁塞尔自由大学伊拉斯姆大学医院医学指导

     让·查尔斯·普雷泽


  3. 比利时布鲁塞尔自由大学 CHIREC 医院重症监护室

     丹尼尔·德巴克


  4. 麻醉科和重症监护医学系，石勒苏益格-荷尔斯泰因大学医学中心，基尔校区，Arnold-Heller-Str。 3 Haus 12, 24105, 基尔, 德国

     冈纳尔·埃尔克

 作者

  1. Christian Stoppe查看作者出版物


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  2. Jean-Charles Preiser查看作者出版物


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  3. Daniel de Backer查看作者出版物


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  4. Gunnar Elke查看作者出版物


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 竞争利益


Stoppe 博士报告说，他过去曾从 Baxter Healthcare 和 Fresenius Kabi 收取顾问费。 Preiser 博士报告称，他已收到 Baxter、Fresenius Kabi、Nestlé HealthScience 和 Nutricia Danone 的差旅费、演讲费和咨询酬金。埃尔克博士报告说，他已收到费森尤斯·卡比 (Fresenius Kabi) 的差旅费、演讲费和咨询酬金。 De Backer 博士声明他没有利益冲突。

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 引用这篇文章


Stoppe, C.、Preiser, JC.、de Backer, D.等人。重症监护室脓毒症成人静脉注射维生素 C：仍然喜欢吗？重症监护26, 230 (2022)。 https://doi.org/10.1186/s13054-022-04106-w

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