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[JAMA述评]:大剂量维生素C对脓毒症患者有益吗?
2019年10月16日 研究点评, 进展交流 暂无评论

Editorial October 1, 2019

Is High-Dose Vitamin C Beneficial for Patients With Sepsis?

Emily B. Brant, Derek C. Angus

JAMA. 2019;322(13):1257-1258. doi:10.1001/jama.2019.11643

For centuries, scurvy was the scourge of naval exploration. Then, in 1747, in arguably the first clinical trial, James Lind assigned sailors sick with scurvy to alternative acid treatments, and noted that those who received citrus fruits, as sources of ascorbic acid (vitamin C), were the only ones who recovered.1 Of note, scurvy was not eradicated immediately: Lind had not randomized the sailors and questioned whether their good outcomes were predestined rather than due to the ascorbic acid.2 Decades elapsed before the British Navy began to routinely load fresh citrus on all voyages.

Today, scurvy is rare and easily treated. What remains unclear, however, is the role of vitamin C in clinical situations other than overt scurvy or severe vitamin C deficiency, such as with infection. Although unproven, common folklore holds that orange juice and lemons speed recovery from both influenza and the common cold, apparently due to a boost to the immune system. Linus Pauling, winner of 2 Nobel prizes, claimed a beneficial role for vitamin C across a wide range of diseases, including terminal cancer.3 More recently, researchers and clinicians have begun advocating for vitamin C as treatment for various critical illnesses, most notably sepsis.4

There are several explanations for the growing scientific enthusiasm. First, vitamin C deficiency, albeit less profound than that seen in classic scurvy in which plasma concentrations are less than 11 μmol/L, is common in patients with sepsis.5 Observational studies have estimated that nearly 40% of patients with sepsis are vitamin C deficient, defined as plasma concentrations less than 23 μmol/L (to convert values to mg/dL, divide by 56.78).4,6 Furthermore, mean plasma vitamin C concentrations are significantly lower in patients with septic shock compared with patients without sepsis and approached scurvy levels in one study (mean [SD], 15.3 [7.9] μmol/L).6 Second, plasma concentrations of vitamin C in early sepsis are inversely correlated with measures of multiorgan dysfunction.5 Third, vitamin C plays a critical role in many physiologic processes typically deranged in sepsis. For example, vitamin C is crucial for endogenous synthesis of catecholamines.7 Moreover, preclinical work has demonstrated that vitamin C ameliorates cytokine surges implicated in sepsis-induced organ dysfunction.8 Fourth, small trials and retrospective cohort studies of vitamin C in humans have demonstrated promising results among patients with burns, sepsis, and septic shock.4,9,10 Nevertheless, no rigorous clinical trial has demonstrated a clear reduction in mortality among patients with sepsis and sepsis-associated organ dysfunction.

In this issue of JAMA, Fowler and colleagues11 report the results of the CITRIS-ALI randomized trial, a double-blind, placebo-controlled multicenter clinical trial in which 167 adults with sepsis and acute respiratory distress syndrome (ARDS) were randomized to receive high-dose intravenous vitamin C (50 mg/kg) or placebo every 6 hours for 96 hours. The trial was conducted among patients in the intensive care unit (ICU) with sepsis who were receiving mechanical ventilation and developed ARDS within 24 hours of ICU admission. Sepsis was defined as suspected or proven infection with presence of at least 2 of 4 systemic inflammatory response syndrome criteria,12 and ARDS was defined using the Berlin criteria.13 Mechanical ventilation and fluid management strategies were consistent with the NHLBI ARDS Network recommendations.14,15

Based on prior work,10 the authors hypothesized that the administration of high-dose vitamin C may attenuate organ dysfunction, inflammation, and vascular injury. Thus, the primary outcomes were a change from baseline to 96 hours in the modified Sequential Organ Failure Assessment score (mSOFA) and changes from baseline to 168 hours in C-reactive protein (a marker of inflammation) and thrombomodulin (a marker of vascular injury). The authors also evaluated 43 secondary outcomes, including a variety of measures of inflammation and organ recovery.

The cohort was well-balanced between the groups, with features typical of sepsis and severe ARDS. Pneumonia and intra-abdominal sepsis were the most common sources of infection and most patients were in septic shock at enrollment. Baseline median vitamin C concentrations were similarly deficient in both groups (22 μmol/L in both groups). Plasma vitamin C concentrations were significantly higher in the treatment group during the infusion (median vitamin C concentration at 96 hours, 169 μmol/L [IQR, 87-412] vs 26 μmol/L [IQR, 9-41]; P < .001) and remained higher after treatment completion (median vitamin C concentration at 168 hours, 46 μmol/L [IQR, 19-66] vs 29 μmol/L [IQR, 12-39]; P < .002).

None of the 3 primary outcomes was statistically significantly different between the treatment groups. At 96 hours, mSOFA scores decreased overall but were not significantly different between groups (difference, –0.1 [95% CI, –1.2 to 1.0]; P = .86). In addition, at 168 hours, plasma levels of C-reactive protein and thrombomodulin also were not significantly different between groups (C-reactive protein difference, 7.94 [95% CI, –8.23 to 24.11]; P = .33; thrombomodulin difference, 0.69, 95% CI, –2.8 to 4.2; P = .70).

In secondary analyses, 28-day all-cause mortality rates were 29.8% in the treatment group and 46.3% in the placebo group, with a hazard ratio of 0.55 (95% CI, 0.33-0.90) favoring the treatment group, which was statistically significant without adjusting for multiple comparisons (P = .01), an obvious concern in a study with so many secondary outcomes. At 28 days, treatment was associated with more ICU-free days and more hospital-free days to day 60, although it is notable that mortality also contributes to these outcomes. None of the other secondary analyses, including ventilator-free days or vasopressor use, showed a statistically significant difference. There were no reported adverse events.

The study has considerable strengths. First, it represents the largest randomized, placebo-controlled clinical trial of vitamin C administration in patients with sepsis. Second, the trial was performed well, with excellent protocol adherence, strong evidence that the intervention raised circulating vitamin C concentrations, and only 2 patients were lost to follow-up across 7 centers. Third, the enrolled patients appear representative of the target population. Fourth, considerable clinical and biological data were collected.

The study also has several important limitations. First, the timing of vitamin C administration in this cohort may make the null primary outcomes difficult to interpret. CITRIS-ALI was designed using pilot data from a phase 1 trial of patients who received vitamin C in the very early phases of sepsis.10 Enrollment in the present study required that patients have both sepsis and ARDS, potentially delaying drug administration. It is not clear if the lack of effect on organ dysfunction and plasma biomarkers was because vitamin C was given too late. Second, the authors tested only a single relatively high dose, which led to supranormal plasma vitamin C concentrations that were consistent with those of other studies reporting a potential benefit.9-11 Nonetheless, it remains possible that the lack of effect on the primary outcomes was due to dosage.

Despite this rigorous clinical trial, the question remains: does administration of vitamin C in patients with sepsis with organ dysfunction confer benefit? The difference in mortality is tantalizing and likely to spur much debate. However, this outcome was one of many secondary outcomes, and although reported as statistically significant, that finding was without adjustment for multiple comparisons. It is also concerning that none of the other outcomes that might explain why mortality would differ, such as organ dysfunction, or the inflammatory and vascular injury markers, appeared to differ between groups. Perhaps this lack of correlation is because the wrong measures were chosen, and vitamin C works via alternative mechanisms. Alternatively, the difference in mortality rates could be due to chance alone. No adverse events were reported, vitamin C is generally considered safe, and it is not expensive.

For all these reasons, further evaluation in a larger trial seems warranted. Should such a study be conducted, it would be helpful to reconsider optimal dosing and timing, as well as the likelihood that any potential benefits may only accrue to subsets of patients, given the underlying heterogeneity of sepsis. The search for an effective therapy for sepsis has thus far proven elusive. If vitamin C does indeed confer important benefits for patients with sepsis, it seems prudent to remember James Lind’s doubts over his own study design and take all efforts to ensure that poor study design does not obfuscate the path to truth.

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