CITRIS-ALI: Vitamin C in Patients with Sepsis and Severe Acute Respiratory Failure

Background: In 2016, Paul Marik published a study in Chest [2] demonstrating a decrease in hospital mortality of 32% for sepsis patients treated with vitamin C, thiamine and hydrocortisone.  The Marik protocol(as it has come to be known), entails IV vitamin C 1.5g q6hr for 4d + IV hydrocortisone 50mg q6hr for 7d + IV thiamine 200mg q12hr x4d. The authors’ hypothesis was that vitamin C, hydrocortisone, and thiamine have synergistic effects that reverse vasoplegic shock and potentially limit the duration of vasopressor treatment resulting in a reduction in organ and limb ischemia from vasopressors themselves.  Although the results of the study are promising, it is important to remember that this was only a hypothesis generating study.  We have been waiting for a randomized clinical trial to recreate the results of this study and finally we have our first of many… CITRIS-ALI. This randomized trial looks to see if high-dose vitamin C could reduce organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.

What They Did:

• Determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS
• Randomized, double-blind, placebo-controlled, multicenter trial
• Conducted in 7 medical ICUs in the US
• 167 patients with sepsis and ARDS present for <24hrs
• Patients randomized to intravenous infusion of vitamin C (50mg/kg in dextrose 5% in water) vs placebo (Dextrose 5% in water only)

Outcomes:

• Primary:
  • Change in organ failure (modified Sequential Organ Failure Assessment score) from baseline to 96 hours
  • Plasma biomarkers of inflammation (c-reactive protein levels) measured at 168hrs
  • Vascular injury (thrombomodulin levels) measured at 168hrs
• Secondary:
  • 46 pre-specified secondary outcomes (All of them not listed here)
  • All-cause mortality at day 28
  • Ventilator-free days to day 28
  • ICU-free days to day 28
  • Hospital-free days at day 60 

Inclusion:

• Undergoing mechanical ventilation through an endotracheal tube
• Had a PaO2 to FiO2 ratio <300mmHg
• Bilateral opacities on CXR within 1 week of known clinical insult
• Had new or worsening respiratory symptoms without evidence of left atrial hypertension
• Suspected or proven infection
• Met 2 of 4 systemic inflammatory response criteria
• All criteria met within a 24hr period

Exclusion:       

• Known allergy to vitamin C
• No ability to obtain informed consent
• <18 years of age
• Non-English speaking
• Ward of the state
• >48hrs had elapsed since meeting ARDS criteria
• No patient surrogate or physician committed to full support
• Pregnant or breastfeeding
• Moribund and not expected to survive 24hrs
• Required home mechanical ventilation (via tracheostomy or noninvasively)
• Receiving home O2 >2L/min
• Had interstitial lung disease
• Diffuse alveolar hemorrhage
• DKA
• Active kidney stone

Results:

• 167 patients randomized
  • 103 (62%) completed the study to day 60
• Mean Modified Sequential Organ Failure Assessment Score (mSOFA) from Baseline to 96 Hours:
  • Vitamin C: 9.8 to 6.8 (3pts)
  • Placebo: 10.3 to 6.8 (3.5pts)
  • 95% CI -1.23 to 1.03; p = 0.86
• C-Reactive Protein Levels at 168hrs:
  • Vitamin C: 54.1 ug/mL
  • Placebo: 46.1ug/mL
  • 95% CI 08.2 to 24.1; p = 0.33
• Thrombomodulin Levels at 168hrs:
  • Vitamin C: 14.5 ng/mL
  • Placebo: 13.8 ng/mL
  • 95% CI 02.8 to 4.2; p = 0.70
• 28d Mortality:
  • Vitamin C: 29.8% (25/84)
  • Placebo: 46.3% (38/82)
  • Between Group Diff: 16.58% (95% CI 2% – 31.1%)
  • P = 0.03
• ICU Free Days to Day 28:
  • Vitamin C: 10.7
  • Placebo: 7.7
  • Mean Diff: 3.2; 95% CI 0.3 to 5.9; p = 0.3
• No study-related adverse events occurred during the trial

Strengths:

• Largest randomized clinical trial of vitamin C in patients with sepsis
• Excellent protocol adherence
• Asks a clinically important question
• Investigators blinded from onset of enrollment to completed analysis of primary and secondary outcomes
• Mechanical ventilation was performed with ARDS Network tidal volume settings
• Used a conservative fluid administration protocol as described in the ARDSNet FACTT Lite trial [3]
• Patients were fairly balanced in terms of illness severity

Limitations:

• 1092 of 1262 patients were excluded due to exclusion criteria meaning this was a very select patient population
• Didn’t seek to answer the question of combination therapy (Marik protocol) instead looked at isolated high dose vitamin C therapy.It is unclear if patients received steroids/thiamine
• 64 patients that were randomized didn’t complete trial, which is almost 50% of those actually studied
• Primary endpoints are not patient centered
• Modified the SOFA score eliminating bilirubin during the blinded analysis period as this value was missing secondary to clinicians determining that this was not a clinically indicated value…this may have affected the predictive ability of SOFA for mortality
• Used high-pressure liquid chromatography to quantify plasma vitamin C levels, which is not something that is done clinically nor is this feasible
• This trial was based off a previous phase I trial of vitamin C administered to patients in the very early stages of severe sepsis, not ARDS.Inclusion criteria required ARDS with endotracheal intubation which could have delayed vitamin C administration in the treatment group
• This was a small trial and may have been underpowered to detect a difference in mSOFA scores and biomarker levels
• The dosage of vitamin C used in this trial (50mg/kg q6hrs for 96hrs) may be insufficient for optimal care of sepsis associated ARDS. Higher dosages or longer administration times may have produced different results
• This was a proof-of-concept trail and designed to measure the effect of ascorbic acid on organ failure and laboratory measures of inflammation rather than mortality

Discussion:

• When you have 46 secondary outcomes, it is inevitable that you will have a handful that will be positive. This is why secondary outcomes are hypothesis generating only in addition to not being powered correctly for these outcomes
• Mortality was significantly different, but the confidence intervals are very wide and a secondary outcome.
• This study doesn’t look at the combination therapy that Marik is touting
• Mean modified SOFA Scores did not change much from randomization to 96hrs:
  • Vitamin C Group: 9.8 to 8.02
  • Placebo Group: 10.3 to 6.96
• The lack of change in mSOFA scores between groups is something called survivorship bias (a type of selection bias which results from evaluating survivors, while overlooking those who died). In other words, if the sickest patients were to die in the control group, then we make the control group look better on average.This can be seen by the fact that mortality is higher in the control group than the vitamin C group (secondary outcome) without change in the mSOFA score

Author Conclusion: “In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury.  Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.”

Clinical Take Home Point: In this study of high dose vitamin C in patients with sepsis and ARDS, there was not statistical difference in the primary outcomes of change in modified SOFA score at 96hrs, plasma biomarkers of inflammation (CRP), nor plasma biomarkers of vascular injury (thrombomodulin ). Normally, I don’t get too excited about secondary outcomes, however in a study of sick patients with sepsis induced ARDS, with high mortality rates, maybe we should consider using vitamin C.  With no adverse events and how inexpensive vitamin C is, one could argue that this is an option we should try (kitchen sink mentality).  On the other hand, with 46 secondary outcomes, it is possible that the mortality benefit was from chance alone.  Regardless of which side of this debate you fall on, one thing is certain…evaluation of vitamin C in a larger trial seems to be warranted looking at multiple dosing and timing strategies.

References:

1. Fowler AA 3^rd et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA 2019. PMID: 31573637
2. Marik PE et al. Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A retrospective Before-After Study. Chest 2016. S0012-3692(16)62564 – 3. PMID: 27940189
3. Grissom CK et al. National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Fluid Management with a Simplified Conservative Protocol for the Acute Respiratory Distress Syndrome. Crit Care Med 2015. PMID: 25599463

For More Thoughts on This Topic Checkout:

• PulmCrit: CITRIS-ALI – Can a Secondary Endpoint Stage a Coup D’Etat?
• EMNerd: The Case of the Sour Remedy
• REBEL EM: The Marik Protocol – Have We Found a “Cure” for Severe Sepsis and Septic Shock?
• The Bottom Line: Vitamin C Sepsis

 Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

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