Intro

Date: July 16th, 2022 Reference: Lamontagne F et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. NEJM 2022. Guest Skeptic: Dr. Salim R. Rezaie completed his medical school training at Texas A&M Health Science Center and continued his medical education with a combined Emergency Medicine/Internal Medicine residency at East Carolina University.  Currently, Salim works as a community emergency physician at Greater San Antonio Emergency Physicians (GSEP), where he is the director of clinical education.  Salim is also the creator and founder of REBEL EM and REBEL Cast, a free, critical appraisal blog and podcast that try to cut down knowledge translation gaps of research to bedside clinical practice. Case: A 59-year-old woman presents to the emergency department (ED) with fever, tachycardia, and hypotension.  She is found to have a urinary tract infection.  She requires vasopressor therapy, intravenous fluids, and intravenous antibiotics.  She is admitted to the intensive care unit (ICU) for septic shock. The ICU team is considering using Vitamin C therapy for this patient. Dr. Paul Marik Background: Dr. Paul Marik got the critical care world all excited when he claimed a Vitamin C cocktail (Vitamin C, hydrocortisone and thiamine) as a possible cure for sepsis. His position was in part based upon a retrospective before and after study he conducted at his hospital. The SGEM did a structured critical appraisal of Dr. Marik’s observational study on SGEM#174. A dozen top EM skeptics commented about the validity of the study. The SGEM bottom line was that Vitamin C, hydrocortisone and thiamine was associated with lower mortality in severe septic and septic shock patients in this one small, single centred retrospective before-after study but causation has yet to be demonstrated. We also did an episode looking at a SRMA of using Vitamin C in an adult critically ill ICU patient or cardiac surgery patients (SGEM#268). While there were several limitations to this study the bottom line was there was not enough evidence to support the routine use of Vitamin C in critically ill patients. There is a pathophysiologic basis for why Vitamin C may be beneficial in critically ill patients like those with sepsis. Vitamin C can potentially mitigate tissue injury induced by oxidative stress, but it cannot be synthesized by humans.  Vitamin C levels are low in many critically ill patients. The reasonable hypothesis would be that by correcting these levels you could have a patient-oriented outcome (POO) of benefit. However, before accepting the claim of net benefit it would need to be demonstrated with high-quality evidence. Multiple studies have now been conducted and published looking at Vitamin C as a potential treatment. Only one randomized control trial (CITRIS-ALI), using a higher dose of vitamin C (50mg/kg every six hours) reported a lower 28 day risk of death compared to those randomly allocated to placebo. This outcome however was one of 46 secondary outcomes, making it hypothesis generating. No other study reported a statistical difference in the objective outcome of mortality. Clinical Question: In adult patients with sepsis, in the ICU, on vasopressor therapy, does Vitamin C reduce the risk of death or persistent organ dysfunction at 28 days compared to placebo? Reference: Lamontagne F et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. NEJM 2022. Population: Adult patients 18 years of age and older admitted to the ICU in less than 24 hours with proven or suspected infection as main diagnosis, and receiving vasopressor therapy Exclusions: Contra-indications to Vitamin C therapy, receipt of open-label Vitamin C, or expected death or withdrawal of life-sustaining therapy within 48 hours. Intervention: 50mg/kg infusion of Vitamin C mixed in 50cc of 5% dextrose solution every six hours for up to 96 hours Comparison: 5% dextrose in water or normal saline infusion every six hours for up to 96 hours Outcome: Primary Outcome: Composite of death or persistent organ dysfunction (defined as use of vasopressors, invasive mechanical ventilation, or new renal replacement therapy) on day 28 Key Secondary Outcomes: Number of days without organ dysfunction in the ICU up to day 28 and 6 months Trial: Phase 3, Multicenter, Randomized, placebo-controlled trial Authors’ Conclusions: “In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Unsure Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Financial Conflicts of Interest. Study was funded by the Lotte and John Hecht Memorial Foundation. Nova Biomedical Canada provided glucometers, testing strips, and control solutions to trial sites that requested them Results: They enrolled and analyzed 863 patients 429 in the vitamin C group and 434 in the placebo group).  The mean age was 65 years, almost two-thirds were male, and 83% were medical admissions. Almost all the patients (97%) received at least 90% of the scheduled doses of Vitamin C or placebo. Median length of stay in the ICU was six days and 16 days in the hospital. Key Result: No superiority of Vitamin C over placebo for the primary outcome.  Primary Outcome: Composite of death or persistent organ dysfunction on day 28 Vitamin C 44.5% vs Placebo 38.5% Risk Ratio 1.21 (95% CI; 1.04 to 1.40) p = 0.01 Secondary Outcomes:  Death at 28d: Vitamin C 35.4% vs Placebo: 31.6% Risk Ratio 1.17 (95% CI 0.98 to 1.40) Persistent Organ Dysfunction: Vitamin C 9.1% vs. Placebo: 6.9% Risk Ratio 1.30 (95% CI; 0.83 to 2.05) 1. Composite Outcome of Unequal Value: We understand why researchers create composite outcomes to help ensure they have a trial that is powered well enough. However, when the outcomes included in the composite outcome are of unequal value, it makes it more difficult from a clinical standpoint to know what to do with that information. 2. Reproducibility of Results: We worry that we have expended so much finite time, money, and effort researching this topic which has been consistently reproduced as not beneficial. This is what we dream of in EBM…reproducibility of results. Perhaps we should have stopped studying this four trials ago. As Professor Altman so eloquently stated years ago, “we need less research, better research and research done for the right reasons” (BMJ 1994). Yes, it is more difficult to prove a negative but at some point, we need to recognize that there may not be any utility in investigating this further. Our time, money and valuable patient volunteers should be utilized to investigate other potential therapies. 3. Consecutive Sample or Convenience Sample: They assessed 2,234 patients were for eligibility, and 872 underwent randomization. However, another 528 patients who were eligible were not enrolled for various reasons. This is over half the sample size included.  Additionally, study recruited from 35 ICUs from November 8, 2018 to August 15, 2021 ). This makes us unsure whether it was a consecutive sample and if some selection bias may have been introduced. 4. Assumptions Made Prior to the Study: The authors state that in the control group there would need to be risk of death at 28 days or persistent organ dysfunction in the control group of approximately 50% to achieve an 80% power to detect an absolute between group difference of 10%. In the control group the primary outcome only occurred 38.5%. They based this on the retrospective before and after Marik study from 2017 (Link is HERE). This is a flawed assumption as there have since been multiple RCTs that show a 10% difference to be great.  Should the difference have been smaller?  In a disease that affects thousands world-wide even a 3% decrease could be clinically meaningful. 5. Subgroup Analysis: In the patients with COVID-19 there were trends toward vitamin C having benefit compared to patients without COVID-19. However, the problem with subgroup analysis is they can be misleading. The more subgroups you investigate, the more likely you are to find a statistically significant effect by chance. Rarely are subgroups investigated further to confirm the hypothesis. We’ve mentioned before the study by Wallach et al JAMA Intern Med 2017. They evaluated how often subgroup claims are corroborated by subsequent RCT and meta-analyses. They concluded that: “Attempts to corroborate statistically significant subgroup differences are rare; when done, the initially observed subgroup differences are not reproduced.” Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors conclusion that in adults with sepsis receiving vasopressor therapy in the ICU, those who received vitamin C therapy had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo