Critical Analysis of Study Methodology in Emergency Medicine

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