September 14, 2020

Background: Though it’s been stated numerous times on this blog, it bears repeating: the pillars of sepsis care remain early identification of sepsis, early appropriate empiric antibiotics, source control, and supportive care. The focus should be on getting the basics right but, it is important to evaluate whether other adjunctive therapies can help decrease mortality in a common and frequently fatal condition. Ascorbic acid and thiamine deficiency have been described in patients with sepsis and are thought to be due to reduced intake and increased metabolic demands.  Corticosteroids have had mixed results but seem to improve shock reversal in patients with septic shock based on best available evidence (Link is HERE). There have been a slew of RCTs evaluating this metabolic cocktail (vitamin C, thiamine, & corticosteroids) in recent months. Though biologically plausible, this treatment approach has not been shown to improve patient-oriented outcomes.

July 16, 2020

Background: The cornerstones of sepsis management continues to include early identification, early appropriate empiric antibiotics, definitive source control, and vasopressors to support end organ perfusion. There have been multiple studies looking at the co-administration of hydrocortisone, ascorbic acid, and thiamine (known as HAT therapy or the metabolic cocktail) to help reduce mortality and reverse shock. Despite the original Marik study showing an association between HAT therapy and a 31.9% overall decrease in mortality and a 3-fold decrease in time to vasopressor discontinuation in patients presenting with severe sepsis and septic shock, the mortality benefit has not been reproduced in subsequent randomized clinical trials.  Studies focused specifically on the use of corticosteroids have demonstrated reduced time on vasopressors in patients in septic shock.  The bigger question is does vitamin C and thiamine add anything additional to help improve mortality (The ORANGES Trial)?

May 18, 2020

Background: Getting the basics right in all illness is vital. In sepsis, this means appropriate use of antibiotics, judicious fluid resuscitation, and early identification.  Vasopressor support is also essential in the sickest sepsis patients (i.e. septic shock). Should the metabolic cocktail (thiamine, vitamin C and hydrocrotisone) be part of that initial package? We’ve previously reviewed the key articles in this area: CITRIS-ALI, VITAMINS, and the original before and after Marik trial. Now we have our next RCT, the HYVCTTSSS trial. From a pathophysiologic standpoint, Vitamin C levels are thought to be low in critically ill patients with sepsis. Vitamin C is an antioxidant that prevents vascular endothelial damage and helps maintain microvascular integrity. Additionally, it is a cofactor for catecholamine synthesis which helps maintain vascular tone and cardiac output.  Glucocorticoids have been shown to reduce time to shock relief and length of ICU stay, but not mortality. The addition of thiamine can help promote oxalate decomposition, which reduces vitamin C metabolites from depositing and crystalizing in kidneys.  While these medications are cheap, the more important question is do they improve patient-oriented outcomes? The previous literature on whether this translates to patient oriented benefits has been mostly negative thus far.

January 27, 2020

Background: The combination of vitamin C, hydrocortisone and thiamine in sepsis has been a topic of hot debate in the past couple years.  There is a hypothetical pathophysiological basis to make an argument for the use of this combination of medications, but as with anything it is important to ensure there are no untoward effects either. In Dr. Marik’s before and after study [1] we saw some pretty amazing results showing that treatment reduced hospital mortality  by 31.9% (Treatment Group 8.5% vs Control Group 40.4%). Too good to be true?  Well in short, YES…the major issues with this study were it was not a randomized controlled trial, had a small sample size, was a single center study, and had significant selection bias.  Well we finally have our first randomized controlled trial evaluating the “metabolic cocktail” in a general population of septic shock adult patients.

November 25, 2019

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.
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