Vitamin C. . . The Holy Grail for Sepsis Treatment?

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This study is sending shock waves through the medical community:

Marik P et al 2017:  Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock:  A retrospective before-after study.  Chest. 2016 Dec 6. pii: S0012-3692(16)62564-3. doi: 10.1016/j.chest.2016.11.036. [Epub ahead of print]

This look at hospital survival in septic patients treated with vitamin C, thiamine, and hydrocortisone compared to controls is big news . . . but is it too good to be true? 

 

THE PHYSIOLOGIC RATIONALE FOR THE TREATMENT:

  • Vitamin C is important in endothelial function, as an antioxidant, and in generation of catecholamines and cortisol.
  • Vitamin C levels are low in basically all septic patients.
  • A couple of very small (24 patients each) RCT’s of vitamin C in sepsis have shown safety and decreased vasopressor dose/duration.
  • Thiamine levels are often low in sepsis.
  • The authors describe “multiple and overlapping effects” of vitamin C, thiamine, and hydrocortisone to explain why this combined intervention might be effective. 
 

 THE INTERVENTION:

  • This single-center study started when three patients with fulminant sepsis and septic shock were given intravenous vitamin C as a desperation move . . . and all three survived and did well.
  • The intervention group consisted of patients with severe sepsis or septic shock and procalcitonin >/= 2ng/ml (i.e. sick patients with high risk of organ dysfunction).  Patients under 18, pregnant, or with limitations on care were excluded.
  • The intervention protocol consisted of vitamin C 1.5 grams Q6hr, thiamine 200 mg IV q12hr, and hydrocortisone 50 mg IV q6hr.
  • Patients who underwent treatment were compared to similar patients from before the protocol was initiated.
  • Otherwise sepsis care was compliant with accepted guidelines and the authors identified no other protocol changes during the time period of the study that could confound results.
 

THE RESULTS:

  • Mortality was 40.4% in the preintervention group vs 8.5% in the postintervention group (p<0.001).  Check out this chart—impressive, huh?
  • None of the patients in the intervention group died of sepsis, though the authors report that four died of their underlying disease (including dementia, heart failure, sarcoidosis, and COPD) after recovering from sepsis and being transferred out of the ICU.

 

 

 

SOME THOUGHTS ON THESE RESULTS:

“We haven’t seen a patient die of sepsis since we began using the combination therapy a year ago. We have completely changed the natural history of sepsis.”
— Paul Marik, MBBCh
  • Dr. Marik presented this work at the Critical Care Reviews conference in a presentation (watch below) entitled “Cure for Sepsis” . . . the popular media has been all over this and many news stories have used similarly extreme language (i.e. Deadly Sepsis, Miracle Treatment Discovered by Doctors), though many, such as NPR, are a bit more skeptical.  Don’t be surprised if patients and their families have heard about this and start asking about it.
  • The paper states that “due to a lack of clinical equipoise and the ethics of withholding a potentially lifesaving intervention, we were unable to initiate a randomized clinical trial in our center.”  This has become standard of care throughout Dr. Marik’s hospital system (he is Chief of Critical Care at Eastern Virginia Medical School).
  • The update from Dr. Marik on the excellent PulmCrit blog states that they have now treated >150 patients with this protocol . . . and only one has died from sepsis.
  • There is an RCT in progress on vitamin C alone in sepsis-induced acute lung injury, the results of which will undoubtedly help us interpret this data.  I also hope we will get more information from institutions that implement this treatment and share their experience.
  • In the study, treatment was started “within 24 hours of ICU admission” and I saw no data on what the times from presentation to administration were.  Since then, however, the treatment has been “initiated by residents in the emergency department” at the same time as antibiotics at Dr. Marik’s hospital. 
  • Historically there have been dozens of potential “magic bullets” in sepsis treatment that have not borne out— the table above is from a 1996 JAMA commentary entitled “Why sepsis trials fail” and lists just some of the many “failures” that had been studied up to that point.  This is even mentioned in the intro to the Marik paper: “Over the last 3 decades, over 100 phase II and phase III clinical trials have. . . ultimately failed to produce a novel pharmacologic agent to directly target the pathophysiologic effects of severe sepsis.”  This historic perspective will (appropriately?) influence how people think about the “latest and greatest."
  • The response to this paper is and will continue to be interesting to watch.  There is certainly an argument that these results are “too good to be true” and that the current evidence is inadequate to support adoption of the protocol . . . on the other hand many will argue that there doesn’t seem to be harm and that this is a reasonable intervention to apply immediately based on the existing data alone (though consider those "unlikely to do harm" things that it turns out can harm patients, like IV fluids or oxygen).  It will be fascinating to watch what happens . . . I imagine we will be discussing this at our institution and all of us involved in treating septic patients should consider what we think—both in terms of the specific study results and the broader question of a threshold to apply a possibly highly effective treatment in the absence of randomized data.
 

Watch Paul Marik (Norfolk, USA) discusses his observational study demonstrating an association between the administration of vitamin C, hydrocortisone and thiamine and outcome in patients with septic shock.

REFERENCES

1.  Marik P et al 2017:  Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock:  A retrospective before-after study.  Chest. 2016 Dec 6. pii: S0012-3692(16)62564-3. doi: 10.1016/j.chest.2016.11.036. [Epub ahead of print]

2.  Fowler, AA et al.  Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.  J Transl Med. 2014; 12: 32.

3.  Mohadeseh H. et al.  Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock.  J Res Pharm Pract. 2016 Apr-Jun; 5(2): 94–100.

4.  Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI), Clinical Trials.Gov registered trial.

5.  Bone RC. Why Sepsis Trials Fail.  AMA. 1996;276(7):565-566. doi:10.1001/jama.1996.03540070061032

 

Written by Samantha Wood, MD

Edited and Posted by Jeffrey A. Holmes, MD