Dr. Paul Marik Responds: Vitamin C in Sepsis

marik

Dr. Paul Marik

On April 7, 2017, Paging MDCalc published an interview with three critical care experts regarding the Marik et al study on vitamin C in sepsis. Here is Dr. Marik’s response:

There are $20 billion reasons why there are so many skeptics, and they simply don’t understand the enormous body of research. We did not suck this out of thin air. I really don’t mind the skeptics; it generates discussion, and has raised awareness of the treatment and sepsis (that’s good). Unfortunately, patients will die while skeptics debate its merits.

Our resuscitation protocol is now being used around the world with reproducible results. I have had over 100 emails (from treating physicians as well as grateful patient family members) reporting positive results (one example below). At least 400 patients have now been treated at over 20 medical centers.

An independent data analytics firm has evaluated the sepsis mortality at our hospital (the protocol has been used in our MICU for a year). They have shown that the mortality in patients with a diagnosis of sepsis (at our entire hospital) has halved since we started this protocol. Although only instituted in one ICU, our hospital has one of the lowest sepsis mortality in this country.

Our hospital collects severity-adjusted outcomes for every ICU in our hospital. The predicted/actual mortality has fallen from 0.69 to 0.33 in our MICU during this period while it has remained relatively stable in all the other ICUs.

The skeptics would say this is the play of change.

Based on this independent data, the CEO and president of our hospital system plans to initiate this protocol system-wide (18 hospitals). One does not need to do a randomized controlled trial to prove that parachutes save lives when you jump out of an airplane. The findings in themselves are compelling.

Nevertheless, we plan to embark on a number of RCTs. One has just started in Athens.


Case (some identifying details removed):

Elderly man with baseline systolic heart failure (EF 35%) developed intra-abdominal sepsis with E. coli and Clostridium tertium bacteremia, rapidly deteriorating with lactate of 10 mM, mottling, anuria, respiratory exhaustion requiring intubation, and shock requiring three pressors. One of my colleagues suggested giving him IVIG with the concept that he was actively dying. I started him on your cocktail and the next day he was off pressors. The following day he was extubated.

Meanwhile, his AKI resolved, so today he left the ICU with no sequelae.


Important Addendum:

It is very important to emphasize that we use a fluid restrictive strategy1,2, which is integral to the outcomes we see. I believe that the 30cc/kg bolus is harmful, unphysiologic and not supported by science. In patients with septic shock we start norepinephrine early (a peripheral line is fine) and with the metabolic resuscitation protocol (vitamin C, steroids, and thiamine) they are off pressors in an average of 18 hours. So by the time pressors are off, the patients are not drowning in fluid. This is integral to our management plan.

The cumulative fluid balance was almost identical between the two study periods.


Counterpoints to statements by Jarone Lee, Christopher Seymour, and Gregg Chesney:

“For example, the way sepsis is treated might have changed dramatically between now and his historical controls and as such, this result could be just from improved protocols, nursing care, general ICU care, technology, antibiotic choices, etc…  Lots of factors that cannot be controlled for or evaluated in a retrospective, propensity-matched trial.” (Jarone Lee)

There was absolutely no change in the management of sepsis during the two time periods. This is clearly stated in the paper. The only difference was the seasons of the year; I am unaware that sepsis mortality is influenced by the position of the sun.

Some folks have suggested that scurvy is pandemic in Norfolk. If one were to review the literature, multiple investigators from across the world have reported that critical illness is associated with low or undetectable levels of vitamin C. Furthermore, the sicker the patient (by higher APACHE Score or SOFA Score), the lower the vitamin C level.

“…but this has not been subjected to rigorous study” (Christopher Seymour)

A RCT in surgical sepsis3 showed a reduction in mortality from 64% to 14%—more impressive than our results. Nathens, in a large RCT of less sick surgical patients4, demonstrated that the combination of vitamins C and E reduced the risk of multi-system organ failure.

Two recent RCTs5,6 have demonstrated that a single dose of pre-operative vitamin C prevents etomidate induced adrenal suppression in patients undergoing surgery. (Vitamin C is essential for the synthesis of cortisol and is secreted by the adrenal gland during stress.)

Fowler did a small placebo controlled RCT7 comparing 50 mg/kg/day to 200 mg/kg/day of vitamin C in patients with sepsis. While not powered to detect differences in mortality, both dosages were shown to be completely safe, with both doses of vitamin C associated with a more rapid decline in SOFA Score.

A RCT using VERY VERY high dose Vitamin C (100 grams) in burn patients showed decreased requirement for fluid and faster recovery8.

A RCT in hospitalized patients showed that provision of oral vitamin C improved the mood and happiness of those receiving Vitamin C9.

Clearly these are small studies; larger studies are to follow.

“This is… a far cry from the rigorous randomized control trials that are the underpinning of our evidence-based approach to sepsis care as evaluated in the Surviving Sepsis guidelines” (Gregg Chesney)

THIS IS A RIDICULOUS STATEMENT. Not a single recommendation in the “3 or 6 hour bundle” of the Surviving Sepsis Campaign Guideline (2004, 2008, 2012, 2016) is supported by a scrap of scientific evidence; indeed, the evidence shows that a number of these interventions may be harmful. Notably, a number of hospitals in the US have been successfully sued for death by salt water drowning by following the SSC fluid guidelines. 

“Unlike hydrocortisone and thiamine, vitamin C IV is not a regular medication given.  As we start giving more, there will be unanticipated side effects despite no current reports.  We want to not do harm, so I would recommend considering this protocol mostly in patients that have failed our regular, and maximized sepsis care.” (Jarone Lee)

In the doses used, vitamin C is absolutely safe. The package insert lists no complications, side effects or precautions. Patients with cancer have safely been given doses up to 150 g—ONE HUNDRED times the dose we give. In the patients with renal impairment we have measured the oxalate levels; these have all been in the safe range. Every single patient who received the protocol had an improvement in renal function.

The other reported contraindication is in patients with G6PD deficiency. However paradoxically, low doses of vitamin C prevent hemolysis in these patients.

“There’s also a very large phase 3 randomized trial called ADRENAL that’s underway in Australia and New Zealand that will likely give us state-of-the-art evidence across hundreds of center in many thousands of patients, about the role of this potentially dangerous medication that is included as part of this cocktail…” (Christopher Seymour)

This is totally incorrect. I was the Chair of the SCCM Guidelines on steroids10. While the mortality benefit may be questioned, stress dose steroids are NOT associated with any harms… this is very clear. Furthermore, we used a short course (4 days). To suggest harm is ridiculous.

“…and steroids in sepsis have been associated with critical illness polymyoneuropathy.” (Gregg Chesney)

WRONG. Myopathy was not increased in the CORTICUS study11.

“Maybe not as cheap as it seems. According to my critical care pharmacist, the course of treatment costs approximately $1,550.” (Gregg Chesney)

This is incorrect. Depending on the number of patients being treated simultaneously (1 to 4), the cost of vitamin C for an entire course varies from $320 to $80. $1,550 is just not correct, unless they are buying the drug from a street dealer. The preparation and stability are indicated on our website.

Once the vial is open, it is only stable for 6 hours. The resulting product is given 24 hours stability. When first ordered, 4 doses are made then and sent to the nurse. For next day, they will wait until 1 hour prior to make the next batch.


Update, April 18, 2017

Response from Jarone Lee: I thank Dr. Marik for his responses and agree that there a good amount of data supporting use of vitamin C in the basic science arena and emerging data in the clinical realm. I definitely hope that metabolic resuscitation becomes the cure for sepsis we are all striving for! However, there are numerous examples where multi-centered, rigorous studies have disproved early results, amazing results, from single centers. This is especially true in critical care. Some specific examples including vasopressin in septic shock, tight glucose control in the critically ill, steroids in relative adrenal insufficiency in sepsis and many more. I am hopeful and look forward to seeing the results of these multi-center trials that Dr. Marik is currently undergoing.

References:

  1. Marik PE, Linde-zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43(5):625-632.
  2. Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016;116(3):339-49.
  3. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-100.
  4. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236(6):814-22.
  5. Das D, Sen C, Goswami A. Effect of Vitamin C on adrenal suppression by etomidate induction in patients undergoing cardiac surgery: A randomized controlled trial. Ann Card Anaesth. 2016;19(3):410-7.
  6. Nooraei N, Fathi M, Edalat L, Behnaz F, Mohajerani SA, Dabbagh A. Effect of Vitamin C on Serum Cortisol after Etomidate Induction of Anesthesia. J Cell Mol Anesth. 2016;1(1):28-33.
  7. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
  8. Kahn SA, Beers RJ, Lentz CW. Resuscitation after severe burn injury using high-dose ascorbic acid: a retrospective review. J Burn Care Res. 2011;32(1):110-7.
  9. Zhang M, Robitaille L, Eintracht S, Hoffer LJ. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. 2011;27(5):530-3.
  10. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-49.
  11. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-24.

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