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Critical Care Medicine

A Critical Appraisal of Metabolic Resuscitation for Sepsis

Owen Stell, MD and Julia West, MD

Over the last 20 years, the focus on early antibiotic administration and fluid resuscitation in sepsis care has brought the mortality rate for cases of severe sepsis and septic shock from 30-40%1, 2 to approximately 20-25%.3, 4   However in the past several years, it seems that we have reached a plateau in improving the treatment of sepsis. But in March of 2017, Dr. Paul Marik of Eastern Virginia Medical School, one of the most distinguished intensivists in the United States, published a study that he believes may drastically turn the tide on the battle against this deadly disease. He and his colleagues published an intriguing clinical study evaluating a “sepsis cocktail” of intravenous vitamin C, corticosteroids, and thiamine,5 which they claim can alter the natural course of sepsis.

“Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study” looked at 47 patients during a 7-month period who were treated with traditional therapy prior to implementation of the combination of hydrocortisone, vitamin C, and thiamine, and compared them to another 47 patients during the subsequent 7 months after implementation of this treatment bundle. Hospital mortality decreased from 40.7% in the conventional therapy group to 8.5% in the treatment group, and SOFA scores rapidly decreased in all patients. Furthermore, all of the patients in the treatment group were weaned off of vasopressors at a mean of 18.3 ± 9.8 hours compared to 54.9 ± 28.4 hours in the control group. Undoubtedly, these are impressive findings, and this study has created great interest and debate within the emergency medicine (EM) and critical care communities.6-9 In the years since Dr. Rivers published the early goal directed therapy guidelines, numerous studies have attempted to introduce novel treatments to better fight sepsis, most of which have ultimately been shown to have no benefit, even when initial investigations seemed promising.10, 11 Therefore, clinicians have learned to be skeptical and are raising the question: why should this particular study be any different?

Weaknesses of this study appropriately lead to hesitancy to promptly adopt these interventions as standard practice in sepsis care. The study design has several methodological concerns, as the retrospective before-after study compares patients who are not in the treatment group during a single time period to a different group of patients in a separate time period who are in the treatment group. This methodology introduces confounding factors, such as failure to adequately randomize patients based on age or comorbid conditions, differences in acuity of illness, and differences in seasonal prevalence of certain causes of sepsis. This was only a single center study, which further raises questions about whether these results can be duplicated.

This study analyzed the effects of using vitamin C, thiamine, and steroids in combination, thereby not allowing clinicians to determine which components, and at what doses, may be responsible for the positive effects demonstrated in this trial. While vitamin C and thiamine both have excellent safety profiles, administration of steroids is not without risk,12 and the Surviving Sepsis Guidelines recommend against giving steroids in sepsis unless the patient is hemodynamically unresponsive to fluids and pressors.13 Consequently, this sepsis cocktail endorses the routine administration of steroids in sepsis, which would otherwise not be recommended.

Conversely, this study also has numerous strengths. Vitamin C has been studied previously as a treatment in critically ill patients and has had favorable results. Sepsis is associated with vitamin C deficiency,14,15 and vitamin C is a cofactor in the synthesis of catecholamines.16 Vitamin C administration in septic patients has been shown to lead to decreased SOFA scores15 and decreased vasopressor requirements in clinical studies as well.17 Furthermore, thiamine deficiency can result in high output heart failure and encephalopathy. Thiamine is similarly deficient in sepsis, although administration of thiamine alone has not been shown to reduce lactate levels or reduce mortality.18 Corticosteroids have been used for years in the treatment of sepsis, and steroids have been shown to have a synergistic effect with vitamin C in animal models.19 Therefore, the scientific plausibility behind this study does have a sound physiologic basis; however, this has also been the case for many other studies that have unsuccessfully attempted to find novel therapies for sepsis.

Overall, this recent study leaves us in a quandary. Should clinicians wait until there is more compelling evidence to support these results before providing this therapy to our patients? Or should we administer this potentially life-saving therapy to our septic patients, even with the current low quality of supporting evidence? The argument for early adoption notes that the elements of the treatment have all been shown to be relatively safe, therefore not posing a significant risk to administer. Additionally, not all therapies require randomized controlled trials to warrant implementation. On the other hand, there is evidence to suggest that steroids in sepsis can increase the risk of super-infections that may be complicated by another bout of sepsis and septic shock.20 Moreover, while the individual components of this cocktail have been well-studied, the cumulative effects or optimum doses in a broad population of critically ill patients are unknown. The authors of this current study go so far as to say that that this metabolic resuscitation was observed to be so effective that there was insufficient clinical equipoise to conduct a randomized controlled trial.21 Hopefully our colleagues in EM and critical care will see fit to disagree so that we can further examine this therapy with a sufficiently critical eye.

  1. Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35:1244-1250.
  2. Stevenson EK, Rubenstein AR, Radin GT, et al. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med. 2014;42:625-631. doi: 10.1097/CCM.0000000000000026.
  3. PRISM Investigators. Early, goal-directed therapy for septic shock – a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-2234. doi: 10.1056/NEJMoa1701380. Epub 2017 Mar 21.
  4. ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014:370:1683-1693. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.
  5. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C and thiamine for the treatment of sever sepsis and septic shock: a retrospective before-after study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.
  6. PulmCCM. Could vitamin C save lives in sepsis? These hospitals aren’t waiting for proof. PulmCCM. http://pulmccm.org/main/2017/critical-care-review/vitamin-c-save-lives-sepsis/. Published March 29, 2017. Accessed June 26, 2017.
  7. Mallemat H. The Marik protocol: Have we found a “cure” for severe sepsis and septic shock? Mallemat H. http://rebelem.com/the-marik-protocol-have-we-found-a-cure-for-severe-sepsis-and-septic-shock/. Published April 7, 2017. Accessed June 26, 2017.
  8. Farkas J. PulmCrit – Metabolic sepsis resuscitation: the evidence behind vitamin C. Farkas J. https://emcrit.org/pulmcrit/metabolic-sepsis-resuscitation/. Published March 27, 2017. Accessed June 26, 2017.
  9. Weingart S. Dr. Marik responds to a few touch questions on the metabolic resus of sepsis strategy. Weingart S. https://emcrit.org/emcrit/dr-marik-responds-tough-questions-metabolic-resus-sepsis-strategy/. Published March 31, 2017. Accessed June 26, 2017.
  10. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20:195-203. doi: 10.1016/j.molmed.2014.01.007. Epub 2014 Feb 24.
  11. Angus DC. The search for effective therapy for sepsis: back to the drawing board? JAMA. 2011;306:2614-2615. doi: 10.1001/jama.2011.1853.
  12. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. Intensive Care Med. 2011;37:420-429. doi: 10.1007/s00134-010-2121-0. Epub 2011 Jan 18.
  13. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
  14. Wilson JX, Wu F. Vitamin C in sepsis. Subcell Biochem. 2012;56:67-83. doi: 10.1007/978-94-007-2199-9_5.
  15. Fowler AA 3rd, 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. doi: 10.1186/1479-5876-12-32.
  16. Carr AC, Shaw GM, Fowler AA, et al. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 2015;19:418. doi: 10.1186/s13054-015-1131-2.
  17. Zabet MH, Mohammadi M, Ramezani M, et al. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5:94-100. doi: 10.4103/2279-042X.179569
  18. Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44:360-367. doi: 10.1097/CCM.0000000000001572.
  19. Fujita I, Hirano J, Itoh N, et al. Dexamethasone induces sodium-dependent vitamin C transporter in a mouse osteoblastic cell line MC3T3-E1. Br J Nutr. 2001;8:145-149.
  20. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;368:111-124. doi: 10.1056/NEJMoa071366.
  21. Weingart S. EMCrit Wee – Edited Version of Paul Marik on the Metabolic resuscitation of sepsis. https://emcrit.org/emcrit/edited-marik-metabolic-sepsis/. Published March 28, 2017. Accessed June 26, 2017.

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