JAMA editorial helps set record straight on unproven sepsis therapy

Newswise — The Jan. 17 issue of the Journal of the American Medical Association (JAMA) features an important study about sepsis with an accompanying editorial by a University of Nebraska Medical Center expert. The study and editorial sets the record straight on an unproven therapy some physicians use to treat sepsis, a deadly infectious disease. 

The editorial, written by Andre Kalil, M.D., M.P.H., professor of infectious diseases in the UNMC Department of Internal Medicine, writes in support of the new and rigorous international study based on a randomized clinical trial in Australia, published in the same issue. The editorial appears in the Jan. 17 online issue and also will appear in the Feb. 4 print edition. 

The study has major implications for patients with sepsis and the medical community. 

“The combination of high-dose vitamin C, thiamine and hydrocortisone has been suggested to provide benefits based on a small single-center retrospective observational study,” Dr. Kalil said. “Even though not tested in more rigorous studies, such as randomized controlled trials, and not approved for clinical practice, many doctors have been using this therapy.” 

“Until now, no rigorous clinical trial had been done. This new randomized trial does not confirm previous beliefs about the high-dose vitamin C, thiamine, and hydrocortisone purported benefit, and there are potential safety issues for both patients and society associated with the continuation of its use without providing survival benefits,” Dr. Kalil said. 

Sepsis is the body’s dysregulated response to infection that can lead to organ damage and death. Dr. Kalil said even with the best standard of care, 20-30% of patients die from sepsis. 

The recently completed trial involved 216 patients in Australia, New Zealand and Brazil. The intervention group received intravenous vitamin C, hydrocortisone and thiamine plus usual care, and a control group received intravenous hydrocortisone plus usual care.

The study suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock and does not decrease mortality compared with controls. 

Dr. Kalil was invited to write the editorial because of his recognized expertise in the field and the high relevance of the study.

SIDEBARS

Dr. Kalil is one of a number of UNMC faculty adding to the body of knowledge on sepsis with involvement in clinical trials. In a recent national, multi-site, randomized study called Vitamin C, Thiamine and Steroids in Sepsis, Aaron Barksdale, M.D., led the UNMC study site. Study participants received combination therapy or placebo. Dr. Barksdale is an associate professor and vice chair of research in the UNMC Department of Emergency Medicine. Results are expected soon. 

According to the Centers for Disease Control and Prevention, each year, at least 1.7 million adults in America develop sepsis. Nearly 270,000 Americans die as a result of sepsis and one in three individuals die in a hospital have sepsis.

Dr. Kalil's editorial is as follows:

Lack of benefit of high-dose vitamin C, thiamine, and hydrocortisone combination for patients with sepsis

Andre C Kalil, MD, MPH¹*

Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska

*Corresponding author:

Andre C Kalil, MD, MPH

Professor

University of Nebraska Medical Center

Email: [email protected]

Phone: 402 559-8650

Word count: 1108 

Key words: vitamin C, thiamine, sepsis, shock

The use of vitamin C for treatment of patients with sepsis has generated substantial interest and controversy. In 2017, a single center observational study suggested that the combination of high-dose vitamin C, thiamine, and hydrocortisone in conjunction with usual care was associated with reduced mortality (8.5% for combination treatment vs. 40.4%for controls)¹. Despite the small sample size (n=94 patients), lack of concurrent controls and randomization, and important baseline imbalances between study groups, the study garnered significant attention. There were reports that some physicians were keen to adopt the strategy as part of routine practice, even though this approach had not been tested in a rigorous clinical trial.

In this issue of JAMA, Fujii and colleagues² report the findings from a randomized clinical trial (RCT) that evaluated  the effects of combination therapy with high-dose vitamin C, thiamine, and hydrocortisone for patients with sepsis. The RCT compared the combination therapy in conjunction with usual care (intervention group, n= 109) to hydrocortisone plus usual care (control group, n =107). The primary outcome was duration of time alive and free of vasopressors at day 7 (i.e., vasopressor free-days); 28-day mortality and 90-day mortality were 2 of 10 secondary outcomes. The trial was designed to have 90% power to detect a between-group difference of 25 hours alive and vasopressor free, and the final recruitment of 216 patients was consistent with the statistical analysis plan.

The results showed an almost identical median time alive and free of vasopressors in the two study groups: 122.1 hours (IQR: 76.3-145.4) in the intervention group, compared to 124.6 hours (IQR: 82.1-147.0) in the control group, p=0.83; with no significant difference in 28-day mortality (22.6% in the intervention group vs 20.4% in the control group, p=.69) or 90-day mortality (28.6% in the intervention group vs. 24.5% in the control group, p=0.51)². Limitations of this trial include lack of blinding and the moderate sample size. Strengths include the randomized design, high protocol adherence, low attrition rate, rapid implementation of the intervention, and achievement of supranormal plasma levels of vitamin C in the intervention group.

 The primary biologic rationale for this therapeutic approach has been that sepsis occurs in a setting of vitamin C and thiamine deficiency. Absolute deficiencies of vitamin C and thiamine both cause severe disease (scurvy and beri beri). Although the very low levels characteristic of scurvy and beri beri are uncommon in sepsis, the theoretical rationale is that relatively low levels are implicated in the pathogenesis of sepsis. However, a standardized approach to assess serum levels of these vitamins in critically ill patients is lacking, and the causal path between relative vitamin deficiency and adverse outcome from sepsis has not been clearly demonstrated. Glucocorticoid steroids are pleiotropic agents that have a number of potential actions in sepsis. However, because the trial by Fujii et al² assigned the same dose of hydrocortisone to both intervention groups, any difference between study groups would not be due to a direct effect of steroids. The design of the current study also precludes analysis of the individual effects of vitamin C and thiamine, but the absence of any benefit in both primary and secondary outcomes suggests either that both agents were ineffective or that both were fully antagonistic, which seems unlikely.

Several other prior studies have evaluated thiamine and vitamin C in sepsis. In an observational study of 369 patients, thiamine was associated with improved lactate clearance and survival ³, but a randomized trial involving 88 patients did not replicate the results.⁴  Vitamin C has now been evaluated as a treatment for sepsis and septic shock, either alone or in combination, in 8 RCTs and 6 observational studies that reported data on all-cause mortality (mostly hospital and 28-day outcomes).  Of the eight RCTs ^2,5-11, 6 (including a total of 635 patients) showed no significant effect of vitamin C on mortality ^2,5-8,10. The reported mortality rates were in favor of vitamin C in the other 2 trials ^9,11, although in one trial ⁹ the sample size was small (n= 28 patients),  and there were important baseline differences between groups, and in the other trial ¹¹, mortality was not the primary outcome and lack of adjustment for multiple testing weakened the inference for the mortality outcome. ^9,11 Of the 6 observational studies ^1,12-15 (which included  a total of 1483 patients), 5 studies (n=1389) ^12-16 demonstrated no association between vitamin C and improved survival in sepsis, and the  single center observational study ¹ that found an association had important limitations¹⁷.  

However, more studies of vitamin C administration in sepsis are ongoing or planned.  According to clinicaltrials.gov ¹⁸, 37 trials are examining vitamin C as a treatment for sepsis in Asia, Africa, Europe, North and Latin America, of which 18 studies are testing the triple combination therapy, 12 studies are testing vitamin C alone, 3 are testing vitamin C plus thiamine, and 4 are testing other combinations. Twelve studies are completed although the findings have not yet been reported, 21 are recruiting, and 4 are not yet recruiting. Considering the available evidence from more than 2,000 patients’ studies in both observational and randomized studies, there is insufficient equipoise to continue enrolling more patients in sepsis trials involving high-dose Vitamin C administration.  

While new diagnostic and therapeutic tools are being developed, it is important to continue to provide the care that maximizes the chances of survival for patients with sepsis. For instance, two studies performed in non-overlapping eras with distinct septic shock populations and different scientific methodology consistently demonstrated that every hour delay on time-to-antibiotic initiation increased the risk of mortality by 7.5-10% ^19,20. Thus, rapid initiation of appropriate antibiotics should be an absolute priority for the treatment of all patients with septic shock in clinical practice as well as in clinical research.

The results of the clinical trial by Fujii et al in this issue of JAMA², added to the cumulative evidence from 13 different studies performed in 10 different countries, indicate that high-dose vitamin C with or without thiamine and steroids does not provide significant survival benefits for patients with sepsis or septic shock. Given that other studies are forthcoming, there appears to be no immediate justification for adoption of high-dose Vitamin C, alone or in combination, as a component of treatment for sepsis. Moreover, the use of high-dose vitamin C in combination or alone “just in case” or as a “measure of last resort”, despite providing no survival benefits, could have several other potential  consequences, including  diverting funding from needed research to examine  sepsis mechanisms and diagnostics; stifling  the development of other sepsis therapies; perpetuating  false hopes for patients, families, and clinicians; and delaying proven life-saving therapies such as prompt initiation of antibiotic therapy.

Conflicts of Interest: None

REFERENCES:

1. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238.
2. Fujii. JAMA NEW REF. 2020.
3. Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock. Crit Care Med. 2018;46(11):1747-1752.
4. 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(2):360-367.
5. Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med. 1997;23(5):768-774.
6. Ferron-Celma I, Mansilla A, Hassan L, et al. Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery. J Surg Res. 2009;153(2):224-230.
7. Schneider A, Markowski A, Momma M, et al. Tolerability and efficacy of a low-volume enteral supplement containing key nutrients in the critically ill. Clin Nutr. 2011;30(5):599-603.
8. 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.
9. 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.
10. Nabil-Habib T AI. Early Adjuvant Intravenous Vitamin C Treatment in Septic Shock may Resolve the Vasopressor Dependence. International Jounrnal of Microbiology & Advanced Immunology. 2017;5:77-81.
11. Fowler AA, 3rd, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261-1270.
12. Shin TG, Kim YJ, Ryoo SM, et al. Early Vitamin C and Thiamine Administration to Patients with Septic Shock in Emergency Departments: Propensity Score-Based Analysis of a Before-and-After Cohort Study. J Clin Med. 2019;8(1).
13. Litwak JJ, Cho N, Nguyen HB, Moussavi K, Bushell T. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application. J Clin Med. 2019;8(4).
14. Ahn JH, Oh DK, Huh JW, Lim CM, Koh Y, Hong SB. Vitamin C alone does not improve treatment outcomes in mechanically ventilated patients with severe sepsis or septic shock: a retrospective cohort study. J Thorac Dis. 2019;11(4):1562-1570.
15. Mitchell AB, Ryan TE, Gillion AR, Wells LD, Muthiah MP. Vitamin C and Thiamine for Sepsis and Septic Shock. Am J Med. 2019.
16. Sadaka F, Grady J, Organti N, et al. Ascorbic Acid, Thiamine, and Steroids in Septic Shock: Propensity Matched Analysis. J Intensive Care Med. 2019:885066619864541.
17. Kalil AC, Johnson DW, Cawcutt KA. Vitamin C Is Not Ready for Prime Time in Sepsis but a Solution Is Close. Chest. 2017;152(3):676.
18. https://clinicaltrials.gov/ct2/home. Accessed on 12/23/2019.
19. Kalil AC, Johnson DW, Lisco SJ, Sun J. Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials. Crit Care Med. 2017;45(4):607-614.
20. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.