e-appendix 1. Protocol Number: #16-08-WC-0179 Date of approval by the EVMS IRB: August 12 th 2016 Background and Significance:

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1 e-appendix 1. Protocol Number: #16-08-WC-0179 Date of approval by the EVMS IRB: August 12 th 2016 Background and Significance: The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. 1 With more timely diagnosis and improvement in supportive care the 28-day mortality from sepsis in high income countries has declined to about 25%, however, the mortality from septic shock remains as high as 45%. 2;3 Moreover, the mortality from sepsis and septic shock in low income countries remains as high as 60%. 4-6 In addition to short term mortality, septic patients suffer from numerous short- and long-term complications with a reduced quality of life and are at an increased risk of death for up to five years following the acute event. 7;8 Over the last 3 decades over 100 phase II and phase III clinical trial have been performed testing various novel pharmacologic agents and therapeutic intervention in an attempt to improve the outcome of patients with sepsis and septic shock; all of these studies have failed to improve patient outcomes. 9 New therapeutic approaches to sepsis are desperately required. Considering the global burden of sepsis these interventions should be effective, cheap, safe and readily available. We were recently confronted with three patients with fulminant sepsis who were almost certainly destined to die from overwhelming septic shock. Based on experimental and emerging clinical data we decided to administer intravenous vitamin C to these patients as a life-saving measure Moderate dose hydrocortisone was added for its theoretical synergic benefit. All three of these patients made a dramatic recovery and were discharged from the ICU within days with no residual organ dysfunction. Based on this experience and the reported safety of this therapeutic intervention, the combination of intravenous vitamin C and corticosteroid become the standard of care in our ICU. The combination of intravenous vitamin C and hydrocortisone has become the routine standard of care in our ICU as well as our colleagues with the Sentara Medical Group. Patients with sepsis predictably have very low serum vitamin C levels, that can only be corrected with intravenous vitamin C in a dose in excess of 3g per day. 13;15;16 Based on published clinical data, vitamin C pharmacokinetic modeling as well as the package insert we decided to administer 6g vitamin C per day divided in 4 equal doses. 13;15-20 This dosage is entirely devoid of any reported complications or side effects. Dosages as high as g have been safely administered to patients with burns and malignancy. 14;21;22 Hydrocortisone was dosed according to the consensus guidelines of the American College of Critical Care Medicine. 23 Experimental studies performed over the last 20 years have demonstrated that both vitamin C and hydrocortisone have multiple and overlapping beneficial

2 pathophysiologic effects in sepsis. Furthermore, both agents have been in clinical use since 1949 and have a long safety record which. 24;25 Intravenous thiamine (vitamin B1) was added to the vitamin cocktail. Thiamine deficiency is common is patients with sepsis and in itself is associated with an increased risk of death. 26 Specific Aims of the Study: The aim of this study is to determine the effect of the combination of intravenous vitamin c and hydrocortisone on the clinical course of patients with severe sepsis and septic shock compared to a control group of patients who were treated in our ICU with the same management strategy except for treatment with vitamin C and hydrocortisone. Study Design: This is a retrospective review of existing Electronic Medical Record (EMR) data, namely the EPIC system. We will be querying the EPIC database for data from 1/1/2016 to 08/1/2016 (7 months) to identify all adult patient records meeting the following criteria: i. Admission to the GICU under the EVMS critical care team ii. Diagnosis of sepsis or septic shock iii. Age iv. Procalcitonin (PCT) level > 2ng/ml v. Treatment with the combination of intravenous vitamin C and hydrocortisone The diagnosis of sepsis and septic shock will be based on the Third International Consensus Definitions of Sepsis and Septic shock. 27 This definition has subsequently been changed to the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions. 28 PCT is routinely measured in our hospital as a screening tool for sepsis and to follow the evolution of the disease. We used a threshold PCT of 2 ng/ml to increase the certainty that the patients had severe sepsis Excluded patients: i. Age < 18 years ii. iii. Pregnant DNR/DNR with limitations of care

3 Control Group: The control group will consist of patients admitted to the GICU from June 2015 to December 2015 (7 months) who meet all the inclusion and exclusion criteria as outlined above, except that they did not receive treatment with the combination of vitamin C and hydrocortisone. Patients during both time periods were treated according to the same evidence-based approach. Data Collection: Data collection will commence once the project is approved by the IRB and Sentara Office of Research. It is anticipated that the total sample size will not exceed 120 patients. It is anticipated that the data collection period should take no longer than 2-4 months. The following deidentified demographic and clinical data will be collected: i. Age (18-90); patients over age 90 will be recorded as 90 years ii. Sex iii. Weight iv. Admitting diagnosis v. Co-morbidities, including diabetes, hypertension, cardiac failure, COPD, malignancy vi. Requirement for mechanical ventilation. vii. Use of vasopressor agents. The hourly dosage of vasopressors was recorded as the norepinephrine equivalent dosage. 33;34 viii. Daily urine output (for first 4 days) ix. Presence of acute kidney injury (AKI). Presence of AKI: Acute kidney injury (AKI) was defined using the KDIGO criteria; namely, an increase of the s-creatinine > 0.3 mg/dl or a level > 1.5 times the baseline value. [27] If the baseline s-creatinine was not known a value > 1.6 mg/dl was regarded as diagnostic of AKI. x. Fluid balance after 24 and 72 hours xi. Length of ICU and hospital stay xii. ICU and hospital survival xiii. Routine laboratory data for 4 days including: a. serum creatinine b. white cell count (WBC) c. platelet count d. total bilirubin e. PCT f. lactate level

4 xiv. The patients admission APACHE II and APACHE IV scores which include the APACHE IV predicted hospital mortality and predicted ICU length of stay (LOS) will be recorded. xv. The daily SOFA (Sepsis-related Organ Failure Assessment) score will be recorded for the first 4 treatment days The APAPCHE II score (incrementing score of 0-71) and APACHE IV score (incrementing score 0-286) are standardized measures of disease severity that are used to predict hospital mortality and ICU LOS. 35;36 The SOFA score was designed to sequentially assess the severity of organ dysfunction in patients who are critically ill from sepsis (incrementing score 0-24). 37. The SOFA scores is calculated 24 hours after admission to the ICU and daily thereafter. SOFA scores that increase by about 30 percent are associated with a mortality of at least 50 percent. 38 Data will be collected in an Excell spreadsheet. No personal identifiers will be recorded on the spreadsheet. We will not be recording names, dates of birth, social security or EMR numbers or any other HPI data in the data collection spreadsheet. Each record will be assigned a unique study ID number (subject ID key). A separate password protected spreadsheet will have a list of subject ID number and the corresponding medical record numbers. This spreadsheet will only be accessible to the principle investor and sub-pi. After completion of the study the subject key file will be destroyed. Data analysis: The primary outcome is hospital survival. Secondary outcomes included time to vasopressor independence, 39 and the change in serum PCT and the SOFA (Sepsis-related Organ Failure Assessment) score over the first 72 hours and the ICU length of stay (LOS). 30;38;40-42 The procalcitonin clearance (PCTc) is calculated using the following formula: initial PCT minus PCT at 72 hours, divided by the initial PCT multiplied by ;43 Summary statistics will be used to describe the clinical data and presented as mean ± SD or percentages as appropriate. Chi squared analysis with Fisher s exact test (when appropriate) and Student s t test (Mann Whiney U test for non-normal distributions) will be used to compare data between the treatment and protocol groups with statistical significance declared for probability values of 0.05 or less. Statistical analysis will be performed using NCSS 11 (Kaysville, Utah). Data Safety & storage: The main risk to subjects is the accidental release of PHI. Careful record management methods will be in place to ensure this type of privacy breach does not occur. Subject ID Key: Each subject will be given a unique subject ID number. A subject ID key will be used to match the subjects Medical Record Number (MRN). The subject ID key, linking the subject ID numbers to

5 the MRN will be kept in a password-protected file and stored separately from the data set in the locked office of the principal investigator. Only the research team (PI and sub PI) will have access to this information, and they will not disclose this information to any other person or entity. The subject ID key will be destroyed as soon as possible after the data set has been completely abstracted and validated for accuracy and completeness. Data set: Similarly, the data set will be kept in a password-protected file and stored separately from the subject ID key in the locked office of the principal investigator. Only the research team will have access to this information, and they will not disclose this information to any other person or entity. Three years after the completion of the study, all collected data will be destroyed by permanently deleting electronic copies. Reference List (1) Adhikari NK, Fowler RA, Bhagwanjee S et al. Critical care and the global burden of critical illness in adults. Lancet 2010; 376(9749): (2) Kaukonen KM, Bailey M, Suzuki S et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, JAMA 2014; 311: (3) Gaieski DF, Edwards JM, Kallan MJ et al. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013; 41: (4) Silva E, de Almeida Pedro M, Beltrami Sogayar AC et al. Brazilian Sepsis Epidemiological Study (BASES study). Crit Care 2004; 8(4):R251-R260. (5) Sales JA, David CM, Hatum R et al. Sepse Brasil: Estudo Epidemiologico da Sepse em Unidades de Terapia Intensiva Brasileiras. An epidemiological study of sepsis in Intensive Care Units. Sepsis Brazil Study. Rev Bras Ter Int 2006; 18:9-17. (6) The10 leading causes of death by country income group WHO factsheets. World Health Organization, (7) Wang HE, Szychowski JM, Griffin R et al. Long term mortality after sepsis. Chest (8) Yende S, Austin S, Rhodes A et al. Long-term qualityof life among survivors of severe sepsis: Analyses of two international trials. Crit Care Med 2016; 44:

6 (9) Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med 2013; 41: (10) Fisher BJ, Kraskauskas D, Martin EJ et al. Attenuation of sepsis-induced organ injury in mice by vitamin C. JPEN 2014; 38(7): (11) Fisher BJ, Seropian IM, Masanori Y et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med 2011; 39(6): (12) Zhou G, Kamenos G, Pendem S et al. Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis. Am J Physiol Regulatory Integrative Comp Physiol 2012; 302(4):R409-R416. (13) Fowler AA, Syed AA, Knowlson S et al. Phase 1 safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014; 12:32. (14) Tanaka H, Matsuda T, Miyagantani Y et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 2000; 135(3): (15) Long CL, Maull KL, Krishman RS et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 2003; 109(2): (16) de Grooth HJ, Choo WP, Spoelstra-de Man AM et al. Pharmacokinetics of four high-dose regimens of intravenous Vitamin C in critically ill patients [Abstract]. Intensive Care Med (17) Padayatty SJ, Sun H, Wang Y et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004; 140(7): (18) Nathens AB, Neff MJ, Jurkovich GJ et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002; 236(6): (19) Zabet MH, Mohammadi M, Ramezani M et al. Effect of high-dose ascorbic acid on vasopressor requirement in septic shock. J Res Pharm Pract 2016; 5: (20) Ascorbic Acid Injection. The Torrance Company, (21) Ohno S, Ohno Y, Suzuki N et al. High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer. Anticancer Research 2009; 29(3):

7 (22) Stephenson CM, Levin RD, Spector T et al. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemotherapy & Pharmacology 2013; 72(1): (23) 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: (24) Klenner FR. The treatment of poliomyelitis and other virus diseases with vitamin C. South Med Surg 1949; 111: (25) Hench PS, Kendall EC, Slocumb CH et al. The effect of a hormone of the adreanl cortex (17- hydroxy-11-dehydrocorticosterone:compund E) and the pituitary adenocorticotrophic hormone on rheumatoid arthritis. Preliminary report. Ann Rheum DIs 1949; 8: (26) 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: (27) Singer M, Deutschman CS, Seymour CW et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315: (28) Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: (29) Wacker C, Prkno A, Brunkhorst FM et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13: (30) Schuetz P, Maurer P, Punjabi V et al. Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients. Crit Care 2013; 17:R115. (31) Charles PE, Tinel C, Barbar S et al. Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and outcome. Crit Care 2016; 13:R38. (32) Reynolds SC, Shorr AF, Muscedere J et al. Longitudinal changes in procalcitonin in a heterogeneous group of critically ill patients. Crit Care Med 2012; 40:

8 (33) Mancl EE, Muzevich KM. Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous vasopressor therapy. JPEN 2013; 37(5): (34) Russell JA, Walley KR, Singer J et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358: (35) Knaus WA, Draper EA, Wagner DP et al. APACHE II: A severity of disease classification system. Crit Care Med 1985; 13: (36) Zimmerman JE, Kramer AA, McNair DS et al. Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment for today's critically ill patients. Crit Care Med 2006; 34(5): (37) Vincent JL, Moreno R, Takala J et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22(7): (38) Ferreira FL, Bota DP, Bross A et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001; 286(14): (39) Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358: (40) Karlsson S, Heikkinen M, Pettila V et al. Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study. Crit Care 2010; 14(6):R205. (41) de Azevedo JR, Torres OJ, Beraldi RA et al. Prognostic evaluation of severe sepsis and septic shock: procalcitonin clearance vs DELTA Sequential Organ Failure Assessment. J Crit Care 2015; 30(1): (42) Guan J, Lin Z, Lue H. Dynamic change of procalcitonin, rather than concentration itself, is predictive of survival in septic shock patients when beyond 10 ng/ml. Shock 2011; 36(6): (43) Ruiz-Rodriguez JC, Caballero J, Ruiz-Sanmartin A et al. Usefulness of procalcitonin clearance as a prognostic biomarker in septic shock. A prospective pilot study. Medicina Intensiva 2012; 36(7):

9 e-table 1. Factors assessed for association with receiving the Vitamin C protocol Propensity score for the likelihood of receiving the Vitamin C protocol included these factors. Odds Ratio 95% CI p-value AGE Gender APACHE Pressors Mechanical Ventilation WBC Lactate Procalcitonin Creatinine e-table 2. Model with odds ratio for mortality with adjusting factors of vitamin C protocol use, propensity score for the patient s likelihood to receive the vitamin C protocol, and age. Odds Ratio 95% CI p-value Vitamin C Protocol Propensity Score Age Odds Ratio 95% CI p-value Vitamin C Protocol Propensity Score

10 e-figure 1. Propensity score distribution among the patients in the treatment group (Rx=1) and the Control Group (Rx=0)

11 e-figure 2. APACHE IV score distribution in the Treatment(Rx=1) and Control Groups (Rx=0) by outcome (0=dead, 1=alive)