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Orange Juice, Steroids, and Kit-Kats® for Sepsis:New Magic Bullet or Protein-C Part II?Kirstin Kooda, PharmD, BCPS, BCCCP

Pharmacy Grand Rounds8/1/2017

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Objectives1. Review the pathophysiology of sepsis and

describe the rationale for vitamin C, thiamine, and hydrocortisone use

2. Asses the human evidence for the use of these therapies in sepsis

3. Define patient populations where use of vitamin C, thiamine, and hydrocortisone could be considered

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Evolution of Mortality

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40

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1991‐1995 1996‐2000 2001‐2005 2006‐2009

Severe Sepsis Mortality

% M

orta

lity

Stevenson EK et al. Crit Care Med. 2014(42.3):625-631.

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Attempted Adjuncts

Early Goal Directed Therapy Naloxone

Activated Protein‐C Statins

Glucose control B blockers

Hydroxyethyl starch Specific receptor antagonists

Antithrombin III N‐acetylcysteine

Hydrocortisone TNF‐alpha antagonist

IVIG Filgrastim

Removal of cytokines via filtration

Growth hormone

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Sepsis and Septic Shock

Steroid Mechanisms

↑ Inflammatory cytokines↑ Neutrophil recruitment↑ Systemic response

TNFα

NFκB

Steroid

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Vitamin C and Thiamine

Steroid

Vitamin C:Enzyme cofactor↓ Reactive oxygen species↑ Capillary blood flow↑ Response to vasopressors↓ Endothelial permeability

Thiamine:Enzyme cofactor for mitochondrial function↓ Lactate productionEnhances oxygen utilization

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Thiamine?• Deficiency associated with increased risk of

death in sepsis• Thiamine alone had no significant impact on

mortality or lactate in septic shock

Donnino MW, et al. Crit Care Med. 2016;44(2):360-7.

Thiamine Deficient Subgroup

Thiaminen = 15

Controln = 13 p value

Mortality 2 (13%) 6 (46%) p = 0.10Survival curve p = 0.047

Lactate (24 hour) 2.1 (1.4‐2.5) 3.1 (1.9‐8.3) 0.03

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Steroids: a well-traveled path

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Annane 2002 Sprung 2008

SteroidsControl

% M

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lity

Annane D, et al. JAMA. 2002;288:862-871.Sprung CL, et al. N Engl J Med. 2008;358:111-124.

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Vitamin C in Burn VictimsDesign • Prospective, randomized by month of admission

Population • 37 consecutive burn victims with >30% TBSA• December 1992 – December 1997

Inclusion • ≥ 16 years old• Injury within 2 hours of admission• No history hepatic, respiratory, cardiac, renal

dysfunction, or coagulopathyIntervention • Vitamin C continuous infusion 66 mg/kg/hour over 24

hours in 19 patients• 70 kg patient = 111 g Vitamin C

Primary Outcome • Determine effects of vitamin C on fluid resuscitation requirements

Tanaka H, et al. Arch Surg. 2000;135:326-331.

Burn Victim Results

Tanaka H, et al. Arch Surg. 2000;135:326-331.

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Infused Volume Retained Fluid

Vit CControl

mL/

kg/%

bur

n

p < 0.004 p < 0.01

Vitamin Cn = 19

Controln = 18 p  value

Hospital Stay, d 40  ± 28 49 ± 44  0.46

Length of Mechanical Ventilation, d 12.1 ± 8.8 21.3 ± 15.6 0.03

Mortality, n (%) 9 (47.4) 7 (38.9) 0.97

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Safety in Severe SepsisDesign • Prospective, randomized, double-blind, placebo

controlled

Population• 24 patients with severe sepsis within 48 hours of ICU

admission• 1:1:1 randomization

Exclusion • Terminal cancers• Lack of consent or ability to obtain consent

Intervention• n = 8: D5W• n = 8: 50 mg/kg/24 hours x 4 days• n = 8: 200 mg/kg/24 hours x 4 days

Primary Outcome • Safety of vitamin C

Secondary Outcomes

• Organ failure• Inflammatory biomarkers• ICU outcome data

Fowler AA, et al. J Trans Med. 2014;12:32.

Placebo Lo‐AscA Hi‐AscA

Vasopressor Days 3.9 (1‐10) 2.1 (1‐6) 3.6 (2‐8)

Ventilator Free Days 7.6 (0‐23) 8.4 (0‐22) 4.8 (0‐19)

ICU LOS 11.0 (2‐25) 8.1 (1‐19) 9.1 (2‐26)

28‐Day Mortality 62.5% 38.1% 50.6%

Results

Fowler AA, et al. J Trans Med. 2014;12:32.

*data as mean (range)

Placebo Lo‐AscA Hi‐AscA

Baseline SOFA, mean ± SE  13.3 ± 2.9 10.1 ± 2.0 10.8 ± 4.4

Fowler AA, et al. J Trans Med. 2014;12:32.

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Vitamin C and Pressor DosageDesign • Prospective, randomized, double-blind placebo

controlledPopulation • 28 surgical ICU patients with septic shock requiring

vasopressor support

Exclusion • Concomitant anti-oxidants• Corticosteroid administration• Contraindication for high-dose vitamin C

Intervention • n = 14: 25 mg/kg vitamin C every 6 hours for 3 days• 70 kg patient 7 g vitamin C/day

Primary Outcome • Determine effects of vitamin C on vasopressor requirements

Secondary Outcomes

• Adverse effects• Clinical outcomes

Zabet MH, et al. J Res Pharm Pract. 2016;5:94-100.

Results

Placebo Vit C p value

24 hour NE dose (mcg/min) 12.58 ± 5.99 6.51 ± 3.53 0.003

72 hour NE dose (mcg/min) 13.79 ± 6.48 7.44 ± 3.65 0.004

Duration of vasopressors (h) 71.57 ± 1.60 49.64 ± 25.67 0.007

ICU LOS (d) 20.57 ± 13.04 21.45 ± 10.23 0.85

28‐Day Mortality 9 (64.28) 2 (14.28) 0.009

*data as mean ± SD

Zabet MH, et al. J Res Pharm Pract. 2016;5:94-100.

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Vitamin C, Steroids, and Thiamine

Design • Before and after interventional period

Population • Severe sepsis/septic shock and PCT ≥ 2 ng/mL in first 24 hours of ICU admission

Intervention• n = 47: Jul-Dec 2015 control group• n = 47: Jan-Jun 2016 vitamin C 1.5 g Q6H, thiamine

100 mg Q6H, HCT 50 mg Q6H for 4 days

Primary Outcome • Hospital mortality

Secondary Outcomes

• ICU length of stay• Duration of vasopressors• Need for RRT• Delta SOFA in 72 hours

Marik PE, et al. Chest. 2017;151(6):1229-1238.

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010203040506070

ControlTreatment

% P

atie

nts

Control Treatment

Age 62.2 ± 14.3 58.3 ± 14.1 

WBC 17.1 ± 13.4 20.6 ± 13.5

Lactate (mmol/L) 3.1 ± 2.8 2.7 ± 1.5

Procalcitonin (ng/mL) 15.2 (5.9‐39.0) 25.8 (5.8‐93.4)

APACHE IV 82.0 ± 27.4 79.5 ± 16.4

Day 1 SOFA 8.7 ± 3.7 8.3 ± 2.8

Marik PE, et al. Chest. 2017;151(6):1229-1238.

Marik PE, et al. Chest. 2017;151(6):1229-1238.

Marik PE, et al. Chest. 2017;151(6):1229-1238.

Marik PE, et al. Chest. 2017;151(6):1229-1238.

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Current Usage• Dr. Marik et al believe they lack clinical

equipoise to conduct RCT• Current standard of practice for Eastern Virginia

Medical School hospitals• Significant attention increasing from media• Dr. Marik claims 1 in 150 subsequent patients

have died from sepsis

http://www.npr.org/sections/health-shots/2017/03/23/521096488/doctor-turns-up-possible-treatment-for-deadly-sepsis

Our Experience?• Single patient usage• Septic shock associated with SSTI

• Source control achieved via amputation• Ongoing significant pressor need (2 agents

at high dosages)• After initiation of vitamin C, thiamine,

steroids, pressor needs decreased

Forthcoming Literature• Three studies actively recruiting vitamin C in

sepsis• Randomized controlled trial assessing

change in SOFA score• Randomized controlled trial assessing acute

lung injury• Pharmacokinetics of high-dose IV vitamin C

in critically ill patients

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Should we attempt?• Theoretical mechanism would most benefit

early sepsis• Small, single center studies with septic shock

show benefit• Not enough data to recommend addition to

standard of care

Who to consider?• Discuss in patients with septic shock requiring

multiple escalating vasopressors despite maximal other therapies

• Patients without other anticipated terminal illness

• Vitamin C 1.5 g Q6H x 96 hours• Must be IV

• Thiamine 100 mg Q12H x 96 hours• Hydrocortisone 50 mg Q6H

Question 1• What are the proposed mechanisms for the

efficacy of vitamin C in septic shock?• A: Improved response to vasopressors• B: Enhanced killing of bacteria• C: Function as an enzyme cofactor• D: Restoring endothelial integrity• E: All of the above• F: A, C, and D

Question 2• Vitamin C administration appears to be

associated with improved SOFA score and decreased in-hospital mortality.

A. TrueB. False

Question 3• Which is the most appropriate patient for

consideration of Vitamin C, thiamine, and steroids?

• A: 23 F with sepsis from UTI not requiring pressors

• B: 77 M with terminal pancreatic cancer and intra-abdominal infection on norepinephrine 0.3 mcg/kg/min and vasopressin 0.04 unit/min

• C: 64 F with escalating pressor doses after source control of SSTI

Question 4• Based on the presented information, will you

consider the use of vitamin C, thiamine, and steroids in septic shock?

• A: Yes• B: No

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Questions & Discussion