The Cure For Sepsis! A Real World Experience. Paul Marik, MD,FCCM,FCCP. Disclosures. Stocks Advisory boards Grants Speakers Bureau.

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1 The Cure For Sepsis! A Real World Experience Paul Marik, MD,FCCM,FCCP Disclosures Stocks Advisory boards Grants Speakers Bureau None 1

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3 Ongoing Sepsis Trials Sepsis in a Global Problem Global burden million cases/year Mortality ~ 60% resource poor countries 3

4 Failed Novel Pharmacologic Agents for Sepsis > 100 Phase II and III clinical trials E.Coli J5 antisera Anti-lipid A E5 mab Anti-lipid A HA1A mab Anti-TNF mab Chimeric TNF mab Humanized TNF mab stnfr1:fc stnfr2:fc Anti-CD 14 mab Tissue factor pathway inhibitor Platelet activating factor receptor antagonist IL-1 receptor antagonist Bactericidal permeability increasing protein Selenium Immunoglobulins Ibuprofen rhdl and phospholipid complexes Activated Protein C N-acetyl cysteine Antithrombin III Statins NOS inhibitors Phospholipase A-II inhibitor Granulocyte stimulating factor Bradykinin antagonist Elastase inhibitor TAK-242, Toll-4 inhibitor Eritoran, MD2-TLR4 antagonist Anti-β2 integrin Lactoferrin RT-123, r-human soluble thrombomodulin the best hope for therapeutic advances [in sepsis] will depend on broad-base targeting, in which multiple components are targeted at the same time. Aird, W.C., Blood,

5 The Magic Bullet for Sepsis: Drug A + Drug B Drug A Anti-inflammatory Increases pressor sensitivity Preserves/restores endothelial integrity Readily available Cheap Safe Drug B Anti-inflammatory Increases pressor sensitivity Preserves/restores endothelial integrity Readily available Cheap Safe The Magic Bullet for the Rx of Sepsis Drug A? Drug B? 5

6 The Magic Bullet for the Rx of Sepsis Drug A Drug B Steroids Vitamin C Paul E Marik, MD,FCCM,FCCP Vitamin S: (Hydrocortisone) 50 mg q 6 hr for 7 days or until ICU discharge Vitamin C: 1.5g IV q 6 hourly for 4 days or until ICU discharge For good measure : Vitamin B1: (Thiamine) 200mg IV q12 hr for 4 days or until ICU discharge Crit Care Med 2016; 44:1228 Paul E. Marik, MD, FCCP; Vikramjit Khangoora, MD Michael Hooper, MD, Msc; John D Catravas, PhD, FAHA, FCCP Racquel Rivera, Pharm D 6

7 Methods Treatment Group January 2016 to July 2016 (7 months) All consecutive pts adm. to MICU with primary diagnosis of sepsis Procalcitonin (PCT) > 2ng/ml Rx: Vitamin C protocol within 24 hours ICU admission Control Group June 2015 to December 2015 (7 months) All consecutive pts adm. to MICU with primary diagnosis of sepsis Same inclusion criteria (as above) Standard evidence based management strategy during both time periods Exclusion Criteria Age < 18 yrs Pregnancy Limitations of care Management Strategy Broad spectrum antibiotics then deescalation Physiologic based conservative approach to fluids and vasopressors Lung protective ventilatory strategy Bolus feeding, whey-based nutritional formula after 24 hours Permissive hyperglycemia DVT prophylaxis with enoxaparin and SCD No stress ulcer prophylaxis Limited sedation, Early mobility Procalcitonin and lactate daily for 4 days Outcome Measures Primary Hospital Survival Secondary Duration of vasopressor therapy Procalcitonin time course 72 hours SOFA score course over 72 hours Requirement for renal replacement therapy ICU LOS 7

8 Characteristic Patient Characteristics Treatment n=47 Control * n=47 Age 58.3 ± ± 16.5 Male 27 (57%) 23 (49%) Mechanical ventilation 22 (47%) 26 (55%) Vasopressors 22(46%) 22 (46%) WBC 20.6 ± ± 13.4 Lactate (<2 mmol/l) 2.7 ± ± 2.0 Creatinine (mg/dl) 1.9 ± ± 1.1 AKI (KDIGO 1) 31 (66%) 30 (64%) PCT (<0.05 ng/ml) 25.8 ( ) 15.2 ( ) BC +ve 13 (28%) 13 (28%) Vitamin C (40-60 umol/l) n= ± * No significant differences between groups; excluding neutropenic patients; excluding CRF Patient Characteristics - Comorbidities Characteristic Treatment n=47 Control n=47 None 2 (4%) 1 (2%) Hypertension 20 (43%) 25 (53%) Cardiac Failure/CAD 15 (32%) 16 (34%) COPD 8 (17%) 7 (15%) Cirrhosis/liver failure 4 (12%) 3 (6%) CVA 8 (17%) 5 (11%) Malignancy 5 (11%) 7 (15%) CRF 7 (15%) 8 (17%) Morbid obesity 6 (13%) 8 (17%) Immunocompromised 6 (13%) 4 (9%) Drug abuse 5 (11%) 5 (11%) Patient Characteristics Site of Sepsis Diagnoses Treatment n=47 Control n=47 Pneumonia 18 (38%) 19 (40%) Urosepsis 11(23%) 10 (21%) 1 o bacteremia 7 (15%) 7 (15%) GI/ Biliary sepsis 6 (13%) 6 (13%) Other 5 (11%) 5 (11%) 8

9 Patient Characteristics Severity of Illness Characteristic Treatment n=47 Control n=47 Day 1 SOFA 8.3 ± ± 3.7 APACHE II 22.1 ± ± 5.7 APACHE IV 79.5 ± ±27.4 Predicted Mortality* 39.7 ± ± 24.2 *APACHE 4 model includes APS, Chronic Health Conditions, Origin (ER, floor, OR, etc) and Diagnosis Fluid Management Treatment n=47 Control n=47 Fluid Balance -24 hours 2.1 ± 3.2 L 1.9 ± 2.7 L Fluid Balance -72 hours 1.9 ± 3.7 L 1.6 ± 3.3 L Outcome 9

10 Outcome * Predicted Mortality Actual Mortality * p< Control Treatment Logistic Multivariate Analysis Propensity Adjusted Outcome 10

11 Outcome Treatment n=47 Control n=47 Hospital Mortality 4 (9%) 19 (40%) Predicted Hospital Mortality* Duration of vasopressors (hrs) 18.3 ± ± 28.4 Delta SOFA (72 hr) 4.8 ± ± 2.7 Procalcitonin clearance (72 hr) 86.4 ( ) 33.9 ( ) Need for RRT for AKI 3/31 (10%) 11/30 (33%) ICU LOS 4 (3-5) 4 (4-10) p< 0.001; p= 0.02 * Based on APACHE IV Score Time to pressor discontinuation Treatment Group Pressor Dosage Over Time Norepineprine eq ug/min Hours Mean time to discontinuation of all pressors 18.3 ± 9.8 Time to pressor discontinuation 40 Norepinephrine eq ug/min Hours Treatment Control-Alive Control-Dead 11

12 Sofa Score Over Time S-Cr over time Treatment Group Excluding CRF S-Creatinine mg/dl Discharge 5 6 Day s-lactate over time Lactate mmol/l Days Lactate - Treatment Lactate - Control 12

13 Procalcitonin Over Time 1000 Procalcitonin ng/ml Day Treatment Control Procalcitonin Clearance Patients 28 critically ill surgical patients in septic shock Methods Randomized to either 25 mg/kg intravenous ascorbic acid every 6 h or matching placebo for 72 h End-points Duration of vasopressor dependency Mortality 13

14 80 70 p=0.007 p= Vasopressors (hrs) Mortality (%) Vit-C Placebo For the Sceptics! Vitamin C Ascorbic acid 14

15 Oxalate Ascorbic Acid 70 kg goat synthesizes about 13 g/day 15

16 domestic goats Ascorbic Acid An essential vitamin for humans who lack L-gulono-lactone oxidase, the final enzyme in the biosynthetic pathway Vitamin C acts anti-oxidant and co-enzyme multiple reactions Absorbed by gut by sodium-dependent transporters (SVCT1) Vitamin C circulates in human plasma at μm Transported into cells by SVCT2 reaches mm concentrations 16

17 Sodium-Vitamin C Transporters- SVCT Ascorbic Acid Powerful antioxidant - superoxide and peroxynitrite Recycle other oxidants α-tocopherol Tetrahydrobiopterin (endothelial function and enos) Maintains Fe++ and Cu++ many enzymes Hydroxylation (collagen) Mono- and dioxygenase (cortisol, catecholamines, neurotransmitters) Binds adrenergic receptors Epigenetic effects - demethylation Ann Intern Med 2004;140:533 17

18 Ascorbic Acid All mammals except primates and Guinea Pigs increase Vitamin C synthesis during stress Vitamin C levels are typically very low in critically ill patients Low levels likely due to enhanced metabolic turnover (oxidant stress) Increased urinary loss (? Decreased SVCT1 expression) Low levels despite PO supplementation 1500 mg/day Inflammatory cytokines decrease expression of SVCT2 Mechanistic Pathways in Sepsis Vitamin C potent antioxidant preventing activation of NFκB Vitamin C preserves tight junctions (anti-oxidant) Vitamin C preserves microcirculation Vitamin C enhances T cell function Vitamin C enhances macrophage activity Vitamin C prevents sepsis induced immunosuppression Mechanistic Pathways in Sepsis Vitamin C is a cofactor for the synthesis of norepinephrine Vitamin C is a cofactor for the synthesis of vasopressin Vitamin C is a cofactor for the synthesis of dopamine Vitamin C is a cofactor for the synthesis of cortisol Vitamin C is a cofactor for the synthesis of collagen Vitamin C binds α-adrenergic receptors increasing activation Vitamin C binds β-adrenergic receptors increasing activation 18

19 Vitamin C influences multiple pathways Chain of evidence Validated mechanistic basis Supported by basic scientific experiments Support by clinical studies Thiamine, Oxalate and Vitamin C 19

20 32% Donnino MW et al. Crit Care Med 2016; 44; 360 Oxidation to CO2 Oxidation to Co2 Pyridoxal phosphate (reqd coenzyme) Thiamine-pyrophosphate (reqd coenzyme) The Synergy Between Glucocorticoids and Vitamin C 20

21 Oxidation of cysteine thiol groups of the GR affect ligand and DNA binding Biochem Pharmacol 1998;56:79 Gene transactivation Biochem Pharmacol 1998;56:79 Br J Nutrition 2001; 86:145 21

22 Restoration of Endothelial Barrier Function with Vitamin C and Hydrocortisone in Cells Treated with LPS Vikramjit khangoora, MD John Catravas, Phd Nektarios Barabutis, Phd Paul E. Marik, MD Methods Cells: Human Lung Vascular Endothelial Cells Media: DMEM/Low Glucose, +FBS, +P/S, +Amphotericin Electrical Cell Impedance Sensor (ECIS) used to measure Trans-endothelial electrical Resistance (TEER) Cells incubated in 25ml of media until determined to be confluent under microscopy Cells then seeded into 16 wells split among 2 arrays Once TEER plateaued and was within acceptable range (~ ohm) wells were grouped (3 or 4 wells per group) Cells were pretreated with ascorbic acid and/or hydrocortisone was added at concentrations of 1000uM and 4uM, respectively, for 16hrs. LPS at concentration of 0.5eU added at 16 hours Concomitantly an additional dose of ascorbic acid was given at the time of LPS treatment Results: Vitamin C and LPS AA LPS + (AA) 22

23 Results: Hydrocort.+ Vitamin C and LPS AA +HC LPS + (AA) P COFILIN COFILIN ACTIVE RHOA RHOA P 53 Β ACTIN HC: 4uM AA: 1000uM LPS: 0.5 eu/ml VEH LPS 1H (HC+AA) 24H (HC+AA) 24 H LPS (1H) (HC+AA) 48H (HC+AA) 48H LPS (24H) HC 48H AA 48H Mechanisms Regulating Barrier Permeability 23

24 Improvement in mood and Happiness Index Nutrition 2011; 27:530 The Magic Bullet for Sepsis They leave the ICU alive and Happy MARIKLEJuice Now Available IV MARIKLEJuice 24

25 Linus Pauling Theoretical Chemist and Mathematical Physicist Nobel Prize Chemistry 1954 Nobel Peace Prize Father of molecular biology Homo sapiens need an intake of ascorbic acid similar to the amount synthesized by other mammals Validation studies Observational Studies Pragmatic multi-center RCT Expensive Takes Time 25

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