10/4/18

1

Refractory ShockSpencer Laehn, PharmD, BCCCP

Eileen T. Shannon, PharmD, MS, BCCCP

Pharmacist Objectives1. Review the Surviving Sepsis Bundle 2018 update and pertinent

pharmacologic aspects of the 2016 Surviving Sepsis Campaign2. Describe mechanisms of novel pharmacologic hemodynamic support in

refractory shock3. Identify evidence based clinical rolls of novel pharmacologic hemodynamic

supportTechnician Objectives1. Demonstrate importance of timely application of hemodynamic supporting

medications2. Understand the use of various agents for refractory shock

Objectives

Overview§ Review of Septic Shock

o Updated definitionso Treatment summaryo 2018 bundle update

§ Refractory Shocko Definitiono Pathophysiologyo Treatment: angiotensin II, acidemia reversal, nitric oxide inhibitors, metabolic resuscitation

Updated Sepsis Definitions§ Sepsis: life threatening organ dysfunction caused by dysregulated host

response to infection (qSOFA score >/=2)§ Septic shock: subset of sepsis with circulatory and cellular/metabolic

dysfunction associated with a higher risk of mortality (persistent hypotension requiring vasopressors and lactate > 2 mmol/L)

Old Sepsis Definitions

§ Sepsis: 2 or more SIRs criteria + likely source of infectiono SIRs: WBC >12,000 or <3,000, HR>90, RR>20, temp >38 or <36

§ Severe sepsis: sepsis with signs of end organ damageo Elevated lactate, hypotension

§ Septic shock: severe sepsis refractory to fluid resuscitation

Crit Care Med. 2017;45(3):486-552.

Surviving Sepsis Guidelines 2016Initial management:

§ Fluid resuscitation with crystalloid 30 ml/kg and additional PRN based on hemodynamic status

§ Broad spectrum antibiotics within 1 hour§ Target mean arterial pressure (MAP) of 65§ Trend lactate, provide fluid resuscitation until normalized§ Initiate vasopressors to achieve MAP goal if unresponsive to fluid

o Norepinephrine as first choice pressoro Add vasopressin or epinephrine if cannot achieve MAP goal or to reduce norepinephrine

requirement§ IV hydrocortisone (200 mg/day) if fluids + vasopressors are inadequate

Crit Care Med. 2017;45(3):486-552.

Surviving Sepsis Campaign Bundle 2018 Update§ Major change: three and six hour bundles combined into single “Hour 1 Bundle”o Begin resuscitation and

management immediatelyo Reflects clinical reality of clinician at

the bedside

Bundle Elements

Measure lactate level. Re-measure if initial lactate is > 2 mmol/L

Obtain blood cultures prior to administration of antibiotics

Administer broad spectrum abx

Rapidly administer 30 ml/kg crystalloid for hypotension or lactate >/= 4 mmol/L

Apply vasopressors if patient is hypotensive during or after

*Resuscitation may take more than 1 hour**No data specific to burn or immunocompromised populations

Crit Care Med. 2018;46(6):997-1000.

10/4/18

2

What is Refractory Shock?§ No universal consensus definition:

o Failure to achieve a BP goal despite vasopressor therapy

o Need for rescue vasopressoro Need for high vasopressor doses

Drug Dose Norepinephrine Equivalent

Epinephrine 0.1 ug/kg/min 0.1 ug/kg/min

Dopamine 15 ug/kg/min 0.1 ug/kg/min

Norepinephrine 0.1 ug/kg/min 0.1 ug/kg/min

Phenylephrine 1 ug/kg/min 0.1 ug/kg/min

Vasopressin 0.04 units/min 0.1 ug/kg/min

Refractory shock: an inadequate response to high-dose vasopressor therapy (defined as >/= 0.5 ug/kg/min norepinephrine-equivalent dose

Chest. 2018;154(2):416-426.

Pathophysiology of Refractory ShockHypoxia, acidosis, hyperlactemia

Reactive oxygen species overproductionDysregulated nitric

oxide metabolism

HyperglycemiaHypocalcemia

Corticosteroid deficiency

ATP-sensitive K+ channel activation

REFRACTORY VASODILATORY SHOCK

Membrane hyperpolarizationCellular relaxation

Vasorelaxation

Endothelial dysfunctionMitochondrial dysfunction

Altered microcirculatory flowDecreased bactericidal activity

Coagulation modulationDysregulated mitochondrial

respirationImpaired responsiveness

to catecholamine

Vascular smooth muscle relaxation

Uncontrolled production of NO and PGI2

Image adapted from Chest. 2018;154(2):416-426.

Potential Treatments for Refractory ShockTherapy Dose Mechanism of Action Adverse Effects

Angiotensin II Starting: 2-10 ng/kg/minMax: 20-40 ng/kg/min

Angiotensin II receptor activation

Hypertension, metabolic acidosis,risk of clots

Sodium bicarbonate 1-2 mEq/kg Reversal of metabolic acidosis Hypernatremia, ionized hypocalcemia, respiratory acidosis

Hydroxocobalamin 5 g IV over 10 min Scavenetging of NO Interference with hemodialysis sensors

Methylene Blue Bolus: 1-2 mg/kg every 4-6 hInfusion: 0.25-1 mg/kg/h

Inhibition of NOS Serotonin Syndrome, hypoxia, pulmonary hypertension

Thiamine 200 mg every 12 h Improved lactate clearance Minimal

Ascorbic Acid 25 mg/kg every 6 h or 1.5 g every 6 h

Increased catecholamine and vasopressin synthesis

Minimal

Table adapted from Chest. 2018;154(2):416-426.

Vasopressor/Inotrope pharmacology reviewA1 B1 B2 DA V1 V2 PDE3-I

Norepinephrine ++++ ++

Epinephrine ++ +++ ++

Phenylephrine ++++

Vasopressin ++++ ++

Dopamine (low)(High dose)

+++++

+++

++++

Dobutamine + ++++ ++

Milrinone ++++

Isoproterenol ++++ ++++

Circulation. 2008;18(10):1047-1056.

Angiotensin II: Physiology review§ Naturally occurring hormone

from renin-angiotensin pathway§ Potent vasoconstrictor§ Involved in water and sodium

homeostasis

Compr Physiol. 2014;4(3):1201-1228.

Angiotensin II: Physiology review1. Renal blood flow reduced2. Kidney converts pro-renin to renin3. Renin converts angiotensinogen to

angiotensin I4. Angiotensin I is converted to

angiotensin II via angiotensin converting enzyme (ACE)

5. Angiotensin II (potent vasoconstrictor) increases blood pressure via activation of AT1 and AT2

Compr Physiol. 2014;4(3):1201-1228.

10/4/18

3

Angiotensin II: Physiology review

Compr Physiol. 2014;4(3):1201-1228.

History of Angiotensin II use§ Protein first isolated in 1930s§ Case reports describe the successful use of various bovine and human

angiotensin II formulations as rescue therapy for patients with refractory shock

§ Small pilot study published in 2014 supported its use as a vasopressoro 20 patientso Primary endpoint was effect of angiotensin II on standing norepinephrine dose required to

maintain MAP of 65o Mean norepinephrine dose reduced from 27.6 +/- 29.3 ucg/min (in placebo) vs 7.4 +/1 12.4

ucg/min, P=0.06o Determined initial dose range: 2-10 ng/kg/min

Crit Care. 2014;18(5):534.

Clinical Trials: ATHOS-3§ International, multi-center, randomized, double-blind, placebo-controlled trial§ Sponsored by La Jolla (manufacturer of Giapreza)§ Primary Endpoint: the response with respect to mean arterial pressure

(MAP) at hour 3o Response defined as MAP of 75 mm Hg or higher or an increase in MAP from baseline of at

least 10 mm Hg without an increase in the dose of background vasopressor§ Secondary Endpoints: changes in SOFA and cardiovascular SOFA score

from baseline to 48 hours, adverse events, mortality at 7 and 28 days

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 CriteriaInclusion Criteria Exclusion Criteria

§ 18 years or older§ Vasodilatory shock despite IV

volume resuscitation (minimum 25 ml/kg over past 24 hours) and high dose vasopressors

§ Shock defined as MAP between 55- 70 mm Hg

§ High dose vasopressor = norepinephrine dose of 0.2 ucg/kg/min or equivalent dose

§ Burns > 20% BSA§ ACS§ Bronchospasm§ Liver failure§ Mesenteric ischemia§ Active bleeding§ AAA§ Neutropenic patients§ VA-ECMO§ Receiving high dose steroids

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 Methods§ Baseline MAP measured as mean of three readings§ Initial 3 hours: angiotensin II initiated at 20 ng/kg/min and titrated to maintain

MAP of 75 mm Hg (max dose 200 ng/kg/min)o During this period, doses of other vasopressors were held constant

§ After 3 hours, study drug or placebo or background vasopressors were adjusted to maintain MAP 65-75

§ After 48 hours, study drug was titrated off per protocol

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 Results§ Study regimen initiated in 321 patients

o 163 received angiotensin IIo 158 received placebo

§ No differences noted between groups in any baseline characteristics§ Patients in both groups were extremely ill (high APACHE II scores, elevated

baseline vasopressor doses)

N Engl J Med. 2017;377(5):419-430.

10/4/18

4

End Point Angiotensin II (N=163)

Placebo (N=158)

Odds or Hazard Ratio (95% CI) P Value

MAP response at hour 3 - no. (%) 114 (69.9) 37 (23.4) Odds ratio, 7.95 (4.76-13.3) <0.001

Mean change in CV SOFA score at hour 48

-1.75 +/- 1.77 -1.28 +/- 1.65 0.01

Mean change in total SOFA score at hour 48

1.05 +/- 5.50 1.04 +/- 5.34 0.49

Mean change in NE equivalent dose (baseline to 3 hrs) in ucg/kg/min

-0.03 +/- 0.10 0.03 +/- 0.23 <0.001

All-cause mortality at day 7 - no. (%) 47 (29) 55 (35) Hazard ratio, 0.78 (0.53-1.16) 0.22

All-cause mortality at day 28 - no. (%)

75 (46) 85 (54) Hazard ratio, 0.78 (0.57-1.07) 0.12

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 Results

N Engl J Med. 2017;377(5):419-430.

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 Results: Side EffectsAngiotensin II

(N=163)Placebo (N=158)

Adverse event of any grade 142 (87.1) 145 (91.8)

Adverse event leading to discontinuation

23 (14.1) 34 (21.5)

Any serious adverse event with frequency >/= 1% in either study group

99 (60.7) 106 (67.1)

N Engl J Med. 2017;377(5):419-430.

ATHOS-3 Results: Side Effects§ “Special Interest” adverse events were similar in both groups

o Rates of tachyarrhythmias, distal ischemia, ventricular tachycardia, and atrial fibrillation

Angiotensin II (N=163) Placebo (N=148)

Peripheral Ischemia 5 (3.1) 3 (1.9)

Deep vein thrombosis 3 (1.8) 0

Intestinal ischemia 1 (0.6) 3 (1.9)*There were no significant differences (at P <0.05) between the groups in the percentage of patients with adverse events

N Engl J Med. 2017;377(5):419-430.

Study limitations (per the authors)§ Blinding may have been compromised by significant blood pressure response§ Side effects of angiotensin II may have been missed due to small study size§ Study was not powered to detect a difference in mortality§ Follow-up limited to 28 days

N Engl J Med. 2017;377(5):419-430.

10/4/18

5

Additional limitations§ Lack of patients with low cardiac output = unknown effect in this population§ No head to head data, so no use as monotherapy§ Mortality endpoint: null hypothesis cannot be rejected§ No difference in end-organ damage§ Lack of transparency re: fluid status, no reporting of lactate

Author’s conclusion§ The percentage of patients who met the primary end point with respect to

MAP at 3 hours was significantly greater in the angiotensin II group than in the placebo group

§ Patients who received angiotensin II had lower requirements for catecholamines than patients who received placebo

§ Cardiovascular SOFA scores were significantly lower in the angiotensin group than in the placebo group at 48 hours

N Engl J Med. 2017;377(5):419-430.

FDA approves Giapreza for Septic Shock§ Approved December 2017 for septic or other distributive shock§ No contraindications§ Warning and Precautions: there was a higher incidence of venous and

arterial thromboembolic events in patients who received Giapreza compared to placebo treated patients: 13% (21/163) vs 5% (8/158). The major imbalance was in venous thrombosis. Use concurrent VTE prophylaxis

§ FDA medical review: no difference in VTE prophylaxis between groups prior to initiation of therapy

§ https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209360Orig1s000MedR.pdf (page 115-117)

Giapreza [package insert]. San Diego, CA: La Jolla; 2018, Angiotensin II. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc.

Additional Information§ Adverse Reactions (per package insert):

o Cardiovascular: thrombosis (13%), tachycardia (9%), deep vein thrombosis (4%), peripheral ischemia (4%)

o Central nervous system: delirium (6%)o Endocrine and metabolic: acidosis (6%), hyperglycemia (4%)o Hematologic and oncologic: thrombocytopenia (10%)o Infection: fungal infection (6%)

§ Mortality benefit in patients initiated on renal replacement therapyo Post-hoc analysis of the ATHOS-3 Trialo Patients with AKI treated with RRT at initiation of angiotensin II (n=45) or placebo (n=60)o Alive at day 28: 24 (53%) in angiotensin II group, 18 (30%) in placebo groups, survival through

day 28 was significantly longer in angiotensin II group as compated to placebo group (unadjusted HR, 0.52; 95%CI, 0.30-0.87; p=0.012)

Giapreza [package insert]. San Diego, CA: La Jolla; 2018, Angiotensin II. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc., Crit Care Med. 2018;46(6): 949-957.

Sodium Bicarbonate§ Pharmacologic category

o Alkalinizing agent§ Mechanism of action

o Reverse acidosis through acid-base effects§ Dose

o 1-2 mEq/kg§ Evidence

o No studies have shown cardiovascular improvement in humans in shock states with severe lactic acidosis

§ Additional considerationso Possible side effects include intracellular acidosis, respiratory acidosis, ionized

hypocalcemia, hypernatremia

Crit Care. 2015;19(1):175-187.

Nitric Oxide and Shock§ Constitutive nitric oxide synthase

(cNOS)o Constantly active

§ Inducible nitric oxide synthase (iNOS)o Induced via endotoxins, cytokines

Anesth Analg. 2016;122(1):194-201.

10/4/18

6

Hydroxocobalamin

Ann Thorac Surg. 2014. 97:1785-1786.

§ Pharmacologic categoryo Vitamin B12 precursor

§ Mechanism of actiono Nitric oxide scavenger (off-label use)

§ Doseo 5 grams IV over 10 minutes

§ Evidenceo Case reports in vasoplegic syndrome

§ Additional considerationso Remains in the bloodstream and urine for days to weeks, can

interefere with heme sensors on HD machines, no known serotinin considerations

Methylene Blue§ Pharmacologic category

o Inhibition of NOS and soluble guanylate cyclase§ Mechanism of action

o Reverses vasodilation caused by excessive cyclic guanosine monophosphate§ Dose

o 1-2 mg/kg (bolus, repeated boluses, low-dose infusions)§ Evidence

o Only small RTCs (n=15-30)§ Additional considerations

o MAOi activity, increased pulmonary pressures, methemoglobinemia, glucose-6-phosphate dehydrogenase deficiency, inaccurate pulse SpO2

Anesth Analg. 2016;122(1):194-201.

Cautionary Tale for NO pathway modulators?§ Tilarginine (546C88) - Non-selective NOS inhibitor § Phase II - Randomized Placebo Controlled Trial (n=312)

o Resolution of shock at 72 hours: 40% vs 24% (p=0.004) o 28 day survival: 82 (53%) vs 80 (51%) (p=NS)

§ Phase III - Randomized Placebo Controlled Trial (n=797)o Resolution of shock at 72 hours: 27% vs 16% (p=0.001)o All cause mortality by day 28: 59% vs 49% (p=0.003)

§ Failure of tilarginine to improve clinical outcomes casts doubt on other rescue agents affecting NO signaling for refractory shock

Crit Care Med.. 2004;32(1):1-12.; Crit Care Med.. 2004;32(1):21-30.

Thiamine§ Pharmacologic category

o Vitamin deficiency/repletion§ Mechanism of action

o Essential metabolic cofactor§ Dose: 200 mg IV every 12 hours§ Thiamine deficiency in critically Ill

o 20-70% of septic shock patientso Increased metabolic demando Diureticso hemodiafiltration

J Thorac Dis. 2016;8(6):1062-1066.

Thiamine EvidenceStudy Design Outcome Takeaways

Serum Thiamine Concentration as predictors of Mortality (2014)

Prospective Observational Study (n=108)71.3% thiamine deficient

No difference in mortality Thiamine serum concentrations were not associated with mortality

Thiamine in septic shock with EtOH use disorder (2018)

Retrospective cohort study (n=53)Received Thiamine: 64%

Mortality:44% vs 79% (p=0.02)

Thiamine may reduce mortality in septic shock pts with EtOH use disorder

Effect of Thiamine Administration on Lactate clearance and Mortality (2018)

Retrospective matched cohort (n=369)1:2 match

Mortality:0.666 (95% CI: 0.490-0.905)

Thiamine improved lactate clearance and mortality is severely ill septic shock patients

J Crit Care. 2014;29(2):249-52.; J Crit Care. 2018;43(6):61-64.; Crit Care Med. 2018;Epub

Thiamine Randomized Placebo Controlled Trial § Objective: To determine if thiamine reduced lactate in septic shock patients

o 88 patients in septic shock § Outcomes:

o 24 hours lactate concentration difference: 2.5 vs 2.6 (p=0.4)o No difference in secondary outcomes

§ Thiamine deficient patients o 35% (15 vs 13)o 24 hour lactate concentrations:

• 2.1 vs 3.1(p=0.03)o Mortality: 2 vs 6 (p=0.10)

Crit Care Med. 2016;44(2):360-367.

10/4/18

7

Ascorbic Acid (Vitamin C) § Pharmacologic category

o Vitamin deficiency/repletion § Mechanism of action

o Antioxidant, required for pressor synthesis, immune modulator§ Dose

o 25 mg/kg or 1.5 g every 6 hours§ Evidence

o Mostly animal data, several small studies § Additional considerations

o Converted to oxalateo Incrased glucose readings

J Crit Care. 2017;43:230-234.

Vitamin C the Antioxidant § Scavenge reactive oxygen species directly

o Donation of an electron-generating ascorbic radical from ascorbic acido Preventing damage to cellular proteins, lipids, and nucleic acids

§ Reactivate other reactive oxygen species scavengerso Glutathione and alpha-tocopherol

§ Nicotinamide adenine dinucleotide oxidase (NOX) inhibitiono NOX activates superoxide and peroxynitrite

§ Inhibits nuclear factor kappa-Bo Preventing disruption of tight junctions leading to vascular compromise

J Crit Care. 2017;43:230-234.

Vitamin C the Vasopressor Synthesiser§ Cofactor for peptidylglycine alpha-amidating

monooxygenase (PAM)o Increased vasopressin synthesiso Downstream increasing corticosteroid synthesis

§ Needed for catecholamine synthesis o Dopamine Beta-hydroxylase (forms NE)o Recycles cofactor tetrahydrobiopterin

§ Modulates alpha and beta receptorso Enhancing activation by epinephrine

J Crit Care. 2017;43:230-234.

Vitamin C the Immune Modulator§ Vitamin C and leukocytes support

o Plays role in chemotaxis, support lymphocytic proliferationo Assists in oxidative neutrophil killing of bacteria

§ Vitamin C deficiencyo Delayed bactericidal activity of natural killer cello Delayed suppressor T cell activity

§ Inhibit tumor necrosis factor production of intercellular adhesion molecules§ At high doses may even have intrinsic bacteriostatic activity

J Crit Care. 2017;43:230-234.

Vitamin C the Evidence

J Transl Med. 2014;12:32-8.; J Res Pharm Pract. 2016;5:94-100.

§ Phase I randomized, placebo controlled trialo 24 medical ICU patients with severe sepsiso Placebo vs 50 vs 200 mg/kg/day for 96 hourso Reduced organ failure and reduced C-reactive protein and procalcitonin levels

§ Effect on vasopressor requirements in septic shocko 28 adult surgical patients with septic shocko 25 mg/kg every 6 hours vs placeboo Decreased vasopressor requirements, faster weaning of pressorso Reduced 28-day mortalityo No change in ICU LOS

The Paper Heard Around the World§ Design:

o Single center retrospective pre-post analysis • 1/2016 - 7/2016 (n = 47) vs 6/2015 - 12/2015 (n=47)

o Inclusion • Severe sepsis or septic shock patients with a procalcitonin level > 2 ng/ml

o Treatment• 1.5 g IV vitamin C every 6 hours, 200 mg IV thiamine every 12 hours, 50 mg

hydrocortisone every 6 hours§ Outcomes:

o Mortality 8.5% vs 40.4% (p<0.001)o Duration of vasopressor therapy 18.3 hours vs 54.9 hours (p<0.001)

Chest. 2017;151(6):1229-1238.

10/4/18

8

Steroids, Vitamin C, thiamine Synergy§ Glucocorticoids and vitamin C synergy

o Glucocorticoids increase vitamin C cellular uptakeo Vitamin C reverses oxidation of glucocorticoid receptorso Combination protects against vascular endothelium from endotoxin damage

§ Thiamine’s helping hando Reduces vitamin c’s oxalate production

Pharmacol Ther. 2018;Epub

Looking Forward§ HYVITS Trial NCT03380507 - May 2019 (n=212)§ ACTS Trial NCT03389555 - Sept 2019 (n=200)§ VICTAS Trial NCT03509350 - Oct 2021 (n=2000)§ And many, many more...

Cost Comparison (as cost per day) § Thiamine: $16.20-$24.88§ Hydroxocobalamin (as Cyanokit): $985.58§ Ascorbic Acid: $495§ Angiotensin II: $1,800.00§ Methylene Blue: $2,007.00§ Sodium bicarbonate 8.4% (per 50 mEq ampule): $11-$24

Lexi-drugs. Lexicomp. Wolters Kluwer Health, Inc.

Refractory Shock Treatment Takeaways§ Angiotensin II

o Role in therapy yet to be determined§ Nitric oxide pathway modulators

o Temporarily increase SVR, questionable mortality data§ Thiamine

o May be most beneficial in patients with thiamine deficiency§ Vitamin C

o May be of benefit in both severe sepsis or septic shock patients§ Vitamin C, thiamine, and hydrocortisone combination

o May act synergistically

References1. Surviving Sepsis Campaign Guidelines Committee. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552.2. Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Crit Care Med. 2018;46(6):997-1000.3. Jentzer JC, Vallabhajosyula S, Khanna AK, Chawla LS, Busse LW, Kashani KB. Management of refractory vasodilatory shock. Chest. 2018;154(2):416-426.4. Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation. 2008;18(10):1047-1056.5. PubChem. Angiotensin II. https://pubchem.ncbi.nlm.nih.gov/compound/172198#section=Top. Accessed April 29, 2018.6. Spark MA, Crowley SD, Gurley SB, Mirotsou M, and Coffman TM. Classical renin-angiotensin system in kidney physiology. Compr Physiol. 2014;4(3):1201-1228.7. Chawla LS, Busse L, Brasha-Mitchell E et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534.8. Khanna A, English SW, Wang XS et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430.9. Giapreza [package insert]. San Diego, CA: La Jolla; 2018.10. Angiotensin II. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 28, 2018.11. Tumlin JA, Murugan R, Deane AM, Ostermann M et al. Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II. Crit Care Med. 2018;46(6):949-952.12. U.S. Food & Drug Administration. Giapreza Medical Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209360Orig1s000MedR.pdf. Published December 2017. Accessed July 17, 2018.13. Kimmoun A, Novy E, Auchet T, Ducrocq N, Levy B. Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside. Crit Care. 2015;19(1):175-187.14. Cooper J, Walley KR, Wiggs BR, Russell JA. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med. 1990;112(7):492-498.15. Roderique JD, VanDych K, Holman B, Tang D, Chui B, Spiess BD. The use of high-dose hydroxocobalamin for vasoplegic syndrome. Ann Thorac Surg. 2014;97:1785-1786.16. Ascorbic acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 21, 2018.17. Sodium bicarbonate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 21, 2018.18. Thiamine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 21, 2018.19. Hydroxocobalamin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 21, 2018.20. Hosseinian L, Weiner M, Levin MA, Fischer GW. Methylene Blue: Magic Bullet for Vasoplegia?. Anesth Analg. 2016;122(1):194-201.21. Bakker J, Grover R, Mcluckie A, et al. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of

a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med. 2004;32(1):1-12.22. Bakker J, Grover R, Mcluckie A, et al. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of

a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med. 2004;32(1):1-12.23. Mallat J, Lemyze M, Thevenin D. Do not forget to give thiamine to your septic shock patient!. J Thorac Dis. 2016;8(6):1062-1066.24. Costa NA, Gut AL, De souza dorna M, et al. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014;29(2):249-52.25. Holmberg MJ, Moskowitz A, Patel PV, et al. Thiamine in septic shock patients with alcohol use disorders: An observational pilot study. J Crit Care. 2018;43:61-64.26. 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;27. 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):360-7.28. Teng J, Pourmand A, Mazer-amirshahi M. Vitamin C: The next step in sepsis management?. J Crit Care. 2017;43:230-234.29. 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;12:32.30. 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;;5:94–100.31. 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):1229-1238.32. Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018;