Updates in the Management of Sepsis & Septic Shock:

the VICTAS Trial38th Annual Meeting

Association of Physician Assistants in Cardiovascular Surgery Conference

Kate Nugent, MDAssistant Professor

Department of Emergency MedicineDepartment of Anesthesiology, Division of Critical Care Medicine

April 5, 2019

Conflicts of Interest• I am the principal investigator for the VICTAS trial at Emory

University Hospital.

Why Should This Matter to Us?

Burden of Sepsis: Worldwide• Based upon a meta-analysis from 27 high income countries:

• 31.5 million cases of sepsis per year• 5.3 million deaths per year

• In the top 3 most common causes of death worldwide

Fleischmann et al. AJRCCM, 2016

Burden of Sepsis: United States• 1.7 million people develop sepsis annually

• ~300,000-350,000 people die from sepsis each year• Third most common cause of death in the United States• Economic impact: $20 billion annually in the United States

approximately $55 million each day

Rhee et al. JAMA, 2017Nunnally & Patel. Curr Opin Anesthesiol, 2019

Sepsis: 2016-2018• Two of the most high profile years for sepsis to date:

• New definition• New bundles• New version of the Surviving Sepsis Campaign management

guidelines released• Increased awareness CDC and WHO campaigns on sepsis• New critical care journal publications• Numerous ongoing critical care trials

Lecture Objectives• Develop an improved understanding of the most recent

Surviving Sepsis Campaign guidelines in order to optimize medical care for patients with sepsis and septic shock

• Build upon prior knowledge of vasopressor and steroid use in sepsis and septic shock by reviewing recent critical care trial literature

• Develop an improved understanding regarding the use of vitamin C, thiamine, and steroids in patients with sepsis and septic shock

Lecture Outline• Review of the major updates in the 2016 Surviving Sepsis

Campaign: International Guidelines for Management of Sepsis and Septic Shock

• Review of recent critical care medicine trials related to sepsis and septic shock

• Discuss the rationale behind vitamin C, thiamine, and steroids for sepsis and septic shock

JAMA• Third International

Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

• Endorsed by over 30 organizations worldwide

Out with the old…• Sepsis-1 “Definition”:

• Systemic Inflammatory Response Syndrome (SIRS) resulting from infection

• Temp >38 or <36• HR >90• RR >20 or PaCO2 <32• WBC >12 or <4 or >10% bands

• Spectrum is sepsis, **severe sepsis**, and septic shock

In with the new…• Sepsis-3 Definition:

• Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection”.

In with the new…• “Life threatening organ dysfunction”

• Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points

Copyright © 2016 American Medical Association. All rights reserved.

In with the new…• Septic shock:

• Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.

• Key question: • Is “shock” more than hypotension alone?

In with the new…• Patients with septic shock can be identified those with

sepsis plus:• Persisting hypotension requiring vasopressors to maintain MAP

≥65 mm Hg and…• A serum lactate level >2 mmol/L (18 mg/dL) despite adequate

fluid resuscitation.

Hospital mortality (%)

Hypotension + lactate >2 42.3

Hypotension alone 30.1

Lactate >2 alone 25.7

No hypotension and lactate <2 18.7

In with the new…• qSOFA

• For septic patients presenting outside the ICU (emergency department, medical/surgical floor, etc), death or prolonged ICU stay can be predicted by qSOFA:

• Respiratory rate >22 bpm• Altered mentation• Systolic blood pressure <100 mm Hg

0.64 (0.62, 0.66)

<0.01 0.74 (0.73, 0.76)

<0.01 0.20 0.75 (0.73, 0.76)

0.01 <0.01 <0.01 0.66 (0.64, 0.68)

SIRS

SOFA

LODS

qSOFA

ICU encounters N = 7,932

AUROC in-hospital mortality

0.76 (0.75, 0.77)

<0.01 0.79 (0.78, 0.80)

<0.01 <0.01 0.81 (0.80, 0.82)

<0.01 <0.01 0.72 0.81 (0.80, 0.82)

SIRS

SOFA

LODS

Outside the ICU encountersN = 66,522

AUROC in-hospitalmortality

qSOFA

SOFA and LODS superior in the ICU

qSOFA similar to complex scores outside the ICU

In with the new…

But…

CLINICAL MANAGEMENT OF SEPSIS AND SEPTIC SHOCK

Timely Care BundlesClinical Management RecommendationsRecent Publications & Study Results Ongoing Clinical Trials

3 Hour Bundle• Three hour bundle:

• Measure lactate level• Obtain blood cultures prior to administration of antibiotics• Administer broad spectrum antibiotics• Administer 30 ml/kg crystalloid for hypotension or lactate >

4 mmol/L

6 Hour Bundle• Six hour bundle:

• Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a MAP > 65

• In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate >4 mmol/L, re-assess volume status and tissue perfusion

• Re-measure lactate if initial lactate was elevated

Do Bundles Work?• Surviving Sepsis Campaign Data:

• 29,470 subjects• 218 hospitals from 2005-2012• Compliance increased linearly from 10.9% in the first site quarter

to 31.3% by end of year two• Adjusted odds ratio for mortality improved the longer a site was

in the campaign• 0.7% per quarter• Mortality 38.6% with low resuscitation bundle compliance and

29.0% with high compliance

Levy et al CCM, 2015

Do Bundles Work? (continued)

OBJECTIVE: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality.

Do Bundles Work? (continued)• INTERVENTIONS: Four 3-hour Surviving Sepsis Campaign

guideline recommendations: • 1) obtain blood culture before antibiotics• 2) obtain lactate level• 3) administer broad-spectrum antibiotics• 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as

"mean arterial pressure" < 65) or lactate > 4• MEASUREMENTS AND MAIN RESULTS: From 5,072 patients

with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. • The majority of patients had the four 3-hour bundle

recommendations initiated within 3 hours. • The statistically significant time in minutes after which a delay

increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes.

Bundles DO Work…• …at least when being utilized in a clincial study enviroment• Question: Is it possible for them to work outside the context

of a clinical study?

Seymour et al. NEJM 2017

Mandated Protocol for Early Identification and Treatment of Sepsis• 49,331 patients in New York state• 149 hospitals• April 1, 2014 to June 30, 2016• Providers required by state to follow protocols for early

identification and treatment of sepsis • Each hospital got to pick their protocol as long as it complied with

3 hour and 6 hour bundle suggested by the SSC

Seymour et al. NEJM 2017

The Golden Hour

• Which has a higher per patient mortality?• Sepsis vs. trauma• Sepsis vs. STEMI• Sepsis vs. stroke

The Golden Hour of SEPSIS

Antibiotics• Initiate broad spectrum antibiotics within the first hour of

recognition of sepsis • Narrow therapy once pathogen identification and sensitivities

are established and/or adequate clinical improvement is noted • Need additional evidence to support this recommendation?

Kumar et al. CCM 2006

Antibiotics (continued)• Empiric combination therapy:

• Using at least two antibiotics of different antimicrobial classes aimed at the most likely bacterial pathogen for the initial management of septic shock

• Should not be used for ongoing treatment of most other serious infections including bacteremia or sepsis without shock

• Combination therapy typically means a beta-lactam with a fluoroquinolone, aminoglycoside, or macrolide

Antibiotics (continued)• If combination therapy is used for septic shock, de-escalate

within the first few days in response to clinical improvement and/or evidence of infection resolution.• This is for both targeted (culture positive) and empiric (culture

negative) combination therapy.• Without evidence of infection, no antibiotics should be used in

cases of non-infectious SIRS (burns, pancreatitis, etc) • Role of procalcitonin?

Resuscitation and Fluid Management

• Resuscitation from sepsis-induced hypoperfusion should be done with at least 30 ml/kg of crystalloid within the first 3 hours

• After initial resuscitation, additional fluids should be guided by frequent reassessment of hemodynamic status • Use dynamic >>> static variables to predict fluid responsiveness

• Normalize lactate in patients with elevated lactate as a marker of tissue hypoperfusion

• (Balanced) crystalloids should be used as the initial fluid of choice in resuscitation • But what about albumin?!?!?!

Resuscitation and Fluid Management

• ALBUMIN

• SSC Guidelines: Use albumin in addition to crystalloid for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock when patients require substantial amounts of crystalloid.

Vasopressors• 1st choice vasopressor: NOREPINEPHRINE • Add either vasopressin (up to 0.03 U/min) or

epinephrine to norepinephrine with the intent of raising MAP to target or decreasing norepinephrine dose

• Can use dopamine as an alternative to norepinephrine in highly selective patients with low risk of tachyarrhythmias and absolute or relative bradycardia

• Use dobutamine in patients with persistent hypoperfusion despite adequate fluid loading and vasopressor titration.

Vasopressors (continued)

• OBJECTIVE: To compare the effect of early vasopressin vs. norepinephrine on kidney failure in patients with septic shock.

• INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).

Vasopressors (continued)VANISH Trial• PRIMARY OUTCOME: kidney failure–free days during the 28-

day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both.

• Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.

Vasopressors (continued)

• OBJECTIVE: To investigate the effectiveness of angiotensin II for the treatment of patients with refractory vasodilatory shock

• INTERVENTIONS: Patients with vasodilatory shock who were receiving more than 0.2 μg/kg/min of norepinephrine or the equivalent dose of another vasopressor were randomly assigned to receive infusions of either angiotensin II or placebo.

ATHOS-3 Trial• PRIMARY OUTCOME: a response with respect to mean

arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors.

Vasopressors (continued)

• Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial

• Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively)

• Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007).

Steroids• Reserve intravenous hydrocortisone to treat septic shock

for patients in whom adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability.

• Dose: IV intravenous hydrocortisone 200 mg per day• Taper/discontinue steroids when vasopressors are no

longer required.

Steroids (continued)

• OBJECTIVE: To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock.

• RESULTS: No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days

Steroids (continued)

• Patients: mechanically ventilated patients with high suspicion for infection + >/= 2 SIRS criteria + vasopressor requirement

• Protocol: continuous infusion of hydrocortisone 200mg/day vs. placebo

• Results: patients in the hydrocortisone group had faster resolution of shock, shorter duration of initial episode of mechanical ventilation, and received less blood product transfusion.

Steroids (continued)

• Initial plan: multicenter, double-blind, randomized trial evaluating hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos

• Updated plan: hydrocortisone-plus-fludrocortisone therapy vs. placebo

Steroids (continued)APROCCHSS Trial• Patients: “indisputable or probable septic shock” (infection,

SOFA score, vasopressor requirement) for less than 24 hours• Primary outcome: 90-day all-cause mortality• Secondary outcomes: mortality at ICU discharge, hospital

discharge, at day 28 and day 180, and number of days alive and free of vasopressors, mechanical ventilation, or organ failure

• Results: all-cause mortality was lower with hydrocortisone plus fludrocortisone at day 90, at discharge from the ICU and hospital, and at day 180. The time to weaning from vasopressors, to weaning from mechanical ventilation, and to reaching a SOFA score below 6 was shorter in the steroid group.

Steroids (continued)

• “In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.”

• “The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo.”

Rochwerg et al. CCM 2018

Fang et al. JAMA Intern Med 2019

What else is on the horizon?

• Single center, retrospective before-after clinical study • Patients with severe sepsis and septic shock• Treatment group (vitamin C, thiamine, steroids +

standard of care - 47) vs. propensity matched control group (standard of care - 47)

• Primary outcome: hospital survival • Results: the hospital mortality was 8.5% (4 of 47) in the

treatment group compared with 40.4% (19 of 47) in the control group (P < .001).

How About in Cardiac Surgery?

• Single center, double-blinded, randomized control trial • 24 patients (12/12) with septic shock following cardiac surgery

• Treatment group (vitamin C, thiamine, steroids + standard of care) vs. control group (standard of care)

• Primary outcome: vasopressor dose over four days• Secondary outcome: in-hospital mortality • Results: significant reductions in the requirement of vasopressin (P =

0.019) and noradrenaline (P = 0.006) were observed with vitamin C treatment as compared to control group.

Rationale Behind Vitamin CVitamin C as an Antioxidant • Inhibits the enzyme nicotinamide adenine dinucleotide

oxidase (NOX) – an enzyme activated in the setting of endothelial dysfunction during sepsis and other ischemic conditions – which leads to the production of many other reactive oxygen species (ROS)

• Production of these ROS by NOX damages the endothelium leading to extravasation and vascular compromise

• Summary: reduces oxidative damage and stress that otherwise can lead to decreased vascular tone and increased vascular permeability

Rationale Behind Vitamin CVitamin C in Vasopressor Synthesis • Acts as a co-factor for several enzymatic reactions required for

the synthesis of vasopressin, synthesis for the pre-cursor of dopamine (LDOPA), and conversion of dopamine into epinephrine

• Modulates both alpha-adrenergic and beta-adrenergic receptor activity through binding of these receptors and enhancing their activation by epinephrine

• Animal study: knockout of the SVCT2 (Sodium-dependent Vitamin C Transporter 2) transporter in mice results in significantly reduced synthesis of norepinephrine, epinephrine and corticosteroids in the adrenal glands.

Rationale Behind Vitamin CVitamin C in Immune Function • Improves chemotaxis, supports lymphocytic proliferation, and

assists in oxidative neutrophilic killing of bacteria by leukocytes

• Inhibits apoptosis and protects endothelial progenitor cells • Reduces inflammatory modulators by inhibiting nuclear factor

kappa-B leads to stronger endothelial junctions and preservation of the vascular endothelium• Likely synergistic with steroids

Rationale Behind Vitamin C

Marik. Nutrients, 2018

Rationale Behind ThiamineThiamine• Repletion in thiamine deficient patients with sepsis has been

associated with earlier lactate clearance and ?decreased 28-day mortality

• Cofactor in the metabolism of glyoxylate, a metabolite of Vitamin C, whose conversion to oxalate can predispose patients to oxalate nephropathy

• Cofactor for numerous other enzymatic reactions involving energy metabolism

• Has anti-inflammatory effects including suppression of the oxidative stress-induced activation of NF-kB

Woolum et al. CCM, 2018

Vitamin C, Thiamine, & Steroids in Sepsis (VICTAS)• Patients

• Up to 500 adult patients with confirmed or suspected infection and evidence of respiratory or cardiovascular organ dysfunction (e.g. adult sepsis)

• Intervention• Intravenous vitamin C (1.5 grams every 6 hours) • Thiamine (100 mg every 6 hours)• Hydrocortisone (50 mg every 6 hours)• Dosing x 4 days or until ICU discharge

• Comparison• Placebo (unless clinical team desires to give steroids)

• Outcome• Vasopressor and Ventilator Free Days• 30-day mortality

Inclusion Criteria• Suspected Infection

• Blood cultures + antibiotics• Respiratory or Cardiovascular Dysfunction

• Vasopressor at any dose for > 1 hr and required to maintain a MAP ≥ 65 mmHg despite IV crystalloid infusion of at least 1000ml

• Acute hypoxemic respiratory failure defined as persistent hypoxemia (PaO2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 315) requiring (1) intubation and mechanical ventilation, or (2) PPV via tight-fitting face mask (i.e. CPAP or BIPAP) or (3) HFNC ≥ 45 LPM flow and FiO2 ≥ 0.40

• Anticipated ICU Admission

Exclusion Criteria • Age < 18 years of age• Organ dysfunction present > 24 hrs at

time randomization• Limitations of care e.g. “do not intubate”

(DNI) status• Current hospitalization > 30 days • Chronic hypoxemia requiring

supplemental non-invasive oxygen (nasal cannula or NIPPV) or home mechanical ventilation

• Chronic cardiovascular failure requiring home mechanical hemodynamic support (e.g., LVAD) or home chemicalhemodynamic support (e.g., milrinone)

• Known allergy or known contraindicationon to vitamin C, thiamine, and/or corticosteroids

• Receiving intravenous vitamin C as a treatment for sepsis OR any dose of vitamin C exceeding 1 gram daily

• Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of < 30 days unrelated to current sepsis diagnosis(e.g., stage IV malignancy, neurodegenerative disease, etc.)

• Pregnancy or known active breastfeeding

• Prisoner or Incarceration

• Current participation in another interventional study for sepsis

• Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

CONCLUSION

SummaryQuestionsReferences

Summary• Respect the “Golden Hour” of sepsis and septic shock

management.• Bundles really do work (if implemented correctly).• Consider combination antibiotic therapy for patients with

septic shock in whom there is a high suspicion for gram negative infection.

• Consider starting vasopressin slightly earlier than you do at present and keep angiotensin II in the back of your mind for refractory vasodilatory shock.

• Steroids should be considered for patients with septic shock but NOT sepsis.

• Keep an eye/ear out for the results of multiple RCTs looking at the effects of vitamin C, thiamine, and steroids in sepsis and septic shock.

Questions

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