Updates in the Treatment of Sepsis. Devise a treatment strategy for the management of vasopressor therapy for cardiovascular support of septic shock 3. Evaluate recent evidence related

Updates in the Treatment of Sepsis

Mitchell J Daley, PharmD, FCCM, BCPSClinical Pharmacy Specialist, Critical Care

Dell Seton Medical Center at the University of Texas and Seton Healthcare Family

Clinical Adjunct Faculty

University of Texas College of Pharmacy

Conflicts of Interest

Nothing to disclose

Objectives

1. Discuss emerging controversies related to fluid resuscitation in sepsis

2. Devise a treatment strategy for the management of vasopressor therapy for cardiovascular support of septic shock

3. Evaluate recent evidence related to metabolic and endocrine resuscitation in the treatment of sepsis

Outline

✓Definitions

✓ Bundled resuscitation

✓ Fluid Resuscitation✓ Balanced salt vs. “normal” saline

✓ Colloids

✓ Predicting fluid responsiveness

✓ Vasopressor therapy ✓ Catecholamines

✓ Vasopressin

✓ Weaning

✓ Angiotensin II

✓ Metabolic resuscitation✓ Steroids

✓ Vitamin C + thiamine

✓ Early Antibiotics

Sepsis and Septic Shock• Greek for decompensation of organic material by bacteria• Used for 2700 years with little change in meaning

– Hippocrates: “flesh rots and wounds fester”– Historically thought localized infection → bloodstream– Advent of antibiotics really highlighted the “host theory”

• Pro-inflammatory AND anti-inflammatory reactions • Tremendous healthcare burden in the US

– Mortality 20-55% with persistent ↓ physical and cognitive function– Cost: more than $20 billion annually

• Difficult to define clinically with attempts starting in 1992 (SIRS)

Angus DC, et al. NEJM 2013;369:840.

Sepsis Definitions: Version 3.0

Singer M, et al. JAMA 2016; 315: 801.

Septic Shock 2001

Severe sepsis Hypoperfusion

Severe Sepsis 2001

Sepsis≥ 1 sign of organ

dysfunction

Sepsis 2001

Systemic inflammatory response syndrome (SIRS)

Documented or suspected infection

Septic Shock 2016

Metabolic/cellular abnormalities ↑ mortality

Vasopressors for MAP >65

Lactate ≥ 2 despite fluid

Sepsis 2016

Life-threatening organ dysfunction caused by

dysregulated host response to infection

Non-ICU: 2/3 quick SOFA

ICU: SOFA ≥ 2 change

Applying SOFA and qSOFA

Ferreira FL, et al. JAMA 2001;286:1754.

qSOFA

SBP ≤ 100 mm Hg

RR ≥ 22 bpm

Altered mental status (GCS < 15)

Sepsis 3.0: Bad Trilogy? Advantages of Sepsis 3.0

• SOFA and qSOFA superior to SIRS for mortality

• Better reflects biochemical abnormalities

• More specific

Disadvantages of Sepsis 3.0

• Not tests for sepsis but mortality and may lead to late recognition

• Lacks prospective validation and outcome analysis

• Practical consideration (e.g. awaiting labs, chronic organ dysfunction)

• Less sensitive than SIRS which was working…

• Suspected infection remains subjective

• Many professional organizations have not endorsed, core measure still uses SIRS

Simpson SQ, et al. CHEST 2016; 149: 1117.

Case: RM

• RM is a 56 y/o, 66 kg, male admitted to ED w/ CAP• BP 83/47 mm Hg, lactate 6.2 mmol/L; UOP 30 mL/hour• In addition to antibiotics, which would be the best

therapy for RM right now?A. NS - targeting a CVP of 8 mm HgB. Albumin 5% - 500 mLC. LR - 30 mL/kgD. LR - if stroke volume variability >12%

Early Goal Directed Therapy

Angus DC, et al. Intensive Care Med 2015;41:1549.

ProMISe 184/623 181/620 32.23 1.02 (0.80, 1.30)

Jones 34/150 25/150 4.87 1.47 (0.82, 2.60)

Test for overall effect: p=0.90

ARISE 147/792 150/796 30.71 0.98 (0.76, 1.26)

ProCESS 92/439 167/902 21.78 1.17 (0.88, 1.55)

Rivers 38/130 59/133 10.40 0.52 (0.31, 0.86)

Overall 495/2134 582/2601 100.00 1.01 (0.88, 1.16)Test for heterogeneity: I2 =56.7%, p=0.055

0.3 1 3 Favors EGDT

StudyEvents, EGDT

Events, Control Weight %

OR (fixed)(95% CI)

Favors control

Primary Mortality Outcome

Surviving Sepsis Bundle

2016

• Within 3 hours of recognition– Measure lactate, repeat if ↑

– Obtain blood cultures

– Administer antibiotics

– Give 30 ml/kg fluid

• Within 6 hours of recognition– Apply pressor if hypotension

– Focused exam

2018

• Within 1 hour of triage– Measure lactate, repeat if ↑

– Obtain blood cultures prior to antibiotics

– Begin 30 ml/kg fluid for hypotension of lactate >4

– Apply pressors if hypotensive during or after fluid to maintain MAP > 65 mm Hg

Crit Care Clin 2016;32:539-546

Fluid Resuscitation• Primary focus for years has early fluid resuscitation

– Intravenous fluids are given to ↑ preload, ↑ stroke volume, ↑ cardiac output

– Maximize oxygen delivery

• Surviving sepsis recommends 30 mL/kg within 3 hr– Life after “Early Goal Directed Therapy”– Average volume from PROCESS, ARISE and PROMISE (2 L)– Fixed volume facilitate early aggressive resuscitation– Controversial…


Total Body Water (TBW) - 1896Intracellular fluid (ICF)

2/3 total body water

Extracellular fluid (ECF)

1/3 total body water

Intracellular fluid

66% of TBW

Intra-vascular

¼ ECF

8.25% TBW

↑ osmoticpressure

Interstitial

¾ ECF

24.75% TBW

↓ osmotic pressure

Pumps

Sem

iper

mea

ble

m

emb

ran

e

Fluid Resuscitation

VariableNormal saline

Lactated ringers

Plasma

lyteAlbumin 5%

Hetastarch 6%

Osmolarity, mOsm/L 308 280.6 294 309 300-310

Sodium, mmol/L 154 131 140 130-160 154

Potassium, mmol/L - 5.4 5 - -

Calcium, mmol/L - 2 - - -

Magnesium, mmol/L - - 3 - -

Chloride, mmol/L 154 111 98 130-160 154

Volume Expansion, % 20-25 20-25 20-25 70-100 100-200

Myburgh JA, et al. NEJM 2013;369:1243.

Crystalloids

SMART Trial

• Single center, RCT

• 7942 pt (15% sepsis)

• Primary outcome at 30 days: death, RRT or persistent AKI

• Sepsis 30 D mortality– 25.2% LR vs. 29.4% NS

– NNT 24

Emler MW, et al. NEJM 2018;3378:829.

Crystalloid Resuscitation Pearls• Hyperkalemia is likely NOT a contraindication to balanced

salt solutions– Excluded from the SMART trial– Safer than NS in renal transplant studies

• LR should NOT be avoided for fear of lactic acidosis– Sodium lactate ≠ lactate acid – May misinterpret the rise in lactate levels

• Cost comparable • NS may still have a primary role in neurologic injury

Reddy S, Crit Care 2016;20:59.

SVV: stroke volume variation; PPV: pulse pressure variation

Fluid Responsive?• Fluid responsiveness

better predicted by dynamic markers vs. static variables

– AUC: PPV 0.94, SVV 0.84 vs. CVP 0.55

• Rec in Surviving Sepsis but lack outcomes data

Method Mechanism Threshold Main limitations

PPVSVV

Heart-lunginteraction

12% variation

Do not use if spontaneous breathing, arrhythmias, low tidal volume / lung compliance

Passive leg raising

Endogenousfluid challenge

10% ↑ CO Requires direct measurement of cardiac output

Fluid challenge

Exogenousfluid challenge

6% ↑ CO(100 mL)15% ↑ CO(500 mL)

Requires precise monitoring of cardiac output

Monnet X, et al. Ann Intensive Care 2016;6:111.

Fluid Resuscitation

VariableNormal saline

Lactated ringers

Plasma

lyteAlbumin 5%

Hetastarch 6%

Osmolarity, mOsm/L 308 280.6 294 309 300-310

Sodium, mmol/L 154 131 140 130-160 154

Potassium, mmol/L - 5.4 5 - -

Calcium, mmol/L - 2 - - -

Magnesium, mmol/L - - 3 - -

Chloride, mmol/L 154 111 98 130-160 154

Volume Expansion, % 20-25 20-25 20-25 70-100 100-200

ColloidsCrystalloids

Myburgh JA, et al. NEJM 2013;369:1243.

Colloids Post SAFE Trial• Albumin / ALBIOS trial

– Severe sepsis or shock randomized to albumin 20% 300 mL daily vs. placebo to keep level >3g/dL for 28 days

– Quicker time to pressor discontinued

– 90 day mortality benefit in septic shock?

• Similar to SAFE…

Caironi P, et al. NEJM 2014;370:1412.

Colloids Post SAFE Trial• Albumin / ALBIOS trial

– Severe sepsis or shock randomized to albumin 20% 300 mL daily vs. placebo to keep level >3g/dL for 28 days

– Quicker time to pressor discontinued

– 90 day mortality benefit in septic shock?

Caironi P, et al. NEJM 2014;370:1412.

Hetastarch Blackbox warning for AKI and mortality in sepsis Recommended against

Surviving sepsis guidelines: Consider addition of albumin if “substantial amount of fluids…”

Weak recommendation, Low quality of evidence

Case: RM

• RM is a 56 y/o, 66 kg, male admitted to ED w/ CAP• BP 83/47 mm Hg, lactate 6.2 mmol/L; UOP 30 mL/hour• In addition to antibiotics, which would be the best

therapy for RM right now?A. NS - targeting a CVP of 8 mm HgB. Albumin 5% - 500 mLC. LR - 30 mL/kgD. LR - if stroke volume variability >12%

Case: RM

• RM is started on 30 ml/kg LR and norepinephrine up to 0.4 mcg/kg/min but his lactate remains > 4 mmol/L

• His MAP remains <60 mm Hg and he is in Afib w/RVR• He is not predicted to be fluid responsive, which is the best

therapy?A. Vasopressin infusion 0.03 units/min, wean lastB. Dopamine 5-20 mcg/kg/min, wean firstC. Phenylephrine 0.5-3 mcg/kg/min, wean lastD. Epinephrine 0.03-0.3 mcg/kg/min, wean first

Vasopressors


Agent Receptors Preload HR SV CO Afterload

Phenylephrine α1 or or or

Norepinephrine* α1 > β1 or or or or

Dopamine* β1 > α1 or

Epinephrine* α1 = β1 or

Vasopressin V1R, V2R or

Angiotensin II AT-R1, AT-R2 or

Surviving Sepsis: Vasopressors

Rhodes A, et al. Crit Care Med 2017;45:486.

• Norepinephrine (NE) first choice

• Dopamine (DA) alternative to NE in select patients

• Epinephrine (EPI) second line (↑ adverse effects, ↑ lactate)

• Phenylephrine dropped for lack of evidence

• Vasopressin (VP) for relative vasopressin deficiency is a Second line vasopressor or for NE sparing effect (VASST)

• Target a MAP 65 mm Hg (↓ Afib and pressors, = mortality)

DA vs. NE in Septic Shock

De Backer D, et al. Crit Care Med 2012;40:725.

Overall 396/732 330/676 1.12 (1.01-1.20)

Study DA n/N NE n/N28-Day Mortality

RR (95% CI)Martin 10/16 7/16 1.43 (0.73-2.80)

Marik 6/10 5/10 1.20 (0.54-2.67)

Ruokonen 3/5 4/5 0.75 (0.32-1.74)

Mathur 19/25 14/25 1.36 (0.90-2.05)

De Backer 291/542 249/502 1.08 (0.98-1.19)

Patel 67/134 51/118 1.16 (0.89-1.51)

0 1 2 3Test for heterogeneity: I2 = 0%, p = 0.77Test for overall effect: p = 0.035

Favors DA Favors NE

Surviving Sepsis: Vasopressors


• Norepinephrine (NE) first choice

• Dopamine (DA) alternative to NE in select patients

• Epinephrine (EPI) second line (↑ adverse effects, ↑ lactate)

• Phenylephrine dropped for lack of evidence

• Vasopressin (VP) for relative vasopressin deficiency is a Second line vasopressor or for NE sparing effect (VASST)

• Target a MAP 65 mm Hg (↓ Afib and pressors, = mortality)

VANISH

• Baseline characteristics well matched– APACHE II 24, 58% intubated, time to receive study drug 3.5 hours

– 76% received NE prior to enrollment at high doses (0.16 mcg/kg/min)

Gordon AC, et al. JAMA 2016;316:509.

Study Population Intervention Endpoints

Gordon

Multicenter Double blind

RCT

Include:Adult patientsSeptic shock

Within 6 hours

Exclude:Previous VP

Ongoing need for steroidESRD

Vasospastic disease

VP + HCT (n=101)

VP + Placebo (n=104)

NE + HCT (n=101)

NE + Placebo (n=103)

VP up to 0.06 units/minNE up to 12 mcg/min

HCT 50 mg q6h, tapered 11 days

10 endpoint: - Kidney failure free days within 28 days

2o endpoint:- Rates and duration of renal replacement therapy- Length of kidney failure- 28 day, ICU and hospital mortality rates- Organ failure free days (SOFA)

VANISHNo difference in mortality between vasopressor or steroid group

No beneficial interaction between steroids and VP

Gordon AC, et al. JAMA 2016;316:509.

Vasopressin on Mortality


Breaking the BANK!• Vasopressin branded VP through a NDA (4/14)• Price went from $8.67/day → $400/day (50 fold ↑)• Strategies:

– Reduce standard concentration (e.g. 20 units/100 mL)– Remove from emergency carts and kits– Restriction criteria (e.g. sepsis requiring a certain rate NE)– Mandatory approval by pharmacist or attending– Education– Altered clinical care (e.g. dose, weaning strategy, alternative pressors)

Curtis N, et al. AJHP 2017:74:105.

Price escalation appears to have little influence on use in septic shock…

Weaning VasopressorsStudy /Design Patient Population Interventions Results

Hammond DA

J Intensive Care Med

2017

epub ahead of print

Retrospective

154 adult patients

with septic shock on

both NE and VP

Categorized into groups based on

which was discontinued first

NE vs. VP

• More clinically significant hypotension after

VP dc’d first (10.9% vs. 67.8%; p<0.01)

• In adjusted analysis, discontinuing VP first

associated with ↑ clinically significant

hypotension (OR 13.83; 95%CI 3.4-56)

• No difference in mortality of LOS

Sacha GL

Pharmacotherapy

2018

Epub ahead of print

Retrospective

585 adults in the recovery phase of septic shock who received VP + NE for at least 6 hours



NE vs. VP

• No difference noted between groups for

clinically significant hypotension (54.8% vs.

49.8%; p=0.28) but quicker hypotension

• Adjusted analysis showed independent risk

for hypotension with VP dc’d first

• No difference in mortality or LOS

Hypotension: restart pressor, increase alternative pressor or fluid

Weaning VasopressorsStudy /Design Patient Population Interventions Results

Hammond DA

J Intensive Care Med

2017

epub ahead of print

Retrospective

154 adult patients

with septic shock on

both NE and VP



NE vs. VP

• More clinically significant hypotension after

VP dc’d first (10.9% vs. 67.8%; p<0.01)

• In adjusted analysis, discontinuing VP first

associated with ↑ clinically significant

hypotension (OR 13.83; 95%CI 3.4-56)

• No difference in mortality of LOS

Sacha GL

Pharmacotherapy

2018

Epub ahead of print

Retrospective

585 adults in the recovery phase of septic shock who received VP + NE for at least 6 hours



NE vs. VP

• No difference noted between groups for

clinically significant hypotension (54.8% vs.

49.8%; p=0.28) but quicker hypotension

• Adjusted analysis showed independent risk

for hypotension with VP dc’d first

• No difference in mortality or LOS

Hypotension: restart pressor, increase alternative pressor or fluid

My practice:Individualize based on patients physiology

DC NE first if arrythmiaDC VP first due to cost

Case: RM

• RM is started on 30 ml/kg LR and norepinephrine up to 0.4 mcg/kg/min but his lactate remains > 4 mmol/L

• His MAP remains <60 mm Hg and he is in Afib w/RVR• He is not predicted to be fluid responsive, which is the best

therapy?A. Vasopressin infusion 0.03 units/min, wean lastB. Dopamine 5-20 mcg/kg/min, wean firstC. Phenylephrine 0.5-3 mcg/kg/min, wean lastD. Epinephrine 0.03-0.3 mcg/kg/min, wean first

Case: RM

• RM is now refractory to fluids, NE 0.5 mcg/kg/min and increasing, and VP at 0.03 units/min but he remains borderline hypotensive with a persistently elevated lactate. Which rescue therapy has the highest quality of evidence to support a reduction in mortality?A. Angiotensin II 20 ng/kg/min, titratedB. Vit C 1.5 g IVPB q6h + Thiamine 200 mcg IVPG q12hC. Hydrocortisone 50 mg IVP q6h + Fludro 50 mcg q24hD. Epinephrine 0.03-0.3 mcg/kg/min

Refractory Shock

Jentzer JC, et al. Chest 2018;epub ahead of print.

Refractory Shock Treatment:New, Old, Re-Purposed

Angiotensin II

Correa TD, et al. Crit Care 2015;19:98.

ATHOS-3 Trial

• Baseline characteristics well matched– 80% sepsis, APACHE II 28, 28% ARDS, 70% received vasopressin

– Average NE dose was 0.34 mcg/kg/min

Khanna A, et al. NEJM 2017;377:419.


Venkatesh

MulticenterInternationalDouble-blind

Controlled

Include:Adult patients

Mechanical ventilationVasodilatory, high output shock

Treated with vasopressors for >4 hrsNE >0.25 mcg/kg/min for 6 hours

Exclude:Systemic steroids indicated

Received etomidate during stayDelayed enrollment > 24 hours

Angiotensin II20-200 ng/kg/min for 3

hrs, then max 40 ng/kg/min for 2-7 days

n=163

vs.

Placebon=158

Only study drug titrated for 3 hours

10 endpoint: - MAP response at 3 hours (>75 mm hg or ↑ by 10 mm Hg)

2o endpoint:- Changes in CV and total SOFA score at 48 hour- All-cause mortality at 7 and 28 days- Safety

ATHOS-3 Trial

Annane D B, et al. NEJM 2018;378:809.

ATHOS-3 Trial


Angiotensin II in Practice

Tumlin JA, et al. Crit Care Med 2018;46:949.

• Angiotensin II FDA approved in Jan 2018 to ↑ BP in sepsis or distributive shock state… – Dose: 20 ng/kg/min, titrate by 15 ng/kg/min every 5 min up to 80

ng/kg/min for 3 hours, then 40 ng/kg/min

– Warning for thrombosis (13% vs. 5% in ATHOS 3)

– Selection of high output states (e.g. ScVO2 >70% w/CVP <8 mm Hg or CI >2.3)

• Cost: 2.5 mg/mL ~$1,800 = ~1 day cost at starting dose

• Subgroup of ATHOS-3 in 105 pts with AKI requiring RRT– Angiotensin II possible 28-day mortality benefit (30% vs. 53%; p<0.01)

– At day 7, 38% off RRT vs. 15%

Outcomes data desperately needed before wide-spread use

ADRENAL Trial

• Baseline characteristics well matched– Age 62, 60% male, APACHEII 23-24, pulm and abd predominant infection

– Time from shock onset to randomization 21 hours

Venkatesh B, et al. NEJM 2018;378:797.


Khanna


Controlled


Vasodilatory shock despite 25 ml/kg fluid + NE >0.2 mcg/kg/min for 6

hours

Exclude:Longer than 48 hours

Burns >20%, ACS, bronchospasm, liver failure, mesenteric ischemia, active bleeding, AAA, nutropenic,

ECMO, systemic steroids

Hydrocortisone200 mg infusion /day

for 7 D or transfer from ICUn=1832

vs.

Placebon=1826

10 endpoint: - Death from any cause at 90 days

2o endpoint:- Death from any cause at 28 days- Time to resolution of shock- Length of stay (ICU and hospital)- Frequency and duration of mechanical ventilation - Frequency and duration of renal replacement therapy- Secondary infection (bacteremia, fungemia)- Blood transfusion

ADRENAL Trial


APROCCHSS Trial

• Baseline characteristics well matched– Age 66, 66% male, SOFA score 11, pulm and abd predominant infection

– Mean dose of norepinephrine 1 mcg/kg/min

Venkatesh B, et al. NEJM 2018;378:797.


Annane


Controlled

* Initially included activatedprotein C


Probable septic shockSOFA Score 3/4 for 2 organs for 6 hrs

Vasopressors for 6 hours

Exclude:Septic shock for > 24 hours

Pregnancy or lactationPrevious treatment with steroids

Hydrocortisone 50 mg IV q6h +

fludrocortisone 50 mcg daily for 7 days

n=627

vs.

Placebon=614

10 endpoint: - Death from any cause at 90 days

2o endpoint:- Death from any cause at ICU discharge, hospital

discharge and days 28 and 180- Time to weaning form pressors- Duration of mechanical ventilation - % of patients with organ failure free (SOFA < 6 28/90 D)- Length of stay (ICU and hospital)- Safety (superinfection, GI bleed, hyperglycemia,

neurologic sequelae)

APROCCHSS Trial


Steroids in 2018Benefit

• Consistent result in quicker resolution of shock

• Decreased duration of mechanical ventilation

• Less mortality and organ failure in the sickest

Risks

• Hyperglycemia

Suffredini AF. NEJM 378;9:860.

Steroids in 2018Benefit

• Consistent result in quicker resolution of shock

• Decreased duration of mechanical ventilation

• Less mortality and organ failure in the sickest

Risks

• Hyperglycemia

J Burn Care Research 2008;29:257-266

Practical considerations:

Infusion vs. intermittent?HCT alone or HCT + Fludrocortisone?Duration if persistent shock remains?

Metabolic Resuscitation• Vitamins become depleted during sepsis

– Vitamin C ↓ correlates with ↑ multi-organ failure and death– Thiamine deficiency is associated with ↑ mortality

• Deficiencies relevant and cause clinical disease– Thiamine deficiency noted in 35% of shock patients with ↑ lactate

• Essential co-enzyme in Krebs cycle (production of ATP)• Wernicke’s encephalopathy and Beriberi

– Vitamin C • Maintains endothelial boundaries, required to synthesize

catecholamines, antioxidant prevents neutrophil induced lipid oxidation• Deficiency causes scurvy

Marik PE. Pharmacol Ther 2018;epub ahead of print.

Total Body Water (TBW) - 2018

NEJM 2013;369:1243-1251

GlycoproteinsProteoglycans

IV Vitamin C Sepsis Randomized Data Study /Design Patient Population Interventions Results

Fowler et al.

J Transl Med

2014;12:32

RCT

24 patients with

severe sepsis

randomized 1:1:1

Low dose Vit C 50 mg/kg/day

High dose Vit C:200 mg/kg/day

Placebo

Zabet et al.

J Res Pharm Pract

2016;5:94

RCT

28 surgical patients on pressors to maintain MAP > 65 mm Hg

Vit C 25 mg/kg every 6 hours for 3

days

Vs.

Placebo

• Total dose of norepinephrine for 72 hour:

Vit C 156 mcg vs. 302 mcg; p<0.01

• Duration of norepinephrine: Vit C 50 hr

vs. 72 hr; p<0.01

• 28 day mortality: Vit C 14% vs. 64%;

p<0.01

“The Marik Cocktail”

• Baseline characteristics well matched– Age 58-62, 49-57% male, 47-55% intubated, 46% required pressors

– SOFA score 8 with predicted mortality of about 40%

Marik PE, et al. Chest 2017;151:1229.


Marik

Retrospective Before-After

Study

Jan to July 2016

Include:Severe sepsis and septic

shockProcalcitonin > 2 ng/mL

Exclude:<18

Limitations on care

Vit C 1.5 g q6hHydrocortisone 50 mg q6h

Thiamine 200 mg q12hFor 4 days or transfer

n=47

vs.

Placebon=47

10 endpoint: - In hospital survival

2o endpoint:- Duration of vasopressor therapy- Requirement for renal replacement therapy- ICU length of stay- Change in serum procalcitonin over 72 hours- Change in SOFA score over 72 hours

“The Marik Cocktail”

Marik PE, et al. Chest 2017;151:1229.

Implications of Metabolic ResuscitationPro Adoption

• Dramatic effect on mortality

• Supported by basic science research

• Safe (especially with recent steroid papers)

• Not expensive, designer drug

Anti Adoption

• Loss of clinical equipoise for RCT (e.g. glutamine)

• Low quality of evidence (association, not causation)

• Publicity…

• Practical considerations

Oudemans HM, et al. Chest 2017;151:1199.

Practical Considerations• Vitamin C 500 mg / mL x 50 mL ~$100 / vial

– Make 4 doses (1.5g/100 mL NS; 24 hr stability)

– Waste relative to number of active patients• One patient: course about $400 and waste 75%

• Four patients: course about $100 and waste little

– Monitor: osmotic diuresis, AKI, no POC glucose for 24 hrs (↑)

• Thiamine (~$50) and HCT (~120)

https://emcrit.org/isepsis/isepsis-vitamin-c-hydrocortisone-thiamine-metabolic-resuscitation-protocol/

Case: RM

• RM is now refractory to fluids, NE 0.5 mcg/kg/min and increasing, and VP at 0.03 units/min but he remains borderline hypotensive with a persistently elevated lactate. Which rescue therapy has the highest quality of evidence to support a reduction in mortality?A. Angiotensin II 20 ng/kg/min, titratedB. Vit C 1.5 g IVPB q6h + Thiamine 200 mcg IVPG q12hC. Hydrocortisone 50 mg IVP q6h + Fludroc 50 mcg q24hD. Epinephrine 0.03-0.3 mcg/kg/min

Don’t Forget - Early Antibiotics

Seymour CW, et al. NEJM 2017;376:2235.

• NY adoption of bundled care in 49,311 patients

• Longer time to administration of antibiotics associated with in-hospital mortality

– OR 1.04; 95% CI 1.03-1.06

Pushing the Envelope

Alam N, et al. Lancet Respir Med 2018;6:40

• Multicenter RCT (Netherlands)

• Patients with sepsis received ceftriaxone pre-hospital

• Time to antibiotics -26 min vs. 70 min

• Average qSOFA ≥ 2 ~20% of patients

Conclusions

• New definitions controversial, SIRS still used• Time requirement to bundle implementation is

decreasing• Fluid resuscitation

– Shift towards balanced crystalloids– Ongoing administration beyond 30 ml/kg should be

guided by dynamic markers of fluid responsiveness– Albumin considered for “large volumes” of fluid

Conclusions

• Vasopressors– Norepinephrine reigns supreme– No clear benefit to vasopressin and cost barrier– Wean based on physiologic condition

• Refractory septic shock– Angiotensin has an emerging but unproven role– Steroids reverse shock, appear safe and still may ↓ mortality– Vitamin C and thiamine promising but warrant validation

• Early antibiotics remain at the core for treatment of sepsis

Updates in the Treatment of Sepsis

Mitchell J Daley, PharmD, FCCM, BCPSClinical Pharmacy Specialist, Critical Care

Dell Seton Medical Center at the University of Texas and Seton Healthcare Family

Clinical Adjunct Faculty

University of Texas College of Pharmacy

Documents

Updates in the Treatment of Sepsis. Devise a treatment strategy for the management of vasopressor therapy for cardiovascular support of septic shock 3. Evaluate recent evidence related