Advancements in Sepsis

3/2/2016

1

Advancements in SepsisAdvancements in SepsisAdvancements in SepsisAdvancements in Sepsis

Brian Gilbert, PharmDPGY-1 Pharmacy ResidentJackson Memorial Hospital

3/13/2016

www.fshp.org

Disclosure

• I have no disclosures to report.

2

Objectives

• Pharmacist objectives

– Review recent updates in resuscitation strategies

– Describe different monitoring updates

– Analyze appropriate use of adjuvant therapies

• Pharmacy Technician objectives

– Describe pathophysiology of sepsis

– Define systemic inflammatory response syndrome,

sepsis, severe sepsis, and septic shock

– List guideline recommended sepsis treatment goals

3

Epidemiology

• Sepsis is a leading cause of death in the U.S. and most

common among ICU patients

• The associated cost of treating septic patients is rising

with an estimated cost of $24 billion in 2013

• Sepsis mortality rates have been reported as high as 60%

• End organ damage is the strongest predictor of mortality

4Crit Care Med. 2013;41(2):580–637

Virulence. 2014 Jan 1; 5(1): 4–11

3/2/2016

2

Risk Factors for Development of Sepsis

• Age

– Elderly

– Neonatal

• Immunocompromised

– Solid organ transplant

– HIV

– Diabetes

• Predisposing comorbidities

– COPD

– Cancers

• Recent hospitalization

– Prior antimicrobial exposure

within past 30 days

– Prior hospitalization within

past 90 days

5Ann Epidemiol. 2016 Jan;26(1):66-70

Inflammatory Mediators

6

Pro-inflammatory Anti-inflammatory

• Interleukin-1,6,12

• TNFa

• Interleukin-4,10

• TGF-β

Host Response to Sepsis

N Engl J Med 2013; 369:840-851

Pathophysiology of Organ Failure

N Engl J Med 2013; 369:840-851

3/2/2016

3

Sepsis As A Continuum?

9

SIRS Sepsis Severe Sepsis Septic Shock

Hot Off The Presses!

10JAMA. 2016;315(8):801-810

Systemic Inflammatory Response

Syndrome (SIRS) Criteria

11Crit Care Med. 2013;41(2):580–637

Variable Description

Fever > 38 °C or <36°C

White blood cell count >12,000 or <4,000

Heart rate > 90 beats per minute

Tachypnea > 20 breaths/min

Thrombocytopenia <100,000

Hyperlactatemia >1 mmo/L

Creatinine Increase >0.5 mg/dL

Sepsis

+

Crit Care Med. 2013;41(2):580–637

http://www.gaspirtz.com/images/cartoons/bacteria.jpgJAMA. 2016;315(8):801-810

SIRS criteria

3/2/2016

4

“New” Sepsis Definition

“Sepsis is defined as life-threatening organ

dysfunction caused by a dysregulated host

response to infection”

13JAMA. 2016;315(8):801-810

Sequential Organ Failure Assessment

14JAMA. 2016;315(8):801-810

Severe Sepsis

Crit Care Med. 2013;41(2):580–637

Variable Description

Urine output < 0.5 mL/kg/hr for more than 2 hours

despite adequate fluid

Acute lung injury PaO2/FiO2 <250 in the absence of

pneumonia

Acute lung injury PaO2/FiO2 <200 in the presence of

pneumonia

Creatinine > 2.0 mg/dL

Bilirubin > 2 mg/dL

Platelet count < 100,000

INR > 1.5

“New” Severe Sepsis

“The task force emphasis on life-threatening

organ dysfunction is consistent with the view

that cellular defects underlie physiologic and

biochemical abnormalities within specific organ

systems. Under this terminology, “severe sepsis

"becomes superfluous.”

16JAMA. 2016;315(8):801-810

3/2/2016

5

Septic Shock

• Sepsis + hypotension refractory

to fluid resuscitation

• Complex disease state with

poorest prognosis

Crit Care Med. 2013;41(2):580–637

“New” Septic Shock

18JAMA. 2016;315(8):801-810

• “ Septic shock is a subset of sepsis in which

underlying circulatory and cellular/metabolic

abnormalities are profound enough to

substantially increase mortality”

• “….persisting hypotension requiring

vasopressors to maintain MAP=65 mmHg and

having a serum lactate level > 3 mg/dL despite

adequate volume resuscitation”

Definitions Summary

19

Old Classification New Classification

SIRS – nonspecific signs of inflammation SOFA – quantitative measure of organ

failure

Sepsis – SIRS + suspected infection Sepsis –organ dysfunction caused by

dysregulated host response to infection;

SOFA > 2

Severe sepsis – sepsis induced organ failure Severe sepsis – all sepsis is associated with

organ failure; therefore severe sepsis is

redundant

Septic shock – sepsis induced hypotension

refractory to fluids

Septic shock – subset of sepsis defined by

persistent hypotension requiring

vasopressors to maintain MAP = 65 mmHg

despite adequate fluid resuscitation

Current Recommended Surviving

Sepsis Campaign Treatment GoalsTo be completed in 3 hours:

• Measure lactate level

• Obtain blood cultures prior

to antibiotic administration

• Broad spectrum antibiotics

• Administer 30 mL/kg of

crystalloids for hypotension

or lactate > 4mmol/L

To be completed in 6 hours:

• Apply vasopressors for fluid

refractory hypotension

• Measure central venous pressure

(CVP), central venous oxygen

saturation (ScVO2)

• Re-measure lactate levels

20Crit Care Med. 2013;41(2):580–637

3/2/2016

6

The Rivers Trial

Rivers et. al (2001)

• Foundation of early goal

directed therapy (EGDT)

– EGDT group: received more

fluids, vasopressors, and

RBCs

• Mortality

– 28 day and 60 day mortality

– 30.5% vs. 46.5% in hospital

mortality (p=0.009)

N Engl J Med. 2001;345(19):1368-77.

Recent Challenges to the Rivers Trial

• The PROCESS Trial

• The ARISE Trial

• The PROMISE Trial

22N Engl J Med 2014;370:1683-93

N Engl J Med 2014; 371:1496-1506N Engl J Med 2015; 372:1301-131

The PROCESS Trial

• Randomized un-blinded controlled trial

• Objective: To determine effectiveness of EGDT

• Primary endpoint:60 day mortality

• N=1341 septic shock patients from 31 U.S. academic centers

• Three study groups: EGDT; protocolized standard therapy

(PST); “usual care”

23N Engl J Med 2014;370:1683-93

The PROCESS Trial Results

Group (n) 60 day mortality (%) Average ICU days 90 day mortality (%)

EGDT (439)

PST (446)

Usual Care (456)

92 (21.0)

81 (18.2) p=0.83

86 (18.9)

5.1 ± 6.3

5.1 ± 7.1 p=0.63

4.7 ± 5.8

129 (31.9)

128 (30.8) p=0.66

139 (33.7)

24N Engl J Med 2014;370:1683-93

3/2/2016

7

The ARISE Trial


• Objective: To determine effectiveness of EGDT

• Primary endpoint: 90 day mortality

• N=1591 septic shock patients from New Zealand and Australia

• Two study groups: EGDT; “usual care”

25N Engl J Med 2014; 371:1496-1506

The ARISE Trial Results

26N Engl J Med 2014; 371:1496-1506

The PROMISE Trial


• Objective: To determine the effectiveness of EGDT

• Primary endpoint: 90 day all cause mortality

• N=1251 septic shock patients from the U.K.

• Two study groups: EGDT; “usual care”

27N Engl J Med 2015; 372:1301-131

The PROMISE Trial Results

28N Engl J Med 2015; 372:1301-131

3/2/2016

8

EGDT Final Challenge

Meta-analysis; n=4735

• Angus et al

– Rivers Trial (2001)

– Jones Trial (2010)

– PROCESS (2014)

– ARISE (2014)

– PROMISE (2015)

Results

• Mortality

– No difference between

control group vs. EGDT

– p=0.90

• Organ support

– Vasopressor use increased in

EGDT group

– p<0.001

• ICU length of stay

– EGDT was associated with

higher ICU admission

– p<0.00129

Intensive Care Med . (2015) 41:1549–60

Surviving Sepsis Campaign (SSC)

Update

30

Albumin Use in Septic Shock

• Increases oncotic pressure and increased intravascular

volume

• Antioxidant and anti-inflammatory properties

• Acts as a buffer for acid-base equilibrium

• SSC recommends the use of albumin for severe sepsis

and septic shock patients who require large volumes of

crystalloids (grade 2C)

31Crit Care Med. 2013;41(2):580–637

N Engl J Med. 2014; 370(18):1683-93

ALBIOS Trial

n=1795

• Randomized controlled trial

• Objective: To establish

effectiveness of daily albumin

replacement in patients with

severe sepsis

• Randomized to receive either

crystalloids ± 20% albumin daily

• Primary outcome: 28 day

mortality

32http://www.fabulousnurse.com/wp-content/uploads/2012/05/Fun-With-Nursing-Cartoons-1024x760.jpg

N Engl J Med. 2014; 370(18):1683-93

3/2/2016

9

ALBIOS Results

Albumin Replacement Group

• No difference in 28 day mortality

between both groups (p=0.94)

• Higher liver and coagulation SOFA

sub-scores

• Shorter amount of time spent on

vasopressors (p=0.007)

Crystalloids Only Group

• No difference in time spent on

mechanical ventilation, RRT, or

reported acute kidney injuries

• No difference in ICU or hospital

length of stay

• Lower cardiovascular SOFA sub-

score

33

N Engl J Med. 2014; 370(18):1683-93

Mean Arterial Pressure (MAP) in Sepsis

• Observational studies have shown association between

MAP > 65 and good clinical outcomes

• Indirect sign of systemic perfusion

• Individualize to patients

• Initial 6 hour SSC bundle calls for maintaining MAP > 65

– Fluids

– Vasopressors

34Crit Care Med. 2013;41(2):580–637

SEPSISPAM Trial

• Multi-center open label randomized trial

• Objective: To determine if higher MAPs during septic

shock would lead to lower mortality

• N=776 septic shock patients

• Patients were stratified into two groups; MAP (80-85) or

MAP (65-70)

35N Engl J Med. 2014. Apr 24; 370(17):1583-93

SEPSISPAM Results

Outcome Lower Target; n (%) Higher Target; n (%) p Value

28 day mortality 132 (34.0) 142 (36.6) 0.57

90 day mortality 164 (42.3) 170 (43.8) 0.74

Avg. days of vasopressor therapy 3.7 ± 3.2 4.7 ± 3.7 0.0001

Organ support at day 28 241 (62.1) 235 (60.6) 0.66

Rate of new onset A-fib 11 (2.8) 26 (6.7) 0.02

36N Engl J Med. 2014. Apr 24; 370(17):1583-93

3/2/2016

10

TRISS Trial

SSC

• Recommendations are to

transfuse patients in septic shock

to maintain hematocrit > 30% in

first 6 hours of resuscitation

• Hemoglobin should be

maintained 7-9 g/dL in most

patients

• Data is limited to support these

recommendations

n=998 patients

• Multicenter randomized

parallel-group trial

• Stratified to receive

transfusion based off their

hemoglobin (<7 or <9)

• All transfusions consisted of

one unit of packed red blood

cells

37Crit Care Med. 2013;41(2):580–637

N Engl J Med. 2014. 371(15): 1381-91

TRISS Results

38N Engl J Med. 2014. 371(15): 1381-91

Biomarkers

39

Procalcitonin Role in Sepsis

• Production is increased during bacterial infections

• Mixed data on its utility in critically ill patients

• SSC suggests that low procalcitonin (PCT) can assist for the

discontinuation of antibiotics (Low level of evidence; 2C)

• No consensus on cut off values or initial PCT value as it relates

to sight and severity of sepsis

– Highly specific

– Low sensitivity

40Am J Respir Crit Care Med. 2014 Nov 15;190(10)

Crit Care Med. 2013;41(2):580–637

3/2/2016

11

Procalcitonin

Shehabi et al. (2014); n=394

• Blinded RCT

• PCT algorithm in critically ill

adults with suspected sepsis or

undifferentiated infection

• Primary outcome: Time to

antibiotic cessation, hospital

discharge or death

PCT Algorithm

1) Cease antibiotics if:

– Initial or any subsequent PCT

value is <0.10 ng/mL

– Initial or any subsequent PCT

value is 0.1-0.25 ng/mL where

infection is highly unlikely

– Subsequent PCT levels have

decreased 90% of baseline

2) Asses antibiotic appropriateness

and/or adequacy of source

control if PCT level at 48 hours

> 70% of baseline 41

Am J Respir Crit Care Med. 2014 Nov 15;190(10)

Study Results

42Am J Respir Crit Care Med. 2014 Nov 15;190(10)

Selenium

• Oxidative stress in the form of reactive oxygen species is

associated with multi-organ failure

• Selenium is an important precursor in the development of

free radical scavengers

• It causes positive immune modulation in vivo

• Serum selenium values are lower amongst septic patients

• SSC does not recommend the use of IV selenium (grade 2C)

43J Crit Care. 2014 Feb;29(1):150-6

Crit Care Med. 2013;41(2):580–637

Selenium Supplementation

Study Group Intervention Mortality Benefit LOS Benefit MV Benefit

Mishra et al

(2007)

Continuous infusion

of 474 μg x 3 days

No N/A N/A

Angstwurm

et al (2007)

1 mg bolus; then 1

mg continuous

infusion x 14 days

N/A Yes Yes

Valenta et al

(2011)

1 mg bolus; then 1.5

mg continuous

infusion x 14 days

N/A N/A Yes

Angstwurm

et al (1999)

535 μg x 3 days

285 μg x 3 days

155 μg x 3 days

No No No

44

Crit Care, 11 (2007), p. R73

Crit Care Med, 26 (1998), pp. 1536–1544Intensive Care Med, 27 (2001), pp. 91–100Intensive Care Med, 37 (2011), pp. 808–815J Crit Care. 2014 Feb;29(1):150-6

3/2/2016

12

Ascorbic Acid (AA)

• Proposed antioxidant and anti-

inflammatory effects on the

microvasculature

– Enhanced cell signaling in

vasculature cells

– Role in endogenous

catecholamine synthesis

• SSC has no statement on the use

of AA

45

Critical Care 2015, 19:418

Ascorbic Acid in the Literature

46

Study; n Design Intervention Outcomes

Nathens et al; 301 RCT AA 1 g PO TID Pulmonary morbidity ↓, new MOF ↓,

LOS venTlaTon ↓, LOS ICU ↓

Crimi et al; 105 RCT AA 500 mg q24h Ventilator-free days ↓,

28-day mortality ↓

Collier at al; 2,727 QE* IV or PO AA 1 g

TID

LOS ICU ↓, LOS hospital ↓, mortality ↓;

OR 0.32, 95 % CI 0.22 to 0.46

Berger et al; 102 RCT AA 2.7 g IV x 1

days

AA 1.6 g IV x 4

days

New organ failure ND, new infections ND,

LOS shorter in trauma, CRP ↓ in cardiac

surgery and trauma, recovery of health

aXer discharge ↑

Heyland et al; 307 RCT AA 1.5 g IV or

PO q24h

ND in 28-day mortality or length of stay

• QE; Quasi-experimental• Each study had additional minerals, vitamins added to regimen

• ND; no difference

Critical Care 2014, 18:460

Methylene Blue

• Improves vascular tone and perfusion to tissues

• Inhibits nitric oxide induced guanylate cyclase activation

preventing smooth muscle relaxation

• Limited data on dose and duration

• SSC has no statement on the use of methylene blue in

septic patients

47Pharmacotherapy 2010;30(7):702–715

Methylene Blue (MB) in the Literature

Design Population MB Regimens

Prospective randomized

open-label, placebo

controlled, single-center

study

20 patients diagnosed with

septic shock treated with

at least one vasopressor

and no corticosteroids

N= 10 MB

N= 10 control

2 mg/kg infusion x 15 mins;

0.25 mg/kg/hr x 2 hours;

0.5 mg/kg/hr x 1 hour;

1 mg/kg/hr x 1 hour

Prospective randomized

double blind, placebo-

controlled, single-center

study

30 patients diagnosed with

severe sepsis; patients

receiving corticosteroids or

inotropes were excluded

N= 15 MB

N= 15 control

0.5 mg/kg/hr infusion over

6 hours


3/2/2016

13

Methylene Blue Outcomes

• Increase in MAP

• Decreased vasopressor

requirements

• Increase in cardiac index


Sepsis Induced Immune Dysfunction

50J Clin Invest. 2016;126(1):23-31

IVIG

• Rationale for use is in toxic shock syndrome or

refractory septic shock

• Neutralization of endotoxin and modification of

cytokine release

• SSC does not suggest the routine use of IVIG in adult

patients with septic shock (grade 2B)

51Crit Care Med 2007; 35:2693–2701

Crit Care Med. 2013;41(2):580–637

SBITS Trial

• Randomized, double-blind placebo controlled, multi-center

trial

• N=624 septic shock patients

• The primary objective was to determine if the administration

of IVIG improved mortality among severe sepsis patients

• Patients were stratified to receive either:

– Placebo

– IVIG 0.6 g/kg on day 1; then 0.3 g/kg on day 2

52Crit Care Med 2007; 35:2693–2701

3/2/2016

14

SBITS Trial Results

Outcome IVIG, n=321 Placebo, n=303 P value

28 day mortality 126 (39.3%) 113 (37.3%) 0.6695

ICU LOS 26 days ± 38.9 22.9 ± 20.7 0.3946

Hospital LOS 55.4 ± 50.3 51.9 ± 38.6 0.4397

53Crit Care Med 2007; 35:2693–2701

Emerging Immune Modulating

Therapies in Sepsis

54J Clin Invest. 2016;126(1):23-31

Conclusion

• The way we have defined sepsis has changed

• All aspects of EGDT are not needed when resuscitating a

patient for septic shock

• Procalcitonin is a biomarker that still has mixed data

which should be used with caution

• There are emerging adjuvant therapies which may prove

beneficial for the treatment of septic shock

55

Assessment Question #1

• Procalcitonin is a sensitive biomarker to

identify someone who is septic

– True

– False

56

3/2/2016

15


• Selenium supplementation is appropriate to

decrease length of stay in patients

hospitalized for sepsis

– True

– False

57


• The use of a central venous catheter to

measure ScVO2 is needed for all patients

– True

– False

58

Advancements in SepsisAdvancements in SepsisAdvancements in SepsisAdvancements in Sepsis

Brian Gilbert, PharmDPGY-1 Pharmacy ResidentJackson Memorial Hospital

3/13/2016

www.fshp.org

Advancements in Sepsis

Documents

Transcript of Advancements in Sepsis