263-l01 surviving sepsis campaign guidelines · 2014-12-02 · •decreased stroke volume from low...

Surviving Sepsis Campaign Guidelines Updates

Objectives

• Evaluate recent literature on the management of sepsis

• Apply new and potentially controversial recommendations from the Surviving Sepsis Guidelines to patient cases.

Surviving Sepsis Campaign Guidelines: Update (Early Goal Directed Therapy and Fluids)

Simon Lam, PharmD

Cleveland Clinic

Outline

• Definitions, epidemiology, and pathophysiology

• Goals of therapy

• Protocolized, quantitative resuscitation

• Transfusion

• Fluid therapy choice

Definitions

• Sepsis

• Systemic inflammatory response secondary to infection

• Severe sepsis• Sepsis with organ dysfunction

• Septic shock

• Acute circulatory failure leading to ineffective tissue perfusion

• Hypotension unresponsive to fluid resuscitation

Levy MM. CCM 2003;31:1250‐6

Sepsis Incidence and Outcomes

• Hospital admissions for severe sepsis common and rising

• Over 750,000 cases per year

• Increased 13% per year from 2004 to 2009

• Annual US costs exceed $24 billion

• Eleventh most common cause of death in the US

• Mortality rate depends on severity of illness

• Range 15% (sepsis) to 70% (septic shock and multi‐organ failure)

Angus DC. CCM 2001;29:1303‐10Gaieski DF. CCM 2013;41:1167‐74

Martin GS. NEJM 2003;348:1546‐54

2014 Midyear Clinical Meeting Surviving Sepsis Campaign Guidelines Updates

© 2014 American Society of Health-System Pharmacists 1

Septic Shock Pathophysiology• Features of each shock type

• Decreased preload• Increased venous capacitance• Loss of intravascular contents

• Impaired cardiac output• Decreased stroke volume from low preload• Cytokine‐induced myocardial dysfunction

• Vasodilation• Inappropriate activation of vasodilatory mechanisms• Failure of vasoconstrictive pathways

• Maldistribution of blood flow to organs or in the microcirculation

Landry DW. NEJM 2001;345:588‐95Dellinger RP. CCM 2003;31:946‐55

• MN is a 65 year‐old female presented to the emergency department with hospital‐acquired pneumonia

• Labs and vitalsTemp 100.9°F (38.3°C)HR 105 beats/minRR 31 breaths/minBP 80/55 (mean 63 mm Hg)Lactate 5.5 mmol/L

• Intubated and placed on mechanical ventilation

Case

1981383.8

9915

401.8

18.825.5

8.5 115

Would you recommend placement of a central line and initiation of resuscitation protocol to

target CVP and ScvO2?

Yes

No

SSC Recommendations: Initial Resuscitation

• Protocolized, quantitative resuscitation of patients with sepsis‐induced tissue hypoperfusion

• Goals during the first six hours of resuscitation

• Central venous pressure (CVP) 8‐12 mm Hg

• Goal 12‐15 mm Hg in mechanically ventilated patients

• MAP ≥ 65 mm Hg

• Urine output (UOP) ≥ 0.5 mL/kg/hr

• Central venous oxygen saturation (ScvO2) ≥ 70% or mixed venous oxygen saturation (SvO2) ≥ 65%

Dellinger RP CCM 2013;41:580‐637

Surviving Sepsis Campaign (SSC) Guidelines

• Joint collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine

• Goal is to reduce mortality from sepsis by 25%

• Evidence‐based consensus guidelines for the management of severe sepsis and septic shock

• Third iteration of guidelines published in 2013

• Sponsored or endorsed by 30 international organizations

Dellinger RP CCM 2013;41:580‐637

Severe Sepsis Mortality Over Time

0

5

10

15

20

25

30

35

40

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

% M

ortality

No. of patients 2708 3783 4668 5221 6375 6987 7627 8529 8797 10277 11367 12213 12512

Kaukonen KM. JAMA 2014;311:1308‐16



Sepsis Progress in the Past 1.5 Decades

2000‐2002

Rivers – EGTDAnnane – SteroidsPROWESSLeuven 1ARMA

2004‐2006

SAFEKumar – Early ABXLeuven 2CATSSSC‐1

2008‐2010

CORTICUSSOAP IIVASSTSSC‐2NICE SUGARVISEP

PROWESS SHOCKMyburgh – VoluvenPerner‐ TetraspanSSC‐3 – Feb 2013

2010‐2013

PROCESSALBIOSARISETRISS

2014

Early Goal‐Directed Therapy (EGDT)Systolic BP ≤ 90 mm HgLactate ≥ 4 mmol/L

Arterial catheterCentral venous catheter

Despite fluids (20‐30 mL/kg)

Sepsis criteria

8‐12 mm Hg

≥ 65 mm Hg

≥ 70%

<65 mm Hg

<8 mm Hg

<70%

CrystalloidsColloids

Vasopressors

PRBC for Hct ≤30%

Dobutamine<70%

CVP

MAP

ScvO2

0

6 Hours

Rivers E. NEJM 2001;345:1368‐77

Study Interventions• Standard (S)

•Goals set (CVP, MAP, UOP)

• EGDT•Addition of ScvO2

to goals •Protocol‐driven method for achieving goals

46.5% 49.2%

56.9%

30.5%33.3%

44.3%

0%

20%

40%

60%

Hospital Mortality 28‐Day Mortality 60‐Day Mortality

Standard EGDT

EGDT Outcomes

p=0.009p=0.01

p=0.03n = 263

Rivers E NEJM 2001;345:1368‐77

Controversies with EGDT• Unclear intervention leading to study’s positive findings • Use of a goal‐directed protocol • Addition of ScvO2 monitoring

• Lactate clearance non‐inferior to ScvO2 as a goal

• Both?• High control arm mortality• Use of CVP as a resuscitation goal

• Fluid responsiveness better predicted by dynamic markers

Jones AE. JAMA 2010;303:739‐46Durairaj L, Schmidt GA. Chest 2008;133:252‐63

Huang DT. ICM 2013;39:1760‐75

PROCESS STUDY ‐ Hypothesis

• Is protocol‐based care superior to usual care

• Is EGDT with central hemodynamic monitoring better than protocol‐based therapy

Yealy DM. NEJM 2014;370:1683‐93

PROCESS – Inclusion Criteria

Site

• 31 centers

• 40,000 ED visits / year

• Use lactate as screening for cryptic shock

• No formalized sepsis resuscitation protocol

• No routine use of oximetric central venous catheter

Patient

• Similar to Rivers study

• ≥18 yo

• ≥ 2 SIRS criteria

• Hypotension

• SBP < 90 mmHg or requiring vasopressorafter fluid challenge (1 L)

• Enroll within 12h of arrival and 2h within shock

Yealy DM. NEJM 2014;370:1683‐93



PROCESS ‐ 3 Arms

Protocol‐based EGDT

• Oximetric CVC

• CVP: 8‐12 mmHg

•MAP > 65 mmHg

• ScvO2 >70%

Protocol‐based Standard

• 2 large bore IV

• Fluids• Vasopressors

• Transfusion goal (7.5 g/dl)

Usual Care

• All decisions based on resuscitationteam

Protocol Implemented by Dedicated Team

Early Detection and Fluid Administration

Yealy DM. NEJM 2014;370:1683‐93

PROCESS ‐ Differences in Therapy

EGDT(n=439)

Protocol(n=446)

Usual(n=456)

Pressor* 55% 52% 44%

Dobutamine* 8% 1% 1%

PRBC* 14% 8% 8%

0

1

2

3

4

5

6

EGDT Protocol Usual

IV Fluids –6 Hours (L)

Yealy DM. NEJM 2014;370:1683‐93

*p<0.05

PROCESS – Outcomes

21%

32%

18%

31%

19%

34%

0%

20%

40%

60%

Hospital Mortality 90‐Day Mortality

EGDT Protocol Usual

p=0.83

p=0.66

Yealy DM. NEJM 2014;370:1683‐93

PROCESS – Secondary Outcomes

EGDT Protocol Usual

Reaching MAP goal*

83 84 77

ICU Admission* 91% 85% 86%

AKI* 3% 6% 2.8%

*p<0.05

Yealy DM. NEJM 2014;370:1683‐93

PROCESS VS. RIVERS

Rivers PROCESS

Design Single‐Center Multi‐Center

No. of patients 263 1341

Year 2001 2014

APACHE II 21 21

ScvO2 49% 71%

PRBC / Dobutamine 64% / 14% 14% / 8%

Lactate (mmol/L) 7 5

Mortality ‐ usual care 46.5% 19%

Yealy DM. NEJM 2014;370:1683‐93Rivers E NEJM 2001;345:1368‐77

PROCESS Conclusions

• Early recognition, fluid, and antibiotics remain crucial

• No mortality difference observed when comparing protocolized resuscitation to usual care

• Progress of care may have discounted importance of strict hemodynamic monitoring and resuscitation goals



PROCESS

ARISE

PROMISE

ARISE

• Near identical protocol compared to PROCESS

• 2 arm study – EGDT and usual care

• Initiation of ABX mandated prior to randomization

• N=1600

Peake SL. NEJM 2014;371:1496‐506

ARISE Treatment / Outcomes

• More therapies used in EGDT group

• 2L vs. 1.7L

• Vasopressor: 76% vs. 66%

• PRBC: 14% vs. 7%

• Dobutamine: 15% vs. 3%

18.6% 18.8%

0%

5%

10%

15%

20%

EGDT Usual

90d mortality

Yealy DM. NEJM 2014;370:1683‐93

SSC – Response

• “Required monitoring…via CVC…does not confer survival benefit in all patients who have received timely antibiotics and fluid resuscitation

• “Results of PROCESS and ARISE trials have not demonstrated any adverse outcomes…Therefore, no harm exists in keeping current SSC guidelines intact…”

Possible SSC Clarifications

• Early recognition and antimicrobials remain cornerstones of therapy

• Resuscitation should be systematically targeted to clinician specified criteria for preload and evidence of hypoperfusion

• Blood pressure goals should be individualized to optimize perfusion

NQF – SEPSIS• Measure lactate level• Obtain blood cultures prior to antibiotics• Administer broad spectrum antibiotics• Administer 30 ml/kg crystalloids for hypotension of lactate > 4 mmol/L

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

• Patients with septic shock or initial lactate > 4 mmol/L measure CVP and ScvO2

• Remeasure lactate



Case, continued

• The medical team inserted a central venous catheter in the right internal jugular vein

• Pertinent data

• HR 115 beats/min in sinus rhythm

• MAP 59 mm Hg

• UOP 0.3 mL/kg/hr

• CVP 3 mm Hg

• A venous blood gas was sent from the catheter

• ScvO2 59%

• Lactate 6.3 mmol/L

Which of the following is the recommended initial fluid choice for a patient with severe sepsis

or septic shock?

Hydroxyethyl starch

5% albumin

Lactate Ringer’s solution

Normal saline

SSC Recommendations: Fluids

• Crystalloids as the initial fluid of choice for resuscitation

• Against the use of hydroxyethyl starches (HES)

• Albumin in fluid resuscitation when patients have required substantial amounts of crystalloids

• Initial fluid challenge of at least 30 mL/kg crystalloid

• Fluid challenge technique

Levy MM. CCM 2003;31:1250‐6

18%

7%

17%

6%

0%

10%

20%

90‐DayMortality

RenalReplacement

Therapy

HES

HES in ICU patients and Severe SepsisDiverse ICU population Severe Sepsis

Myburgh JA N Engl J Med 2012;367:1901‐11Perner A N Engl J Med 2012;367:124‐34

n=7000

51%

22%

43%

16%

0%

20%

40%

60%

90‐DayMortality

RenalReplacementTherapy

HES Control n=804

p=0.26

p=0.04

p=0.03

p=0.04°

Overall 726/3473 (20.9) 729/3460 (21.1) 0.99 (0.91‐1.09)

Severe sepsis

Yes 185/603 (30.7) 217/615 (35.3) 0.87 (0.74‐1.02)

No 518/2734 (18.9) 492/2720 (18.1) 1.05 (0.94‐1.17)

Albumin versus Saline for Fluid Resuscitation

• Significantly lower mortality favoring albumin on multivariate analysis of severe sepsis subgroup

0.5 1 2Favors albumin Favors saline

Albumin Saline RR (95% CI)

The SAFE Study Investigators. N Engl J Med 2004;350:2247‐56The SAFE Study Investigators. Intensive Care Med 2011;37:86‐96

28‐Day Mortality

Sepsis Fluid Resuscitation Meta‐Analysis

• Design

• Prospective randomized trials of albumin‐containing solutions

• Only included patients with sepsis

• Results

• Seventeen studies with 1977 participants

• Allocation to albumin associated with a reduction in mortality• Odds ratio 0.82 (95% confidence interval 0.67‐1.0, p = 0.047)

Delaney AP. CCM 2011;39:386‐91



ALBIOS: Study DesignPatients with severe sepsis / septic shock (6‐24hr)

Albumin Crystalloid

Crystalloids

Albumin:[300 ml at 20% in 3* hr]

+Crytalloids

Randomization

Placement of arterial line and CVC

Volume Replacement(Rivers Protocol)

Caironi P. NEJM 2014;370:1412‐21

ALBIOS ‐ Outcomes (n=1818)

Treatment / Vitals

• 7d net fluid: 347 ml vs. 1220 ml (p=0.004)

• Lower HR (p=0.02)

• Higher MAP (p=0.03)

• Time to hemodynamic stability: 3d vs. 4d (p=0.007)

Mortality

31.8%

41.1%

32.0%

43.6%

0%

10%

20%

30%

40%

50%

28d 90d

p=0.94

p=0.29

Caironi P. NEJM 2014;370:1412‐21

ALBIOS ‐ Subgroup

Overall 41.1% 43.6% 0.94 (0.85‐1.05)

Time

<6h 40.6% 40.6% 1.00 (0.82‐1.22)

6‐24h 413% 35.0% 0.92 (0.81—1.05)

Septic shock

Yes 37.0% 32.7 1.13 (0.92‐1.39)

No 518/2734 (18.9) 492/2720 (18.1) 0.87 (0.77‐0.99)

0.5 1 2Favors albumin Favors crystalloids

Albumin Crystalloid RR (95% CI)90‐Day Mortality

Caironi P. NEJM 2014;370:1412‐21

Evidence Grade: Albumin Method

• Level 1: All evidence that supports what I already believe

• Level 3: All evidence that refutes what I already believe

Should Chloride be Avoided?

RIFLE ClassChloride‐Liberal(n = 760)

Chloride‐Restrictive(n = 773)

p

Risk 71 (9.0) 57 (7.4) 0.16

Injury 48 (6.3) 23 (3.0) 0.002

Failure 57 (7.5) 42 (5.4) 0.10

Injury and Failure 105 (13.8) 65 (8.4) <0.001

Data presented as n (%). Classification per the serum creatinine criteria of Risk, Injury, Failure, Loss, and End‐Stage (RIFLE).

Yunos NM. JAMA 2012;308:1566‐72

No difference in mortality: 15% vs 13%, p=0.44

IV Crystalloids and Mortality

OutcomeBalancedfluid

(n=3365)

No Balancedfluid

(n=3365)p

Hospital Mortality 19.6% 22.8% 0.001

ARF with dialysis 4.5% 4.7% NS

Hospital LOS (d) 11.3 11.3 NS

Raghunathan K. CCM 2014;42:1585‐91



IV Crystalloids and Mortality

0

5

10

15

20

25

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Hospital M

ortality (%

)

Percent of Total Fluid That is Balanced by Day 2

Raghunathan K. CCM 2014;42:1585‐91

Possible SSC Clarifications

• Consider balanced fluids

• Patients with increased risk for renal dysfunction

• Large volume of saline have been given

• Electrolyte and acid/base abnormalities from saline administration

• Insufficient data to routinely recommend albumin supplementation post initial resuscitation

Case, continued

• The patient was given a total of 4 liters of Ringer’s Lactate over 3 hours

• Updated patient data

• MAP 65 mm Hg

• UOP 0.4 mL/kg/hr

• CVP 12 mm Hg

• Lactate 5.9 mmol/L

• ScvO2 52%

• Hgb=7.7 g/dl

Would you recommend giving PRBC to optimize oxygen delivery?

Yes

No

SSC Recommendations: Transfusion

• During first 6 hours of resuscitation if central venous oxygenation is below goal despite volume repletion, transfusions to achieve HCT ≥30% is a treatment option

• Once tissue hypoperfusion has resolved, PRBC transfusion when Hgb < 7.0 g/dL is recommended

Levy MM. CCM 2003;31:1250‐6

TRISS Study

OutcomeLower Hgb(n=502)

Higher Hgb(n=496)

p

# of PRBC 1545 3088 <0.001

Median PRBC / pt.1 (0‐3) 4 (2‐7)

<0.001

90d mortality 43% 45% 0.44

Ischemic events 7.2% 8.0% 0.64

Vasopressor use NS

Ventilator use NS

RRT use NS

Holst LB. NEJM 2014;371:1381‐91



SSC Recommendations: Transfusion

• For most critically ill patients a transfusion target when Hgb <7.0 g/dL seems reasonable

Key Takeaways• EGDT

• In the setting of early recognition and early fluids and antimicrobial administration, clinician driven resuscitation goals most likely sufficient

• Fluids

• Preliminary data suggest no additional harm and possible benefit with balanced crystalloids infusion

• Routine replacement of albumin not recommended

• PRBC

• Target of Hgb >7.0 g/dL most likely sufficient for most critically ill patients

Surviving Sepsis Campaign Guidelines: Update (Early Goal Directed Therapy and Fluids)

Simon Lam, PharmD

Cleveland Clinic

Adjunctive Therapies in the Management of Septic Shock

Jeremy DeGrado, PharmD BCPSClinical Pharmacy Specialist – Critical Care

Brigham and Women’s Hospital – Boston, MA

Outline

• Antimicrobial therapy

• Hemodynamic support

• Vasoactive agents

• Corticosteroids

• Glycemic control

The team wishes to initiate antimicrobial therapy for MN as soon as possible. Which regimen would you

recommend?

Ceftazidime + Vancomycin

Cefepime + Levofloxacin + Vancomycin

Ceftriaxone + Levofloxacin

Gentamicin + Ceftazidime + Vancomycin



Antimicrobials/Source Control

• Appropriate cultures prior to antimicrobials

• Does not delay initiation > 45 minutes

• Effective IV antimicrobials within first hour

• Patient‐specific factors

• Medication‐specific factors

• Double coverage when appropriate

• De‐escalation when appropriate

• Source control

Dellinger RP, et al. Crit Care Med 2013;41(2):580‐637

Time from EGDT Qualification to Appropriate Antibiotics

Gaeiski DF, et al. Crit Care Med 2010;38(3)

Mortality 25% 37% 35% 42% 50% 67%

0‐1hr 1‐2hrs 2‐3hrs 3‐4hrs 4‐5hrs 5‐6hrs

Freq

uen

cy

160

140

120

100

80

60

40

20

0

Alive

Dead

Patient Case (continued)

• Initiated on norepinephrine at 5 mcg/min, titrated quickly up to 12 mcg/min

• MAP = 57 mm Hg

• CVP = 12

• ScVO2 = 72%

• Urine output = 20 to 30 mL/hr

• Lactate = 5.3

• ICU team is looking to initiate a second vasoactive agent due to low MAPs

What is your recommendation for a second vasoactive agent

and MAP goal?

Phenylephrine for MAP > 65 mm Hg

Epinephrine for MAP > 85 mm Hg

Vasopressin for MAP > 65 mm Hg

Dobutamine for MAP > 85 mm Hg

Vasoactive Agents2008 SCCM

Recommendations

• NE or DA as 1st line agent

• EPI first alternative

• EPI, PE, VP not recommended as initial vasopressors

• VP as adjunctive therapy for effect equivalent to NE monotherapy…

2012 SCCM Recommendations

NE 1st line agent

EPI first alternative/substitution

VP as adjunctive therapy to increase MAP & decrease NE

VP not recommended as initial vasopressor

DA and PE only in selected patient populations

Dellinger RP, et al. Crit Care Med 2013;41(2):580‐637Dellinger RP, et al. Crit Care Med 2008;36(1):296‐327

Goals of Cardiovascular Resuscitation

Asfar P, et al. NEJM 2014; 370:1583‐93 (adapted)

100

75

50

25

00 28 60 90

Day

Cumulative Survival (%) Low‐target group

High‐target group

No. at riskLow target 379 256 233 225High target 375 249 227 219



Initiation of Vasopressors600

500

400

300

200

100

010 2 3 4 5 6

Initiation Time of Vasoactive Agents (hrs after onset of hypotension

Difference in

0‐6 hour total

equivalent volume (m

L)

Overall p<0.0001

Complications of Catecholamine Therapy

• Tachycardia/ tachyarrhythmias

• Reflex bradycardia (phenylephrine)

• myocardial oxygen supply

• myocardial oxygen consumption

• CO/CI

• Limb ischemia

• splanchnic blood flow

• lactate

• Dopamine

• Prolactin suppression

• glucose

• TSH

• risk of ARF

Hollenberg SM, et al. Crit Care Med 2004;32:1928‐48

Phenylephrine• Efficacy?

• Morelli, et al. 2008 (n = 32 pts w/septic shock)

• Randomized, double‐blind controlled trial• ↑ MAP with NE vs. PE• No difference in % pts achieving goal MAP, CO, SVR

• Safety?• Morelli, et al. 2008 (n = 15 pts w/septic shock)

• Open‐labeled crossover study• ↓ HR with PE vs. NE• ↓ splanchnic perfusion, ↓ creatinine clearance, ↑ arterial lactate

Morelli A, et al. Crit Care 2008;12:R143Morelli A, et al. Shock 2008;29:446‐451

Annane 2007 – NE + DOB vs. EPI

10 20 30 40 50 60 70 80 90

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Probab

ility

Days

NE + DOB

EPI

RR 0.81; p=0.3

RR 0.75; p=0.08

RR 0.86; p=0.31

Annane D, et al. Lancet 2007;370:676‐684 (adapted)

EPI vs. NE – CAT Study

Variable EPI NE p value

Time to MAP goal, median 35.1 40 0.26

Vasopressor‐free days 26 25.4 0.31

28 day mortality, no (%) 31 (22.5) 36 (26.1) 0.48

Study drug discontinued, no (%) 18 (12.9) 4 (2.8) 0.002

Myburgh JA, et al. Intensive Care Med 2008;34:2226‐2234 (adapted)

* **

Baseline 4h 8h 12h 16h

Heart rate (bpm)

* p < 0.01* p < 0.01

* **

*

Lactate (mmol/L)

Baseline 4h 8h 12h 16h

EPI

NE

50

100

150

0

5

10

53%

24%

7%

49%

12%4%0%

20%

40%

60%

28-Day Mortality Arrhythmias Skin ischemia

DA NE

NE vs. DA in Shock Study Outcomes

p<0.001

n = 1679

p<0.001

p=0.10

De Backer D, et al. N Engl J Med 2010;362:779‐89



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

StudyDAn/N

NEn/N

28‐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)

NE vs. DA in Septic Shock Meta‐Analysis

De Backer D, et al. Crit Care Med 2012;40:725‐30

0 1 2 3Overall effect p = 0.035Heterogeneity p = 0.77, I2 = 0%

Favors DA Favors NE

Vasopressin Activity

Receptor Level Location Effect

V1(V1a)

10-200 pmol/L Vascular smooth muscle

Vasoconstriction

V2 < 10 pmol/L Renal collecting ducts

Fluid retention

V3(V1b)

? Anterior pituitary ACTH release

Landry DW et al. N Engl J Med 2001;345:588‐595Hollenberg SM. Chest 2007;132:1678‐1687Szumita PM et al. Am J Health‐Sys Pharmacy 2005; 62:1931‐6Holmes CL et al. Crit Care 2003;7:427‐434

VASST – Vasopressin Levels

Russell JA et al. N Engl J Med. 2008;358:877‐87

Time Norepinephrinegroup (pmol/L)

Vasopressin group (pcmol/L)

Baseline 3.2 3.2

6 hour “no change” 73.6

24 hour “no change” 98.0

VASST – NE requirements

0 1 2 3 4

5

10

15

20

25

Rate of NE (m

cg/m

in) Med

ian + IQR

Time from study drug (days)

Vasopressin

Norepinephrine

Russell JA et al. N Engl J Med. 2008;358:877‐87 (adapted)

VASST – MortalityAll Patients NE group (%) VP group (%) p value

28-day mortality 39.3 35.4 0.26

90-day mortality 49.6 43.9 0.11

Less Severe Shock

NE group (%) VP group (%) p value

28-day mortality 35.7 26.5 0.05

90-day mortality 46.1 35.8 0.04

Russell JA et al. N Engl J Med. 2008;358:877‐87

VASST – Timing is Everything!

• Restoration of organ perfusion

• Antimicrobial therapy & source control

• Vasopressin administration

Time to VP initiation

NE Mortality VP Mortality

< 12 hours 40.5% 33.2%

> 12 hours 37.5% 37.7%

Russell JA. Crit Care 2011;15:226‐245



VASST – Renal Function Using RIFLE Criteria

p=0.03 p=0.02p=0.01

Percent

Gordon AC, et al. Intensive Care Med 2010;36:83‐91 Russell JA. NEJM 2014

Trial MAP (mm Hg) NE rate (mcg/kg/min)

Fluid Balance (mL) RRT (%) Death 28d (%)

Day 0 Day 1 Day 0 Day 1 Day 0 Day 0‐4

Asfar

Low‐target

High‐Target

74 74 0.35 0.45 1,603 ,2800 35.8 34

74 84 0.4 0.58 1,595 2,400 33.5 36

Annane 70 80 0.94 1.09 1,586 ‐2,767 24.8 34

Debacker 58 76 0.54 0.82 2,100 8,300 17 48

Myburgh 70 73 0.26 0.17 2,232 5,712 22.1 26

Rivers 76 81 NA NA 3,500 10,602 NA 49

Russell 72 73 0.28 0.2 1,500 11,000 43.6 39

Case (continued)

• MN is initiated on vasopressin at 0.04 units/min in addition to norepinephrine 12 mcg/min for goal MAP > 65 and UO > 40 mL/hr• MAP = 62

• HR = 95

• CVP = 13

• ScVO2 = 75

• UO ~ 25 mL/hr

• Lactate = 4.9

With MAP and UO goals not achieved on 2 vasoactive agents, the topic of low‐dose corticosteroids is raised. What is your recommendation?

Wait 12‐24 hours to see if achieve hemodynamic stability

Administer hydrocortisone 200 mg/day ASAP for hemodynamic support and mortality benefit

Administer the high‐dose ACTH‐stimulation test to determine cortisol response (> 9 mg/dL)

Avoid corticosteroids due to immunosuppression

Corticosteroids in Septic Shock


IV hydrocortisone only in pts w/o BP response to fluid and vasopressor therapy

No ACTH stim test

No dexamethasone

+/‐ fludrocoritsone

Wean steroids if off pressors

No shock = No steroids

Steroids < 300 mg/d hydrocort


IV hydrocortisone if no BP response to fluid and vasopressor therapy

No ACTH stim test

Wean steroids if off pressors

No shock = No steroids

Hydrocortisone 200 mg/day

Hydrocortisone continuous infusions

PROGRESS Registry

Beale R, et al. Crit Care 2010;14:R102

Percent



• Steroid responsiveness (37%)• Baseline cortisol – 14.1 mcg/dL vs. 33.3 mcg/dL (p<0.0001)

• 95% pts had cortisol < 25 mcg/dL

Test Steroid Responsive (Sensitivity)

Steroid Unresponsive (Specificity)

Random Cortisol 96% 57%

LD test 54% 97%

HD test 22% 100%

Marik PE, et al. Crit Care Med 2003;31:141‐145

Diagnosis of RAI in Septic Shock Days to Shock Reversal with LD CS

Annane 2002 CORTICUS 2008

Placebo LD CS p value Placebo LD CS p value

Non‐responders

10 7 0.001 6.0 3.9 0.06

Responders 7 9 0.49 5.8 2.8 < 0.001

All patients 9 7 0.01 5.8 3.3 < 0.001

Annane D, et al. JAMA 2002;288:862‐871

Sprung CL, et al. N Engl J Med 2008;358:111‐124

Annane 2002 – Mortality

p=0.09p=0.04 p=0.96

Annane D, et al. JAMA 2002;288:862‐871

Percent

CORTICUS 2008 – Mortality

Sprung CL, et al. N Engl J Med 2008;358:111‐124

p=0.69p=1.0

p=0.51

Percent

Heterogeneity of LD CS RCTsAnnane 2002

• SAPS II ~ 60

• Placebo mortality 61%

• Enrolled w/in 8hr

• CS w/in 4hr pressorinitiation

• MAP 55 mmHg

• Hydrocort + fludrocort x 7d

• 60% medical patients

• 77% non‐responders

• Appropriate antibiotics

• > 90% patients

• Time to AA ~ 6 hours

CORTICUS 2008

• SAPS II 48

• Placebo mortality 32%

• Enrolled w/in 72hr

• CS w/in ?? pressorinitiation

• SBP 94 mm Hg

• Hydrocort x 11d (taper)

• 35% medical patients

• 46.7% non‐responders

• Appropriate antibiotics

• ??

• ??

Annane D, et al. JAMA 2002;288:862‐871 Sprung CL, et al. N Engl J Med 2008;358:111‐124

Early Administration of LDCS in Septic Shock

Katsenos CS, et al. Crit Care Med 2014; 42:1651‐1657 (adapted)

100

80

60

20

40

0

200 40 60

Days of vasopressors

Cumulative percent patients off vasopressors

Early LDCS

Late LDCS

p < 0.0001

20

40

60

80

100

0

0 4 8 12 16 282420

Survival (days)

% survival

p = 0.018

Late LDCS

Early LDCS



Vasopressin and LDCS

Percentage

of Clinicians

Patients in Septic Shock

Hsu JL, et al. Crit Care 2012;16:447‐449

VASST – Vasopressin + Low‐Dose Corticosteroids

VASST (n=779)

Steroids (n=589)

No steroids (n=190)

VP (n=296) NE (n=293) VP (n=101) NE (n=89)

Russell JA et al. Crit Care Med 2009;37:811‐818

VASST – VP + LDCS – VP levels

Russell JA et al. Crit Care Med 2009;37:811‐818 (adapted)

Vasopressin levels (pmol/L, m

edian + IQ

R)

20

40

60

80

100

120

140

Baseline 6 hours 24 hours

Corticosteroids

No corticosteroids

VASST – VP + LDCS – Survival

Patients who received steroids (n=589)

NE group (%) VP group (%) p value

28-day mortality 44.7 35.9 0.03

90-day mortality 55.5 45.2 0.01

Days alive w/o OD (survivors)

1 4 0.08

Russell JA et al. Crit Care Med 2009;37:811‐818

VP + LDCS Synergy?

• Time from pressor initiation to first CS dose = 22.2 hours

• Median time to withdrawal of vasopressor support (p = 0.09)

• CS = 65 hours

• No CS = 20 hours

• Patients alive w/o vasopressors at day 7 (p = 0.02)

• CS = 80.9%

• No CS = 47.6%

• CS independently associated with survival w/o vasopressors at day 7

Bauer SR, et al. J Crit Care 2008;23:500‐506Torgersen C, et al. Intensive Care Med 2011 (adapted)

0 5 10 15 20 25 30

Days

Probab

ility of Cumulative Survival

0.2

0.4

0.6

0.8

1.0

VP + LD CS

VP

p=0.001

Bauer, et al Torgersen, et alVP + LDCS Pilot

Gordon AC, et al. Crit Care Med 2014; 42:1325‐1333 (adapted)

Number of days of VP in

fusion

Vasopressin received (hundred units)

25

15

10

5

0

20

12

10

8

6

4

2

0

Hydrocortisone Placebo Hydrocortisone Placebo



Hydrocortisone Bolus vs. InfusionContinuous HC (200mg/d)

Bolus HC (50 mg)

p = 0.47 p < 0.01 p = 0.2

50 mg HC

Blood glucose (mg/dL)

100

200

300

0 6‐12 ‐183

Hours

Weber‐Carstens S, et al. Intensive Care Med 2007;33:730‐733 (adapted)

Case (continued)

• MN is started on IV hydrocortisone 100 mg every 8 hours in addition to NE and VP infusions

• Blood glucose levels

• 198 mg/dL (pre‐LD CS)

• 235 mg/dL

• 310 mg/dL

• 228 mg/dL

Would you advocate for tight glycemic control using an intensive intravenous insulin protocol?

Yes

No

Glycemic Control

• Protocolized approach

• Goal glucose < 150 mg/dL

• Monitor every 1‐2 hours

• All patients receive glucose

• Caution with POCT values

• Protocolized approach

• 2 glucose levels > 180 mg/dL

• Upper limit ≤ 180 mg/dL

• Monitor every 1‐2 hours

• Caution with POCT values

2008 SCCM Recommendations 2012 SCCM Recommendations

Intensive Insulin TherapySelect RCTs of glucose control in the ICU

Leuven I Leuven II VISEP Glucontrol NICE Sugar

Population SICU MICU Sepsis Mixed ICU

Mixed Mixed

Centers Single Single 18 19 42Samp size 1548 1200 488/537 1011 ~6030Excluded 14 863 1,612 ? 34,067Stopped early No No Yes Yes NoPrimary Diet TPN 85% TPN 85% 60% TPN 27% TPN 25% TPNAPACHE II ~9 ~23 ~20 ~15 ~21Mortality ICU: ~ 7%

Hos: ~10%ICU: ~25%Hos: ~40%

28 D: ~27% ICU: ~16%Hos: ~22%

28 D: ~21%

Protocol Leuven Leuven Leuven Variable ? NICETarget 80-110 80-110 80-110 80-110 81-108Control < 180 < 180 < 180 140-180 144-180

Glycemic Variability

70‐99 100‐119 120‐139 140‐179 180+

5

10

15

20

25

30

35

40

0

Q1

Q2Q3Q4

Hospital M

ortality (%

)

Mean glucose levels during ICU stay (mg/dL)

p<0.0001 p<0.0001p=0.0001

p=0.01

Krinsley JS. Crit Care Med 2008;36:3008‐3013 (adapted)



Diabetes vs. No Diabetes

Lanspa MJ, et al. Chest 2013;143:1226‐1234 (adapted)

0 2 4 6 8 10 12 242220181614 26 28 30

0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

Mortality Probab

ility

Days Post ICU Admission

90‐140 mg/dL

80‐110 mg/dL

Non‐DiabeticsIntensive Insulin Therapy

What We Know

• Variability with POCT devices

• Hyperglycemia is associated with poor outcomes

• Hypoglycemia is associated with poor outcomes

• Intensive insulin therapy should be driven by protocols/guidelines to optimize efficacy and safety

What We Would Like to Know

• Validated guidelines/protocols to ensure safety

• Optimal target range

• DM vs. Non‐DM

• Optimal glucose metrics

• Effect of glycemic variability

Other Adjunctive Therapy Concerns in Septic Shock Management• Inotropic therapy• Beta‐blockade• Immunoglobulins• Mechanical ventilation• PAD/NMB management• Renal replacement therapy• Sodium bicarbonate• VTE prophylaxis• Stress ulcer prophylaxis• Nutrition• Selenium

Key Takeaways• Antimicrobial therapy

• Must be appropriate and early

• Vasoactive agent(s)

• Resuscitation must be perfusion‐directed

• Norepinephrine preferred in majority of shock pts

• Low‐dose corticosteroids

• Patients with refractory shock who receive LDCS early are most likely to benefit

• Synergistic effect when administered with vasopressin

• Intensive intravenous insulin

• Patient‐specific goals depending on h/o diabetes

• Must be done safely

Adjunctive Therapies in the Management of Septic Shock

Jeremy DeGrado, PharmD BCPSClinical Pharmacy Specialist – Critical Care

Brigham and Women’s Hospital – Boston, MA

Questions?



References• Annane D, et al. Lancet 2007;370:676‐684

• Annane D, et al. JAMA 2002;288:862‐871

• Bangash MN, et al. Brit J Pharmacol 2012;165:2015‐2033

• Bauer SR, et al. J Crit Care 2008;23:500‐506

• Beale R, et al. Crit Care 2010;14:R102

• Contrael KM, et al. Crit Care Med 2013:41

• Dellinger RP, et al. Crit Care Med 2013;41(2):580‐637

• Dellinger RP, et al. Crit Care Med 2008;36(1):296‐327

• Gordon AC, et al. Intensive Care Med 2010;36:83‐91

• Hollenberg SM, et al. Crit Care Med 2004;32:1928‐48

• Hollenberg SM. Chest 2007;132:1678‐1687

• Holmes CL et al. Crit Care 2003;7:427‐434

• Hsu JL, et al. Crit Care 2012;16:447‐449

• Jiwaji Z, et al. Emerg Med J 2013

• Katsenos CS, et al. Crit Care Med 2014; 42:1651‐1657

• Krinsley JS. Crit Care Med 2008;36:3008‐3013

References• Landry DW et al. N Engl J Med 2001;345:588‐595

• Lanspa MJ, et al. Chest 2013;143:1226‐1234

• LeDoux D, et al. Crit Care Med 2000;28:2729‐2732

• Marik PE, et al. Crit Care Med 2003;31:141‐145

• Morelli A, et al. Crit Care 2008;12:R143

• Morelli A, et al. Shock 2008;29:446‐451

• Myburgh JA, et al. Intensive Care Med 2008;34:2226‐2234

• Russell JA et al. N Engl J Med. 2008;358:877‐87

• Russell JA et al. Crit Care Med 2009;37:811‐818

• Russell JA. Crit Care 2011;15:226‐245

• Sprung CL, et al. N Engl J Med 2008;358:111‐124

• Szumita PM et al. Am J Health‐Sys Pharmacy 2005; 62:1931‐6

• Szumita PM et al. Am J Health Syst Pharm 2006;63;466‐471

• Torgersen C, et al. Intensive Care Med 2011

• Weber‐Carstens S, et al. Intensive Care Med 2007;33:730‐733



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