Oh How Pendulums Swing! Revisiting Severe Sepsis and Septic Shock Chris Droege, PharmD Clinical...

Oh How Pendulums Swing! Revisiting Severe Sepsis

and Septic ShockChris Droege, PharmD

Clinical Pharmacy Specialist, Critical CareUC Health – University of Cincinnati Medical Center

NYSHP Critical Care SymposiumSeptember 19, 2015

Authors of this presentation have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

Disclosures

• The author of this presentation has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter

Objectives

• Describe differences between sepsis, severe sepsis, and septic shock

• Outline the rationale for use of intravenous fluids, catecholamines and vasopressin for the hemodynamic reversal of septic shock

• Design appropriate antimicrobial treatment strategies

• Develop a treatment pathway for that incorporates the 2012 Surviving Sepsis Campaign guideline recommendations and care bundle

Assessing the Burden

• International audit of worldwide ICU patients• 10069 patients from 730 participating centers in

84 countries for up to 28 days of data

• Pharmacist available 24/7?

Hospital Mortality ICU Mortality

Whole Population 24.2 (21.6 – 23.2) 16.2 (15.5 – 16.9)

Sepsis Population 35.3 (33.5 – 37.1) 25.8 (24.2 – 27.4)

Data represented as % (95% confidence interval)

276 (37.8%)

Vincent JL, et al. Lancet Respir Med 2014;2:380-6.

Incidence of Sepsis

Martin GS, et al. N Engl J Med 2003 Apr 17;348(16):1546-54.

Popu

latio

n-Ad

just

ed In

cide

nce

of S

epsi

s (#

/100

,000

)

Systemic Inflammatory Response Syndrome

• Defined as a response to a physiologic insult manifested by two of the following four criteria:1) Temperature > 38°C (101.4°F) or < 36°C (96.8°F)

2) HR > 90 beats/min

3) RR > 20 breaths/min or PaCO2 < 32 mmHg

4) WBC > 12,000 cells/mm3, < 4,000 cells/mm3, or a bandemia > 10%

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

Definitions• Sepsis

• SIRS with an infection present or suspected

• Severe sepsis• Sepsis associated with organ dysfunction or

hypoperfusion

• Septic shock• Severe sepsis along with hypotension refractory to fluid

resuscitation• Acute circulatory failure leading to ineffective tissue

perfusion


Challenge of Definitions

• Difficulty between individuals with specific disorder versus epidemiological purpose• Individual: easy to apply; direct therapeutic and

prognostic implications• Epidemiologic: robust, rigorous; used in clinical trials

• Definitions deemed imprecise and inadequate• Call for further update and revision of criteria• Step away from non-infectious inflammatory disorders

Vincent JL, et al. Lancet 2013; 381:774-5.

Cohen J, et al. Lancet Infect Dis 2015;15:581-614.

Severe Sepsis Mortality – 10 Years

Kaukonen KM, et al. JAMA 2014 Apr 2;311(13):1308-16.

Mor

talit

y (%

)

Sepsis Shock Pathophysiology• Features of each shock type

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

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

• Impaired cardiac output• Stroke volume decreased• Myocardial dysfunction secondary to cytokines

Landry DW, Oliver JA. N Engl J Med 2001;345:588-95.

Inflammatory Response

TOTAL

VOLUME

Proinflammatory

Cytokines

TOTAL

VOLUME

SHOCK

Tone

(SVR)

Septic Shock: Therapeutic Goals

• Restore effective tissue perfusion• Therapy selection dependent on source of

dysfunction

• Fluids increase preload

• Vasopressors increase vascular tone

• Inotropes increase cardiac output

Hollenberg SM. Am J Respir Crit Care Med 2011;183:847-55.

Sepsis Research: Success? Frustration?

• 1975 – 1985: 6,500 papers published• 1996 – 2006: 20,000 papers published• No novel drug has passed the “test of time”

• Hundreds of clinical trials involving tens of thousands of patients and costing hundreds of millions of dollars

• Acknowledgement should not undervalue observed management improvements


Initial Resuscitation Goals• Begin resuscitation immediately in patients with

hypotension or elevated serum lactate >4 mmol/L

• Resuscitation goals (within six hours): CVP 8–12 mm Hg (12-15 if mechanically ventilated) Mean arterial pressure ≥65 mmHg Urine output ≥0.5 mL/kg/hr ScVO2 ≥70%, or mixed venous ≥65%

• Target resuscitation to normalize lactate levels as a marker of tissue hypoperfusion


Fluid Therapy• Crystalloids initial fluids of choice• No hydroxyethyl starch (HES) use • Albumin use when patients require substantial

amounts of crystalloids• Initial fluid challenge of 30 mL/kg of crystalloids • Fluid challenge technique be applied wherein fluid

administration is continued as long as there is hemodynamic improvement


Fluid Challenge Approach

• Attempt to evaluate type, volume, and rate of fluid given in challenge

• Determine triggers to compare further fluid administration based on original response

• Observational study of 2213 ICU patients• Median amount: 500 mL• Median time and rate: 24 minutes; 1000 mL/h

Cecconi M, et al. Intensive Care Med 2015;41:1529-37.

Fluid Challenge CharacteristicsType of Fluid n % of Category % All Fluids

Crystalloids 1713 74.3

NaCl 0.9% 786 45.9 34.1

Balanced 916 53.5 39.8

D5W 4 0.2 0.2

D5 NaCl 0.45% 7 0.4 0.3

Colloids 591 25.6

HES 249 42.1 10.8

Albumin 4-5% 101 17.1 4.3

Gelatin 203 34.3 8.8

Dextran 13 2.2 0.5

Albumin 20% 25 4.2 1.1NaCl, saline; balanced crystalloids with chloride concentration lower than saline; D5W, dextrose 5% in water; HES, hydroxylethyl starch


Indications for Fluid ChallengeIndication n (%)

Hypotension 1211 (58.7)

Weaning vasopressor 146 (7.1)

Cardiac output 62 (3.0)

Oliguria 372 (18.0)

Skin mottling 36 (1.7)

Lactate 128 (6.2)

SvO2/ScvO2 10 (0.5)

SVV/PPV 37 (1.8)

CVP/PAOP 60 (2.9)SvO2, mixed venous saturation; ScvO2, central venous oxygen saturation; SVV, stroke volume variation; PPV, pulse pressure variation; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure


Road to the “Right” Fluid

• Saline versus Albumin Fluid Evaluation study• ICU patients randomly assigned to 4% albumin

or normal saline for resuscitation• Primary outcome: death from any cause during

28-day period after randomization• 6997 patients enrolled

Finfer S, et al. N Engl J Med 2004;350:2247-56.

Patients Albumin Saline Relative Risk (95%CI)

No. of deaths/total no.

Overall 726/3473 729/3460 0.99 (0.91 – 1.09)

Trauma

Yes 81/596 59/590 1.36 (0.99 – 1.86)

No 641/2831 666/2830 0.96 (0.88 – 1.06)

Severe sepsis

Yes 185/603 217/615 0.87 (0.74 – 1.02)

No 518/2734 492/2720 1.05 (0.94 – 1.17)

ARDS

Yes 24/61 28/66 0.93 (0.61 – 1.41)

No 697/3365 697/3354 1.00 (0.91 -1.09)

Locking the SAFE?

Finfer S, et al. N Engl J Med 2004;350:2247-56.

0.5 1.0 2.0Albumin better

Salinebetter

More-Concentrated Albumin

• Albumin Italian Outcome Sepsis study• ICU patients randomly assigned to 20% albumin

and crystalloid or crystalloid alone• Target serum albumin concentration: 3 g/dL or more

• Primary outcome: death from any cause during 28-day period after randomization

• 1818 patients enrolled

Caironi P, et al. N Engl J Med 2014;370:1412-21.

Breaking Down ALBIOS

• First seven days, albumin vs. crystalloid:• Higher MAP (p=0.03); lower HR (p=0.02)• Lower net fluid balance (p<0.001)• Time to hemodynamic instability, 3 v 4d; p=0.007


0

10

20

30

40

50

28 90

p=0.94

Albumin

Crystalloid

p=0.29

32% 32%

41% 44%

Mortality

Per

cen

t

Outcome Day

Septic Shock Conundrum

Caironi P, et al. N Engl J Med 2014;370:1412-21. Supplementary Appendix.

Subgroup No. of Patients

Albumin CrystalloidsRelative Risk (95% CI)

No. of deaths (%)

All patients 1781 365 (41.1) 389 (43.6) 0.94 (0.85 – 1.05)

Enrollment time

< 6 hours 569 115 (40.6) 116 (40.6) 1.00 (0.82 – 1.22)

6 – 24 hours 1212 250 (41.3) 273 (45.0) 0.92 (0.81 – 1.05)

Septic shock

Yes 660 122 (37.0) 108 (32.7) 1.13 (0.92 – 1.39)

No 1121 243 (43.6) 281 (49.9) 0.87 (0.77 – 0.99)

Albumin better Saline better1.0 2.0 4.00.500.25

Determining Transfusion Requirements

• Benefits and/or harms of hemoglobin thresholds in septic shock not well-established

• Multicenter, parallel-group trial with two groups• Lower hemoglobin threshold: 7 g/dL• Higher hemoglobin threshold: 9 g/dL

• Primary outcome: death by 90 days• Analyzed data from 998 patients

Holst LB, et al. N Engl J Med 2014;371:1381-91.

SubgroupLower Group Higher Group

Relative Risk (95% CI)No. events/No. Pts in Subgroup

Age

>70 yr 93/173 98/185 0.98 (0.79 – 1.18)

≤70 yr 123/329 125/311 0.94 (0.75 – 1.14)

Chronic CV disease

Yes 42/75 33/66 1.08 (0.75 – 1.40)

No 174/427 190/430 0.90 (0.75 – 1.06)

Baseline SAPS II

>53 112/207 139/226 0.83 (0.64 – 1.04)

≤53 104/295 84/270 1.10 (0.91 – 1.30)

All patients 216/502 223/496 0.94 (0.78 – 1.09)CV, cardiovascular; SAPS, simplified acute physiology score

Relative Risk of Primary Outcome

Lower hemoglobin threshold better

1.0 1.5 2.00.70.5Higher hemoglobin

threshold better

Holst LB, et al. N Engl J Med 2014;371:1381-91.

Summary of Major Advances: FluidsSource

Setting(Study

Duration)

No. of Pts(% in Septic

Shock)Intervention Control Primary

Outcome

RR (95% CI), Primary

OutcomeConclusions

Caironi et al, 20141

100 Mixed ICUs

(2008-2012)1810 (63) 20% Albumin +

crystalloids Crystalloids alone 28-d mortality 1.00 (0.87-1.14)

No difference in 28-d or 90-d

mortality

Perner et al, 20122

26 Mixed ICUs(2009-2011) 798 (84) HES Ringer acetate 6-mo

mortality 1.12 (0.98-1.29)No difference

in 6-mo or 1-yr mortality

Annane et al, 20133

57 Mixed ICUs(2003-2012) 2857 (54)

Gelatins, dextrans, HES, 4 or 20% albumin

Isotonic, hypertonic saline,

Ringer lactate

28-d mortality 0.96 (0.88-1.04)

No difference in 28-d

morality

Myburgh et al, 20124

23 Mixed ICUs(2009-2012) 7000 (13) 6% HES in 0.9%

sodium chloride0.9% sodium

chloride90-d

mortality 1.06 (0.96-1.18)No difference

in 90-d morality

Perner et al, 20122

26 Mixed ICUs(2009-2011) 798 (84) HES Ringer acetate 90-d

mortality 1.17 (1.01-1.36)Greater 90-d mortality and RRT with HES

RR, relative risk; CI, confidence interval; HES, hydroxyethyl starch; RRT, renal replacement therapy

1Caironi P, et al. N Engl J Med 2014;370:1412-21.

2Perner A, et al. N Engl J Med 2012;367(2):124-34.

3Annane D, et al. JAMA 2013;310(17):1809-17.

4Myburgh JA, et al. N Engl J Med 2012;367(20):1901-11.

Early Goal-Directed Therapy

Rivers E, et al. N Engl J Med 2001 Nov 8;345(19):1368-77.

Sedation, paralysis(if intubated), or both

CVP

MAP

ScvO2

Goalsachieved

Hospital admission

Yes

≥ 70%

≥ 65 and ≤ 90 mmHg

8 – 12 mmHg

Crystalloid

Colloid

Vasopressors

Transfusion of pRBCsuntil hematocrit ≥ 30%

Inotropes

< 8 mmHg

< 65 mmHg> 90 mmHg

< 70%< 70%≥ 70%

Rivers E, et al. N Engl J Med 2001 Nov 8;345(19):1368-77.

Early Goal-Directed Therapy

30.533.3

44.346.549.2

56.9

20

0

40

60

Hospital 28-Day 60-Day

p=0.009

EGDT Usual Care p=0.03n = 263

p=0.01

Mortality

Pe

rce

nt

Focus on “Goal-Directed”

• Three-center randomized, noninferiority trial in patients with severe sepsis or septic shock

• ScvO2 of at least 70% versus lactate clearance of at least 10%• Normalized CVP and MAP

• Primary outcome: absolute in-hospital mortality rate; noninferiority margin of 10%

ScvO2, central venous oxygen saturation; CVP, central venous pressure; MAP, mean arterial pressure

Jones AE, et al. JAMA 2010 Feb 24;303(8):739-46.

Focus on “Goal-Directed”

• 300 patients enrolled; no differences in treatment during initial 72 hours

• No difference in adverse effects

Jones AE, et al. JAMA 2010 Feb 24;303(8):739-46.

23

22

17

17

30

Per protocol

ITT

In Hospital Mortality (%)

Lactate Clearance

ScvO2

Proportion difference: 6% (-3% to 15%)

0 10 20

Proportion difference: 5% (-3% to 14%)

EGDT Controversies

• Internal validity• No blinding process• Unclear which intervention lead to positive outcomes

• Goal-directed protocol? ScvO2 use?

• External validity• Control arm mortality higher than expected

• Baseline ScvO2 remarkably low

• Translation to ICU care never clear

Russel JA, et al. Intensive Care Med 2015;41:1676-8.

ProCESS Study DesignEarly detection and fluid administration

Protocol-based EGDT Protocol-based Standard Usual Care

Venous Access

Bedside providersdirected all care

Oximetric CVC 2 large bore IVs

Protocol Goals

CVP 8-12 mm Hg SBP ≥ 100 mm Hg

MAP 65-90 mm Hg Shock index < 0.8

ScvO2 ≥ 70% (pRBC if Hct <30%)

Adequate perfusion (pRBC if Hgb <7.5 g/dL)

Protocol implemented by dedicated teamCVC, central venous catheter; CVP, central venous pressure; MAP, mean arterial pressure; SBP, systolic blood pressure; ScvO2, central venous oxygen saturation; pRBC, packed red blood cell; Hct, hematocrit; Hgb, hemoglobin

Yealey DM, et al. N Engl J Med 2014;370:1683-93.

ProCESS Study Results

21

6

0

20

40

Hospital Mortality 90-Day Mortality New Renal Failure

EGDT Standard Usual Care

p=0.83

p=0.66

n = 1341

p=0.0418 19

32 3134

3 3

Outcome

Per

cent

Yealey DM, et al. N Engl J Med 2014;370:1683-93.

ARISE Study

• ANZICS group; conducted in 51 academic and non-academic centers

• Antibiotics initiated prior to enrollment• Patients assigned to EGDT or usual care• Primary outcome: all-cause mortality at 90 days

Peake SL, et al. N Engl J Med 2014;371:1496-506.

ARISE Study Results

Peake SL, et al. N Engl J Med 2014;371:1496-506.

EGDT Usual Care

18.8

60

80

Vasopressor Support

n = 1600

40

20

0

18.6

76.3

65.8

90-day Mortality 28-day Mortality

14.8

Outcome

Per

cent

p=0.90 p=0.53

p<0.001

15.9

ProMISe Trial

• England; pragmatic randomized trial conducted in 56 hospitals• Integrated cost-effectiveness analysis

• Assigned to EGDT (6-hour resuscitation) or usual care

• Primary outcome: all-cause mortality at 90 days

Mouncey PR, et al. N Engl J Med 2015;372:1301-11.

ProMISe Trial Results

Mouncey PR, et al. N Engl J Med 2015;372:1301-11.

EGDT Usual Care

29.230

90-day Costs

n = 1251

20

10

0

29.5

17.616.2

90-day Mortality 28-day Mortality

24.8

Outcome

Per

cent

p=0.90

p=0.90 p=0.26

24.5

20

10

0

Dollars (expressed in thousands)

Clear as Mud?

• Systematic review showed no difference in mortality; increased vasopressor and ICU admit

• Estimated versus actual mortality differencesEGDT† ProCESS‡ ARISE‡ ProMISe‡

Mortality, PA ? 15% RRR 30-46% 28% 40%

Mortality, APACHE II 38.9 38.9 23.5 29.1

Actual mortality 49.2 18.9 18.8 29.2

†, based on 28-day mortality; ‡, based on 90-day mortality; all values represented as a %PA, power analysis; APACHE II, Acute Physiology and Chronic Health Evaluation; RRR, relative risk reduction


Angus DC, et al. Intensive Care Med 2015;41:1549-60.

Vasoactive Agents

• 2012 SCCM Recommendations• Only norepinephrine (NE) recognized as first line• Epinephrine (EPI) considered first alternative• Vasopressin (VP) as adjunctive therapy to increase

MAP and decrease NE requirements• Dopamine (DA) and phenylephrine (PE) for use in

select populations• VP not recommended as initial vasopressor


SOAP II Trial

• Multicenter, randomized trial• 1,679 patients randomly assigned to either

dopamine or NE as first line vasopressor• If MAP not maintained with 20 mcg/kg/min of

dopamine or 0.19 mcg/kg/min of NE, open-label NE, epinephrine,or vasopressin could be added

• Primary outcome• Rate of death at 28 days after randomization

De Backer D, et al. N Engl J Med 2010 Mar 4;362(9):779-89.

SOAP II Trial Results

De Backer D, et al. N Engl J Med 2010 Mar 4;362(9):779-89.

Dopamine Norepinephrine

53

75

50

25

0

n=1679

p<0.001 p<0.001

p=0.10

49

2620

24

127 4

p<0.001

28-d Mortality Open Label NE Arrhythmias Skin Ischemia

Per

cen

t

• Enrolled only patients with septic shock• Dobutamine (DBT) added to NE if CI ≤ 2.5 L/min/m2

CATS Study – NE vs. EPI

Annane D, et al. Lancet 2007;370:676-84.

Outcomes at Day 28Epinephrine

(n=161)NE ± DBT(n=169)

p-value

All-cause mortality 64 (40%) 58 (34%) 0.31

Vasopressor-free days 20 (0-24) 22 (6-25) 0.05

At day 14 56 (35%) 44 (26%) 0.08At day 28 64 (40%) 58 (34%) 0.31

*

Day2 3 4

97

5

3

1

0

* * **

2 3 40

7.5

7.4

7.3

7.2

7.1

7.0

Day

EPINE ± DBT

*p<0.01

CATS Study – NE vs. EPI

Annane D, et al. Lancet 2007;370:676-84.

18

40

19

30

60

20

10

0Arrhythmias

p=0.72

n = 330

p=0.3150

40

28-d Mortality

EPINE ± DBT

34

Pe

rce

nt

Vasopressin in Septic Shock Trial

• In septic shock, requiring norepinephrine (NE) at a dose of > 5 mcg/min for at least 6 hours and at least one other organ failure

• Received open-label NE in addition to blinded administration of:

• Vasopressin (0.01 – 0.03 units/min) OR

• Norepinephrine (5 - 15 mcg/min)

Russell JA, et al. N Engl J Med 2008 Feb 28;358(9):877-87.

Vasopressin in Septic Shock Trial

Russell JA, et al. N Engl J Med 2008 Feb 28;358(9):877-87.

n = 778

Per

cen

t

28-d Mortality 90-d Mortality

3935 36

27

43 44

50

44 46

36

53 52

p=0.26p=0.05

p=0.11p=0.04

* Defined as a NE requirement of at least 15 mcg/min or equivalent

Antimicrobial Therapy

• Prompt initiation of appropriate therapy is crucial• Within one hour of severe sepsis or septic shock

diagnosis

• Empiric regimen broad enough to cover all likely pathogens• Local epidemiology; medical history; recent therapies

• Pharmacokinetic-pharmacodynamic optimization


Early Effective Antimicrobial Treatment

Duration of Hypotension (Hours)

• Each hour of delay from hypotension onset was associated with an average decrease in hospital survival of 7.6%

Kumar A, et al. Crit Care Med 2006 Jun;34(6):1589-96.

Mortality and Time to AntibioticsStudy No. of Patients Odds Ratio (95% CI)

Ferrar et al, 2014 5062 1.07 (0.95-1.20)

Puskarich et al, 2011 172 0.77 (0.35-1.68)

Gaieski et al, 2010 261 1.65 (0.93-2.89)

Ferrar et al, 2009 1737 1.43 (1.14-1.78)

Kumar et al, 2006 2174 7.33 (5.44-9.97)

Yokota et al, 2014 358 1.13 (0.68-1.85)

Ryoo et al, 2015 426 1.09 (0.64-1.86)

Bloos et al, 2014 827 1.06 (0.74-1.51)

Pooled OR 1.46 (0.89-2.40)

Sterling SA, et al. Crit Care Med 2015;43:1907-15.

0.2 0.5 1 2 5 10

Antibiotic Therapy

• Regimen could rely on mono- or combination therapy with two or more agents

• Monotherapy: extended-spectrum penicillin with or without β-lactamase inhibitor

Therapy Approach Potential Agents

MonotherapyExtended-spectrum penicillin with or without β-lactamase inhibitor3rd or 4th generation cephalosporinCarbapenem

Combination Therapyβ-lactamAminoglycoside OR fluoroquinoloneAnti-Gram positive agent (e.g., vancomyin; linezolid; daptomycin)

Cohen J, et al. Lancet Infect Dis 2015;15:581-614.Dellinger RP, et al. Crit Care Med 2013 Feb;41(2):580-637.

Mono- vs. Combination Therapy

• Combination therapy found superior to monotherapy for Gram negative sepsis• Primarily retrospective and observational

• Meta-analyses suggest monotherapy as efficacious and less toxic than combination therapy in immunocompetent patients

Cohen J, et al. Lancet Infect Dis 2015;15:581-614.Paul M, et al. Cochrane Database Syst Rev 2014 Jan 7;1:CD003344.

Monotherapy Versus Combination TherapyOutcome or subgroup No. of Studies No. of Patients Risk Ratio (95% CI)

All-cause mortality Same beta lactam Different beta lactam

1331

14314146

0.97 (0.73-1.30)0.85 (0.71-1.01)

All-cause mortality, group Same sepsis Different sepsis

721

8393298

1.08 (0.75-1.55)0.83 (0.69-0.99)

Clinical failure Same beta lactam Different beta lactam

2046

18704933

1.11 (0.95-1.29)0.75 (0.67-0.84)

Bacterial superinfection 28 3135 0.75 (0.57-0.99)

Any nephrotoxicity Once-daily aminoglycoside Twice-daily aminoglycoside Thrice-daily aminoglycoside

4657

24

5269865

11272138

0.30 (0.23-0.39)0.17 (0.06-0.53)0.43 (0.24-0.77)0.28 (0.20-0.39)

Cohen J, et al. Lancet Infect Dis 2015;15:581-614.Paul M, et al. Cochrane Database Syst Rev 2014 Jan 7;1:CD003344.

Guidance for Therapy Duration

• Empiric combination therapy should be continued no longer than three to five days

• De-escalate to appropriate targeted therapy as soon as possible

• Therapy duration typically seven to ten days• Consider use of biomarkers to guide

discontinuation of empiric therapy


Rapid Diagnostics

• Matrix-associated laser desorption ionization-time of flight (MALDI-TOF)

• Peptide nucleic acid fluorescence in situ hybridization (PNA FISH)

• Mass spectroscopy• Polymerase chain reaction (PCR)

• Singleplex; multiplex real-time; broad range; digital


Reduced time to pathogen identification

Reduced time to pathogen identification

Earlier, appropriate tailoring of therapyEarlier, appropriate tailoring of therapy

Improved mortality and morbidity

Improved mortality and morbidity

Antimicrobial Stewardship Programs

• Core responsibilities• Provider education; guideline development; dose

optimization; therapy de-escalation; parenteral to enteral conversions

• Goals• Improving outcomes; decrease “inappropriate”

antimicrobial use; prevent adverse drug reactions; minimize resistance development

DeWaele JJ, et al. Intensive Care Med 2015 Aug 20. [Epub ahead of print]

Surviving Sepsis Campaign Bundles

To be accomplished as soon as possible and scored over first three hours:

To be accomplished as soon as possible and scored over the first six hours:

Serum lactate measured

Blood cultures obtained prior to antibiotics administered

Administer broad-spectrum antibiotics

For hypotension and/or lactate > 4 mmol/L:

Deliver an initial minimum of 30 mL/kg of crystalloid

Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP ≥ 65 mmHg

In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L:

Measure CVP Measure ScvO2

Re-measure lactate if initial lactate is elevated


IMPreSSed with Compliance?Detail Compliance, n (%)

3-h bundle compliance (all patients, n = 1794)Full bundleLactate measurementObtain blood cultures before antibiotic administrationAdministration of broad-spectrum intravenous antibioticsAdministration of 30 mL/kg crystalloid fluid challengeHospital mortality, complianceHospital mortality, non-compliance

340 (19.0)1002 (55.9)883 (49.2)

1155 (64.4)1017 (56.7)

67/340 (19.7)443/1454 (30.5)*

6-h bundle compliance (all patients)Full bundleRepeat lactate measurementApplication of vasopressors for hypotensionHospital mortality, complianceHospital mortality, non-compliance

637 (35.5)1077 (60.0)1479 (82.4)

143/637 (22.4)367/1157 (31.7)*

6-h bundle compliance, hypotension (n = 824)Full bundleRepeat lactate measurementApplication of vasopressors for hypotension

90 (10.9)530 (63.4)544 (66.0)

* Represents p≤0.0001 by Fishers exact test

DeWaele JJ, et al. Intensive Care Med 2015;41:1620-8.

National Quality Forum #0500A. Measure lactate level

B. Obtain blood cultures prior to antibiotics

C. Administer broad spectrum antibiotics

D. Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L

E. Apply vasopressors (for hypotension that does not respond to maintain a MAP ≥ 65 mmHg

F. In the event persistent hypotension after initial fluid challenge or if lactate ≥ 4 mmol/L‡, reassess intravascular volume status and tissue perfusion and document findings.

*To meet requirements, a focused exam including vital signs, cardiopulmonary, capillary refill, pulse and skin findings, or any 2 other items below are required:Measure CVPMeasure ScvO2

Bedside cardiovascular ultrasoundDynamic reassessment of fluid

G. Re-measure lactate if initial lactate is elevated‡ Would also require another fluid challenge

Dellinger RP, et al. Crit Care Med 2015 Sep;43(9):1787-9.

Patient with clinical criteria for septic shockSuspected or documented infection Arterial hypotension (SBP ≤ 90; MAP ≤ 65)Evidence of tissue hypoperfusion

Address suspected infectionImmediately obtain body fluid culturesBegin appropriate broad-spectrum antibioticsConsider diagnostic imagingInstitute prompt infectious source control

Begin fluid bolus therapyIVF, 20-30 mL/kg over 15-30 min;hold if fluid replete or overload

Assess clinical severityMeasure lactate immediatelyObtain additional laboratory tests(e.g., arterial blood gas; troponin)

Initial management

Rapid clinical reassessment within 15-30 min

Is shock still present?

Is shock still present?

Consider focused cardiac ultrasound

Consider arterial catheter for blood pressure monitoring and obtaining blood samplesConsider central venous catheter for reliable vascular access

AAYes

No

LV or RV dysfunction?LV or RV dysfunction?

Advanced diagnosticsConsider formal ECHO,repeat EKG, troponin levelsConsider PCA and ScvO2 measurement

Yes

No

Seymour CW, et al. JAMA 2015 Aug 18;314(7):708-17.

Seymour CW, et al. JAMA 2015 Aug 18;314(7):708-17.

Is there arterial hypotension?Is there arterial hypotension?

Fluid replete or overload?Fluid replete or overload?

Yes

Start vasopressorsNorepinephrine as first-line agent

Yes

Consider IVF to replace ongoing losses

No

Prompt clinical reassess within hoursRepeat lactate levelPerform clinical examination at bedside (mental status; peripheral perfusion; urine output)Reassess if fluid replete or overload

Persistent shock?Persistent shock?

Address treatment of persistent shockReassess etiology of shock and control of infectious sourceConsider vasopressin, 0.04 u/min, if high NE requirementsConsider hydrocortisone if multiple pressorsIf steroids started, consider removing when vasopressors are discontinued

Persistent shock?Persistent shock?

Yes

Yes

De-escalate therapy for septic shock and consider fluid volume removal when safe

De-escalate therapy for septic shock and consider fluid volume removal when safe

AA

No

No

Swing Away!

• First six hours after diagnosis will continue to be time period of greatest interest, but…• What is the right amount of intravascular volume in

septic shock?

• Is one crystalloid preferred to achieve that volume?

• What is the optimal balance between fluid administration and vasopressor use to maintain MAP?

• Do evidence-based monitoring variables exist to facilitate achieving these targets?

Dellinger RP, et al. Crit Care Med 2015 Sep;43(9):1787-9.

Oh How Pendulums Swing! Revisiting Severe Sepsis

and Septic ShockChris Droege, PharmD

Clinical Pharmacy Specialist, Critical CareUC Health – University of Cincinnati Medical Center

NYSHP Critical Care SymposiumSeptember 19, 2015

Authors of this presentation have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

Oh How Pendulums Swing! Revisiting Severe Sepsis and Septic Shock Chris Droege, PharmD Clinical...

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