EGDT There and

BackNathan I. Shapiro, MD, MPH

Beth Israel Deaconess Medical Center

Boston, MA

Disclosures• Grants from the US National Institutes of Health

• Industry Research Grants

– Cheetah Medical, Thermo-Fisher, Rapid Pathogen Sctreening

• Consulting – Cyon Therapeutics

Chest: 1988: 94:1176-1186

• Design: single center, prospective, randomized

• Population: 70 high-risk surgery patients and trauma patients

• Intervention: supranormal oxygen delivery (CI>4.5, DO2>600)

• Outcome: Mortality 4% (Treatment) versus 30% (control)

Shoemaker et al, Chest:1988:94:1176-1186

Boyd et al: JAMA:1993:270:2699-2707

• Design: 56 site multi-center, prospective, randomized trial

• Population: 762 high-risk ICU patients (SAPS > 11)

• Interventions:

A)supranormal oxygen delivery (CI>4.5)

B) Sv02 > 70%

Gattinoni et al: NEJM:1995:333(16): 1025-1032

Gattinoni et al: NEJM:1995:333(16): 1025-1032

Hayes et al: NEJM: 1994:330:1717-1722

Gattinoni - Survival

Kern & Shoemaker: Crit Care Med: 2002:30:8: 1686-1692

• Gattinoni like Hayes….

•“It is impossible to resuscitate dead cells and failed organs, even with oxygen. “

• “Clearly, intensive care unitsgive too much, too late, to too few.”

William Shoemaker, NEJM, editorial

• Early, protocolized resuscitation to targeted physiologic endpoints

• Facilitates early, aggressive resuscitationRivers, Nguyen et al NEJM: 354 (19): November 8,2001

Goal Directed Therapy Treatments

Treatment

(6 hours)

Standard

(6 hours)

P-

Value

Total Fluids 5000cc

(+3000)

3500cc

(+2400)

<0.001

RBC Transfused 64% 19% <0.001

Dobutamine 13.7% 0.8% <0.001

ScvO2 > 70% 95% 60% <0.001

Study Team Yes No

Single Center EGDT Studies

Site Author n design Protocol

Henry Ford Rivers 263 Random EGDT ONLY

Cooper Trzeciak 38 Hist Control YES

BIDMC Shapiro 130 Hist Control YES

Barnes Micek 120 Prosp obs YES

Carolinas Jones 157 Prosp obs YES

River et al. NEJM 2001; Trzeciak et al. Chest 2006.

Shapiro CCM 2006; Micek CCM. 2007;

Jones et al. Chest 2007

Fluids - InitialL

iter

s

Vasopressor Use

0

10

20

30

40

50

60

70

80

90

100

Henry

Ford

Cooper BIDMC Barnes-

Jewish

Carolina

Standard

Protocol

Time to Antibiotics

0

20

40

60

80

100

120

140

160

180

Henry

Ford

Cooper BIDMC Barnes-

Jewish

Carolina

Standard

Control

Mortality

EGDT Validation

Chen C, Kollef MH. Conservative fluid therapy in septic shock: an example of targeted

therapeutic minimization. Critical care (London, England). 2014;18(4):481.

• ProCESS (United States)

• ARISE (Australia)

• ProMISe (England)

3 EGDT Validation Trials

ProCESS

.

ProMISeARISE

PROCESS Investigators. New England Journal of Medicine. 2014;370(18):1683-93

Mouncey PR,, et al. New England Journal of Medicine. 2015.

ARISE Investigators New England Journal of Medicine. 2014;371(16):1496-506.

3 EGDT Validation Trials

Intravenous Fluids in Triad Trials

Vasopressor Administration

Other Processes of Care

PROCESS Investigators, A randomized trial of protocol-based care for early septic shock.

New England Journal of Medicine. 2014;370(18):1683-93

All Fluids Over 72 hours

2.6 2.5 2.1 2.3 2.0 2.0

1.7 2.0 2.32.8

1.8 2.0

4.4 4.3 4.44.5

4.0 3.6

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

ARISE -UsualCare

ARISE -EGDT

ProCESS -UsualCare

ProCESS -EGDT

Promise -UsualCare

Promise -UsualCare

6-72 hr fluids

0-6 fluids

pre-fluids

8.7 8.8 8.79.5

7.87.6

Mortality Rates for EGDT Trials

47%

31%

19%

21%

15% 16%

25% 26%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Rivers ProCESS ARISE Promise

UsualCareEGDT

Implications of EGDT triad trialsBackdrop: All patients received

– Early Identification

– Aggressive Fluid Resuscitation (about 4-5 liters in first 6 hours)

– Early antibiotics (>97% all groups)

– Other care elements provided

1. A team based EGDT protocol or empiric structured protocol was not beneficial compared to usual care in 2009 - 2013

2. Systematic Screening and Aggressive treatment is needed to reproduce these findings

What EGDT does not tell us:

“How much fluids should I give to a septic patient?”

…..While EGDT trials used fluids, they were not fluids trials

The Pendulum is Swinging

Too Much

Fluid

Too Little

Fluid

Each Has Theoretical AdvantagesLiberal Fluids Restrictive Fluids

Augment preload to increase CO and organ perfusion

Reduce overall fluids and positive fluid balance

Decrease vasopressor use and its detrimental effects

Early vasopressors to treat vasodilation

?Increase Microcirculatory Flow Prevent worsening of pathologic edema(due to sepsis-induced barrier dysfunction)

Negative Fluid Balance is Associated with Better Outcomes

Pre-EGDT = Conservative

Post EGDT = Liberal

Era(s) of Fluid Management

Fluids in Usual Care Pre- and Post- Rivers

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Henry Ford Cooper BIDMC Barnes-Jewish

Carolina ARISE ProCESS ProMISE

Standard

Standard

Pre-Rivers Post-Rivers

Mortality in Usual Care Pre- and Post- Rivers

46%44%

29%

48%

27%

16%

19%

25%

0%

10%

20%

30%

40%

50%

60%

Henry Ford Cooper BIDMC Barnes-Jewish

Carolina ARISE ProCESS ProMISE

Standard

Standard

Pre-Rivers Post-Rivers

How much fluids should we give a patient before moving on to

vasopressors?

Crystalloid Liberal Or Vasopressors Early Resuscitation in Sepsis

(CLOVERS)

PETAL Network

Hypothesis

“Conservative”(Vasopressors for followed by rescue fluids)

Versus

“Liberal”(Fluids followed by rescue vasopressors)

Will reduce 90-day in-hospital mortality in Sepsis induced hypotension

Methods

• Multicenter, randomized prospective phase 3 trial

• Sepsis induced hypotension

• Intervention 24-hour fluid titration strategies

• 2,320 patients planned enrollment

• 50 PETAL network hospitals

• Primary outcome: 90-day inpatient mortality

What is the correct “dose” and

“timing” intravenous fluids in

sepsis-induced hypotension?

Questions?

Inclusion Criteria

• A suspected or confirmed infection

• SBP< 100 mmHg or MAP < 65 mmHg after a minimum of at least 1 liter of fluid

Exclusion Criteria (abbreviated)

• Age < 18 years

• Patient already received 3 liters of fluid

• >4 hours elapsed since meeting criteria

• Blood pressure is at known baseline

• Pulmonary edema or signs of new fluid overload

• Physician unwilling to randomize to one of the arms

Vasopressor First(Fluid Conservative)

Norepinephrine Drip –Titrate to MAP > 65

Rescue Fluids Criteria or

Norepi >20 mcg/min

Intervention Needed?

Increase Vasopressors/ add second vasopressor

500ml fluid bolus

No

Intervention Needed?

•SBP < 90 mmHG or MAP <65mmHG

Rescue Fluids Criteria

Yes

• SBP <70 mmHG) • Refractory hypotension (MAP <65) despite

norepi at 20 mcg/min• Persistent lactate > 4 mmol/l and rising• Sinus heart rate > 120 for >15 minutes• Echo/Ultra evidence of extreme

hypovolemia • Suspected central (e.g. bowel) or peripheral

ischemia or mottling

Restrictive Arm

Fluids First(Liberal Fluids)

2000 ml IVF crystalloid bolus

Rescue VP CriteriaOr 5 liter administered

Intervention Needed?

500ml fluid bolus

Norepinephrine DripTitrate to SBP > 90

No

Intervention Needed?

• MAP <65mmHG• persistent lactate > 4 mmol/l• sinus heart rate > 110• Any clinical or measured assessment of

volume status or volume responsiveness (e.g. echo, IVC measurement, CVP, etc) suggesting benefit from additional fluid

Rescue Vasopressor Criteria

• SBP < 70 mmHG• Persistent and rising lactate >

4mmol/liter• Signs of fluid overload• Suspected Central or peripheral

ischemia or mottling

Yes

Liberal Arm (draft)