Sepsis Management: Has anything changed ?

นพ.กลวิชย์ ตรองตระกูล หน่วยเวชบำบัดวิกฤต

ภาควิชาเวชศาสตร์ฉุกเฉิน คณะแพทยศาสตร์วชิรพยาบาล มหาวิทยาลัยนวมินทราธิราช

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Introductions• Pathophysiology of sepsis, severe sepsis and

septic shock

• What is new in septic shock resuscitation?

• Protocolized in resuscitation

• EGDT, CVP, MAP target, ScvO2, and blood transfusion threshold

• Type of fluid resuscitation

• Chloride base, HES, and albumin

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Pathophysiology of Sepsis

Angus DC, et al. New Engl J Med 2013;369:840-51.

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• T ≤ 36, ≥ 38 °C • HR ≥ 90 • RR ≥ 20, or PaCO2 < 32 mmHg • WBC ≥ 12,000 or ≤ 4,000 or >

10% immature WBC

Presence of organ dysfunction

Shock despite adequate fluid resuscitation

SIRS with presume/confirm infections

Sepsis with ≥ 1 sign of organ failure

(renal, respiratory, sepsis induce

hypotension, confusion)

MODs

Sepsis: Disease of continuum

Septic ShockSevere SepsisSepsisSIRS

Infection

Angus DC, et al. New Engl J Med 2013;369:840-51.

Relative hypovolemia

Peripheral vasodilatation

Myocardial suppression

Fluid Vasopressor

Inotrope

4

Oxygen Delivery

Cardiac Output (CO)

Heart

Lung

Vascular

RBC Oxy

gen

deliv

ery

Tissue

Oxygen in atm

X

Oxygen Content (CaO2)

Preload

Contractility

Afterload

Heart rate

Hemoglobin

Oxygen

Fluid

Vasopressor

Inotrope

FiO2

RBC txf

}

BP = CO x SVROxygen Consumption

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การกู้ชีพเบื้องต้น (initial resuscitation) ในช่วง 6 ชั่วโมงแรกของภาวะภาวะติดเชื้อในกระแสโลหิตแบบรุนแรง (severe sepsis) และภาวะช็อกจากการติดเชื้อในกระแสโลหิต (septic shock) จากข้อแนะนำของ SSC 2012

1. ผู้ป่วยที่มีภาวะติดเชื้อในกระแสโลหิตที่ทำให้ความดันโลหิตต่ำ (sepsis-induced hypotension) หรือ แลกเตทในเลือดมากกว่าหรือเท่ากับ 4 มิลลิโมลต่อลิตร ควรได้รับ การกู้ชีพตามข้อกำหนดซึ่งวัดเป็นเชิงปริมาณได้ (protocolized, quantitative resuscitation) ได้แก่ ก) Central venous pressure 8 - 12 มิลลิเมตรปรอท ข) Mean arterial pressure (MAP) มากกว่าหรือเท่ากับ 65 มิลลิเมตรปรอท ค) ปัสสาวะออกมากกว่าหรือเท่ากับ 0.5 มิลลิลิตรต่อกิโลกรัมต่อชั่วโมง ง) Central venous oxygen saturation (ScvO2) หรือ mixed venous oxygen saturation (SvO2) มากกว่าร้อยละ 70 หรือ 65 ตามลำดับ (grade 1C)

2. ในผู้ป่วยที่มีระดับแลกเตทในเลือดสูง ควรให้การกู้ชีพจนค่าแลกเตทเข้าสู่ค่าปกติ (grade 2C)

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Protocolized resuscitation

What is new ?

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Early Goal Directed Therapy Rivers, NEJM 2001

- 263 SS&SSh pts at ED in US randomised to EGDT vs standard therapy - Primary outcome: In hospital mortality

Fluid

Vasopressor

RBC

Inotrope

fluid 500 ml q 30 min crystalloid to achieve CVP 8-12 mmHgVasopressor if MAP <=65, vasodilator if MAP > 90DBT 25 mcg/kg/min, increased by 2.5 q 30 min until ScvO2 > 70 or max 20, decrease or stop if HR > 120 or MAP < 65

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Increasing in Oxygen Demand

Normal condition

Increase demand co2

o2 o2

o2o2

o2 o2

o2co2

Oxygen delivery SaO2 = 100%

Venous Oxygen SvO2 = 75%

co

o2 o2

o2o2

o2 o2

co2

Oxygen delivery SaO2 = 100%

Venous Oxygen SvO2 = 50%

co

co2

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Outcome

Early Goal-Direct Therapy in The Treatment of Severe Sepsis and Septic Shock (EGDT)

EGDT collaborative group, New Engl J Med 2001,345:1368-77.

- 263 SS&SSh pts at ED in US randomised to EGDT vs standard therapy - Primary outcome: In hospital mortality

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CVP is only 56% in predicting fluid responsiveness

Marik PE et al. Chest 2008;134:172-8.Osman et al. Crit Care Med 2007;35(1)

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Limitation of EGDT

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Pace of Goal directed study

EGDT by Rivers

US 263

SS/SSh

EGDT 6 hr vs

usual Rx

In Hos MR

2001 2014 2014 2015

ProCESS

US 1351 SS/SSh

EGDT 6 hr vs

standard usual

Rx

60-MR

ARISE

ANZICs 1600

SS/SSh

EGDT 6 hr vs

usual Rx

90-MR

ProMISe

UK 1260

SS/SSh

EGDT 6 hr vs

usual Rx

90-MR

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A Randomized Trial of Protocol-Based Care for Early Septic Shock (ProCESS study)

1341 patients, of whom 439 were randomly assigned to protocol-based EGDT,

446 to protocol-based standard therapy, and 456 to usual care

ProCESS Study. N Engl J Med 2014;370:1683-93.

Protocol-based standard therapy

No central line

SBP ≥ 100 mmHg

SI (HR/SBP) ≤ 0.8

HB ≥ 7.5 gm/dL

CVP ≥ 8-12 mmHg

MAP ≥ 65 mmHg

SCVO2 ≥ 70 mmHg

Hct ≥ 30 %

Early goal directed therapy

vs vs Usual Care

Usual care therapy

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SI = HR/SBP

*Time Sensitive target

Time allowed7

Corrective action

Fluid bolus (500-1000 ml) 20 minutes 3rd IV or

central line

Initial fluid bolus (2L) 1 hour 3rd IV or

central line

SBP ≥ 100 mmHg 1 hour Vasopressors

-Fluid overload by clinical Dx: JVD, rales, drop in SpO2 -Definition of hypoperfusion: MAP < 65 despite SBP > 100, arterial lactate 4, mottled skin, oliguria and altered sensorium

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A Randomized Trial of Protocol-Based Care for Early Septic Shock (ProCESS study)

ProCESS Study. N Engl J Med 2014;370:1683-93.

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Goal-Directed Resuscitation for Patients with Early Septic Shock (ARISE trial)

• 1,600 enrolled pts, 796 were assigned to EGDT and 804 to usual care • Conducted at 51 enters (mostly in Australia or New Zealand, 3#care and not 3# care centre)

ARISE trial. N Engl J Med 2014;371:1496-506.

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Goal-Directed Resuscitation for Patients with Early Septic Shock (ARISE trial)

ARISE trial. N Engl J Med 2014;371:1496-506.

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Outcome of 3 protocolized studies

EGDT ProCESS ARISE ProMISe

Location US US ANZICs UK

Publications 2001 2014 2014 ~2015

Population 263 1351 1600 1260

Fluid before randomisatio

n

20-30 mL/kg 20 > 30 mL/kg 1000 ml 1000 ml

Hos MR 30.5 vs 46.5, p = 0.009

- - 90-day MR

28 day MR 33.3 vs 49.2, p = 0.01

- 14.8 vs 15.9, p = 0.53 (3°)

n/a

60 day MR 44.3 vs 56.9, p = 0.03

21.0 vs 18.0 vs & 18.9, p = 0.83

- n/a

90 day MR - 31.9 vs 30.8 vs 33.7, p =0.06

18.6 vs 18.8, p = 0.90 (1°)

n/a

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Baseline characteristic EGDT ProCESS ARISE

Location US US ANZICs

Age 67.1±17.4 vs 64.4±17.1

60±16.4 vs 62±16.0

62.7±16.4 vs 63.1±16.5

APACHE II 21.4±6.9 vs 20.4±7.4

20.8±8.1 vs 20.7±7.5

15.4±6.5 vs 15.8±6.5

Lactate 7.7±4.7 vs 6.9±4.5 4.8±3.1 vs 4.9±3.1 4.4±3.3 (6.7±3.3) vs 4.2±2.8 (6.6±2.8)

SBP 106±36 vs 109±34

100.2±28.1 vs 99.9±29.5

78.8±9.3 vs 79.6±8.4

Septic shock 54.7% vs 51.3% 55.6% vs 53.3 70% vs 69.8%

ScvO2 48.6±11.2 vs 49.2±13.3 71.±13 vs n/a 75.9±8.4 vs n/a

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High versus Low Blood-Pressure Target in Patients with Septic Shock (SEPSISPAM)

Outcome Low target (N=388)

High target (N=388)

P value

Death at day 28-no.(%) 132 (34.0) 142 (36.6) 0.57

Death at day 90-no.(%) 164 (42.3) 170 (43.8) 0.74

Doubling S cr 161 (41.5) 150 (38.5) 0.32

No HTN 71/215 (33.0) 85/221 (38.5) 0.32

HTN 90/173 (52.0) 65/167 (38.9) 0.02

RRT day 1- 7 139 (35.8) 130 (33.5) 0.50

No HTN 66/215 (30.7) 77/221 (34.8) 0.36

HTN 73/173 (42.2) 53/167 (31.7) 0.046

SEPSISPAM. N Engl J Med 2014; 370:1583-93.

P=0.57 at 28 days P=0.74 at 90 days

776 pts with SSh in France

Target: High 80-85 mmHg vs Low

65-70 mmHg x for 5 day/wean off

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Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock (TRISS study)

TRISS study. N Engl J Med 2014; 371:1381-91.

998 pts with SSh assigned to receive Leukoreduced PRC for different Hb threshold

in ICU ( 7 vs 9 g/dL)

Exclusion: ischemic heart disease, severe hypoxia, life-threatening bleeding, ischemia developed in the ICU, and ECMO

Primary outcome: death by 90 days

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Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock (TRISS study)

TRISS study. N Engl J Med 2014; 371:1381-91.

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Which vasopressors? Which inotropes?

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Comparison of Dopamine and Norepinephrine in the Treatment of Shock

• Which one agent is superior to the other? • Multicenter RCT in 1679 patients (MAP<70 or SBP<100)

• 858 were assigned to dopamine (20 mcg/kg/min) • 821 were assigned to norepinephrine (0.19 mcg/kg/min)

Mortality Rates

Backer DD. N Engl J Med 2010;362:779-89.

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Comparison of Dopamine and Norepinephrine in the Treatment of Shock

Backer DD. N Engl J Med 2010;362:779-89.

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“Fluid Strategy in Sepsis”

1. Early resuscitation 2. Maintenance fluid

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Fluid resuscitation why?

• Relative hypovolemia

• Arterial and venous dilatation and leakage of plasma to extravascular space

• Low SVR, increase CO2 production, tachycardia, and elevated oxygen concentration in PA = hyper-dynamic shock syndrome

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“Type of fluid using

in Sepsis”

Colloid vs Crystalloid

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Starling’s Law

Qf = net fluid filtration between compartment Kf = Capillary filtration coefficient Pcap = Capillary hydrostatic pressure

Pif = Interstitial hydrostatic pressure ơ = reflection coefficient ¶cap = Colloid osmotic pressure ¶if = Interstitial oncotic pressure

Qf = Kf [(Pcap - Pif) - ơ (¶cap-¶if)]

In Sepsis

• ↑ Pcap, ↓¶ cap = ↑ edema formation

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Resuscitation fluid. New Engl J Med 2013,369:1243-51.

A) Normal endothelial

glycocalyx (EG) layer

B) Damaged EG in sepsis etc.

C) Transvascular exchange

by Starling’s Law

c

Qf = Kf [(Pc - Pi) - ơ (¶c-¶i)]

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Basic fluid therapy

Intracellular 40% of BW

Extra cellular20% of BW

Intra vascu

lar5 % of

BW

Interstitial15 % of

BW

BP,HR,UOP,CVP

Thirst

skin tugor, mucosa

Osmotic (oncotic) and hydrostatic pressure

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Stages of volume status

Volu

me

stat

us

Time

Resu

scita

tion

Opt

imiz

atio

n

Stab

iliza

tion

Dees

cala

tion

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Ideal of fluid resuscitation• Predictable and sustained increase in intravascular

volume

• Chemical composition as close as possible to ECF

• Metabolized and completely excreted without accumulation in tissue

• Does not produce adverse metabolic or systemic effects

• Cost-effective in terms of improving outcomes

Resuscitation fluid. New Engl J Med 2013,369:1243-51.

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Normal saline: toxic to kidney? Chloride solutions may cause renal failure

• Chloride rich fluid (0.9% NSS, 4% gelatine, 4% albumin) vs Chloride restrictive fluids (chloride poor 20% albumin, Hartmann solution, Plasma-lyte 148)

• Serum Creatinine was higher in chloride rich fluid than chloride restriction

• 22.6 (17.5-27.7) vs 14.8 (9.8-19.9) umol/L; p=0.03

• Severity stage of AKI and RRT was lower in chloride restriction group than chloride rich fluid

JAMA 2012;308:1566-72.

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Abnormal saline !!

Renal replacement therapy in ICUAKI stage 2-3 by KDIGO definition

JAMA 2012;308:1566-72.

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Chloride and Kidney

KI 2014, doi:10.1038/ki.2014.105

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Intensive Insulin therapy and Pentastarch Resuscitation in Severe Sepsis (VISEP study)

VISEP study, NJEM 2008,385:125-39.

-537 pts with SS in Germany, 18 ICU (Stopped early due to safety reason) -10% HES 200/0.5 vs Ringer lactate solution in pts with SS&SSh -Primary outcome: Death 28 days, Secondary outcome: AKI

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Intensive Insulin therapy and Pentastarch Resuscitation in Severe Sepsis (VISEP study)

VISEP study, NJEM 2008,385:125-39.

Outcome HES (N=262)

RLS (N=275) P value

Death at 28 days - no./total (%) 70/262 (26.7) 66/274 (24.1) 0.48

Death at 90 days - no./total (%) 107/261 (41.0) 93/274 (33.9) 0.09

Acute renal failure - no./total (%) 91/261(34.9) 62/272 (22.8) 0.002

RRT - no./total (%) 81/261 (31.0) 51/272 (18.8) 0.001

RBC transfusion - no./total (%) 199/262 (76.0) 189/275(68.7) 0.06

No. of RBC transfusion (unit) 6 (4-12) 4 (2-8) < 0.001

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Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis (6S trials)

-798 pts with severe sepsis in Denmark Norway Finland and Iceland, 26 ICUs -6% HES 130/0.4 vs Ringer’s acetate throughout their illness -Primary outcome: Dead or need for dialysis at 90 days after randomization

6S trials, NJEM 2012.

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Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis (6S trials)

6S trials, NJEM 2012.

Outcome HES (N=398)

RA (N=400)

Relative risk (95%CI)

P value

Dead or dependent on dialysis at day 90 - no. (%)

202 (51) 173 (43) 1.17 (1.01-1.36)

0.03

Dead at day 90 - no. (%) 201 (51) 172 (43) 1.17 (1.01-1.36)

0.03

Dependent on dialysis at day 90 - no.(%)

1 (0.25) 1 (0.25) - 1.00

Use RRT - no. (%) 87 (22) 65 (16) 1.35 (1.01-1.80)

0.004

Doubling creatinine level - no. (%)

148 (41) 127 (35) 1.18 (0.98-1.43)

0.08

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Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care (CHEST trials)

CHEST Trail, NJEM 2012,367:1901-11.

-7000 pts admitted to ICU in Australia & New Zealand -6% HES 130/0.4 vs 0.9% NaCl for fluid resuscitation until D/C -Primary outcome: Death, secondary outcome: AKI-I & F and RRT

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Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care (CHEST trials)

CHEST Trail, NJEM 2012,367:1901-11.

Outcome HES Saline RR (95%CI) P value

Death at day 90 - no.total no. (%)

597/3315 (18.0) 566/3336 (17.0) 1.06 (0.96-1.18) 0.26

Renal outcome

RIFLE-R 1788/3309 (54.0) 1912/3335 (57.3) 0.94 (0.90-0.98) 0.007

RIFLE-I 1130/3265 (34.6) 1253/3300 (38.0) 0.91 (0.85-0.97) 0.005

RIFLE-F 336/3243 (10.4) 301/3263 (9.2) 1.12 (0.97-1.3) 0.12

Use RRT 235/3352 (7.0) 196/3375 (5.8) 1.21 (1.00-1.45) 0.04

-7000 pts admitted to ICU in Australia & New Zealand -6% HES 130/0.4 vs 0.9% NaCl for fluid resuscitation until D/C -Primary outcome: Death, secondary outcome: AKI-I & F and RRT

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HES increased AKI in Sepsis/septic shock

Trial VISEP study 6S Trial CHEST Trial CRYSTMAS study

Intervention 10%HES 200/0.5 vs RLS

6%HES 130/0.42 vs RA

6%HES 130/0.4 vs 0.9%NSS

0.6%HES130/0.4 vs 0.9%NSS

Population 537 pts with Severe sepsis

798 pts with Severe sepsis in ICUs

7000 pts within ICU (fluid ressus)

196 pts with Severe sepsis

Outcome Death at 28 days Death or ESKD at 90 days Death within 90 days Volume and time to

reach HDS

Results81/261 (31%) vs 51/272 (18%),

p 0.001

201/398 (51%) vs 172/400 (43%),

p = 0.03

Death Not significant, RRT 235/3352 (7%) vs

196/3375 (5.8%), p = 0.04

Less HES volume was used to reach HDS vs

NSS AKI 24.5% vs 20%,

p = 0.454

Conclusion HES was harmful, increased risk of AKI

HES increased risk of death and RRT HES increased RRT Less volume to reach

HDS by HES vs NSS

Journal NEJM2008;358:125-39. NEJM2012;367:124-34. NEJM2012;367:1901-11. Crit Care2012;16:R94.

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A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit (SAFE study)

: There were 726 deaths in the albumin group as compared with 729 deaths in the saline group at 28 days

SAFE study. N Engl J Med 2004;350:2247-56.

Outcome Albumin Saline RR (95%CI)

P value

Status at 28 days - no./total (%)

Dead 726/3473 (20.9)

729/3460 (21.1)

0.99 (0.91-1.09) 0.87

Alive in ICU

111/3473 (3.2)

87/3460 (2.5)

1.27 (0.96-1.68) 0.09

Alive in hosital

793/3473 (22.8)

848/3460 (24.5)

0.93 (0.86-1.01) 0.10

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A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit (SAFE study)

: There were 726 deaths in the albumin group as compared with 729 deaths in the saline group at 28 days

SAFE study. N Engl J Med 2004;350:2247-56.

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Albumin Replacement in Patients with Severe Sepsis or Septic Shock (ALBIOS study)

ALBIOS study. N Engl J Med 2014;370:1412-21.

1121 patients with septic shock showed significantly lower mortality at 90 days in the albumin group than in the crystalloid group.

In albumin group • Greater proportion reached the targeted

MAP within 6 hours • During the first 7 days, higher MAP,

whereas lower HR and net fluid balance

-1818 pts with SS admitted to 100 ICU in Italy -20% Albumin and crystalloid vs crystalloid alone (keep Alb>3g/dL until D/C) -Primary outcome: Death from any cause at 28 days

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Saline or Albumin for Fluid Resuscitation in Patients with Traumatic Brain Injury (SAFE TBI)

SAFE TBI study. N Engl J Med 2007;357:874-84.

-460 pts with traumatic brain injury (Hx of HI, CT +ve, GCS ≤ 13) -4% Albumin and crystalloid vs crystalloid alone (keep Alb>3g/dL until D/C) -Outcome: Death from any cause at 28 days and 2 years

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Fluid summaryTable 1

Benefits Risks

Saline Less expensiveHypercholemic metabolic

acidosis

Albumin Colloids of choiceExpensive

Increase mortality in TBI

Gelatins Less expensive Hypersensitivity

Hydroxyethyl strach Less expensiveAcute kidney injury

Coagulopathy

Balance salt solution ?? ???

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Fluid therapy of Severe Sepsis

Hemodynamic support and adjunctive therapy,Surviving Sepsis Campaign 2012

1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B).

2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock (grade 1B)

3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients required substantial amounts of crystalloids (grade 2C)

4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients (grade1C)

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Amount of fluid comparison from 3 studies

Total fluid EGDT ProCESS ARISE

Pre hosp n/a2,254±1,472 vs

2,083±1,4052,515±1,244 vs 2,591±1,331

0-6 hr 4,981±2,984 vs 3,349±2,438

2,805±1,957 vs

2,279±1,8811,964±1,415 vs 1,713±1,401

6-72 hr 8,625±5,162 vs 10,602±6,216

4,458±3,878 vs

4,354±3,8824,274±3,071 vs 4,382±3,136

0 - 72 hr 13,443±6,390 vs 13,358±7,729

7,253±4,605 vs

6,633±4,560n/a vs n/a

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Maintenance fluid

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Comparison of Two Fluid Management Strategies in Acute Lung Injury (ARDS Clinical Trails Network)

Data from 1000 patients with ALI with seven days fluid protocol

Fluid accumulation in 7 days 6992±502 ml vs -136±491ml

(P<0.001)

ARDS Clinical Trial Network. New Engl J Med 2006;354:2564-75.

CONCLUSIONSNo significant difference in 60-day mortality. However CONSERVATIVE strategy of fluid improved lung function and shortened duration of mechanical ventilation and ICU without increasing non-pulmonary organ failure.

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Acute inflammatory insult

Ebb phase

Organ dysfunction

Established Acute lung injury

Coexisting condition

Identify and treatment

Flow phase

Recovery

Impaired fluid mobilization

Rivers EP. N Engl J Med 2006;354:2598-600.

Goal in resuscitation in first 6 hr Diuretic

UltrafiltrationHemofiltration

Measure Fluid

responsiveness

Conservative fluid Mx

Fluid management in ALICerda J et al. Blood Purif 2010:29:331-8.

55

ยังต้องทำ EGDT ตาม protocol ของ Rivers ใน SS/SSh หรือไม่ ?

56

JAMA 2010;303:739-46.

Lactate clearance vs central venous oxygen saturation as Goals of Early Sepsis Therapy

ScvO2 > 70% vs lactate clearance at least 10% within 6 hr

% D

eath

0

10

20

30

ScvO2 Lactate

17

23

Observed difference between mortality rates did not reach

the predefined -10% threshold

57

-Surviving Sepsis Campaign 2012-

“Conservative fluid management and keep adequate tissue perfusion”

“Initial protocolized, quantitative fluid resuscitation during the first 6 hours”

58

Key concepts in shock resuscitation

• Early recognition of sepsis syndrome

• Control source of infection

• Appropriate antibiotic and timing of antimicrobial administration

• Early resuscitation with intravenous fluids and vasoactive drugs

59

Effective antimicrobial initiation and survival association

each hour of delay in initiation of effective antimicrobial was associated with mean decrease in survival of 7.6%

60

Sepsis supportive therapyFluid restriction

Nutritional support DVT prophylaxis

Source of Infectious control

De-escalate antibiotic

Glucose control

Restricted blood transfusion

Stress ulcer prophylaxisMechanical ventilation support

Sedation, analgesia, NMBA Renal replacement therapy

61

Conclusion• Continuous ScvO2 monitoring

• +/- Central venous pressure

• Target in mean arterial pressure over 65 mmHg, and keep higher in chronic hypertension

• Hb less than 7 g/dL is the trigger threshold

• Noradrenaline is the vasopressor of choice

• Crystalloid is the fluid of choice

• Early effective antibiotic (within 1 hour)

62

SI = HR/SBP

*Time Sensitive target

Time allowed7

Corrective action

Fluid bolus (500-1000 ml) 20 minutes 3rd IV or

central line

Initial fluid bolus (2L) 1 hour 3rd IV or

central line

SBP ≥ 100 mmHg 1 hour Vasopressors

-Fluid overload by clinical Dx: JVD, rales, drop in SpO2 -Definition of hypoperfusion: MAP < 65 despite SBP > 100, arterial lactate 4, mottled skin, oliguria and altered sensorium

63