Septic Shock Clinical Policy

Surat Tongyoo
Critical care medicine
Siriraj Hospital
 Overview
• Definition
– Diagnostic criteria
• Treatment
– Source identification and control
– Hemodynamic management
• Adequate volume resuscitation
• Acceptable blood pressure
• Adequate tissue perfusion
– Organs and metabolic support
 Overview
• Surviving Sepsis Campaign: International
Guidelines for Management of Sepsis and
Septic shock: 2016
• Surviving Sepsis Campaign Bundle: 2018
Update
• Department of Medicine, Siriraj Hospital
experience
 Diagnostic criteria
• ACCP/SCCM consensus conference 1991

• SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference 2001

• Surviving Sepsis Campaign: International

Guidelines for Management of Severe Sepsis
and Septic Shock: 2012

• Sepsis-3 definition
 Diagnostic criteria
• SIRS :2 or more of the following conditions
– Temperature > 38.5 or < 35.0 oC
– Heart rate > 90 bpm
– Respiratory rate > 20 /min or PaCO2 < 32 mmHg
– WBC > 12,000 /ml, < 4,000 /ml or Immature > 10%

• Sepsis : SIRS + Documented infection

– Culture or Gram stain of blood, sputum, urine, or normally sterile body
fluid positive for pathogenic microorganism
or
– Focus of infection identified by visual inspection, eg, ruptured bowel
with free air or bowel contents found in abdomen at surgery, wound
with purulent discharge
 Diagnostic criteria
• Severe sepsis :Sepsis + 1 organ dysfunction
– Kidney -urinary output of < 0.5 mL/kg for at least 1 h or
-renal replacement therapy or
-creatinine increase > 0.5 mg/dL
– Heart -cardiac dysfunction (echocardiography)
– Lung -acute lung injury/ARDS (PaO2/FiO2 < 300)
– CNS -abrupt change in mental status or abnormal EEG findings
– GI -bowel ileus, absent bowel sound, hyperbilirubin (total > 4mg/dL)
– Skin -areas of mottled skin; capillary refilling of > 3 second
– Peripheral tissue -lactate > 2 mmol/L
– Blood -platelet count of < 100,000 cells/mL or
-disseminated intravascular coagulation,
-coagulopathy (INR > 1.5, aPTT > 60 sec)
 Diagnostic criteria
• Septic shock
– :Severe sepsis + one of the following conditions

– Systemic mean BP of < 70 mm Hg (< 80 mm Hg if previous

hypertension) after 20–30 mL/kg starch or 40–60 mL/kg
serum saline solution or PCWP between 12 and 20 mm Hg

– Need for dopamine of > 5 mcg/kg/min, or norepinephrine or

epinephrine of > 0.25 mcg/kg/min to maintain mean BP at >
70 mm Hg (80 mm Hg if previous hypertension)
Correlation of mortality rate and severity
of disease
Mortality rate
60%
Septic shock (n = 1,134)

40% Severe sepsis (n = 827)

Sepsis (n = 1,063)
20%
Infection, no SIR (n = 584)

0% Days in hospital
0 20 40 60 80

AJRCCM 2003; 168: 77-84.

 Disadvantage of SIRS criteria
• Positive SIRS criteria 87.9%
• Negative SIRS criteria 12.1%
• 1 in 8 patients were missed
diagnosis
• Enrolled 109,663
infection with organ
failure patients
• From 172 ICU in Australia
and New Zealand
– 2000-2013

Kaukonen KM, et al. NEJM 2015

 Definition

• Sepsis is defined as life-threatening organ dysfunction caused

by a dysregulated host response to infection.
– Sepsis is a life-threatening condition that arises when the body’s
response to an infection injures its own tissues and organs.

JAMA. 2016;315(8):775-787
 Definition
• Sepsis
– Life-threatening organ dysfunction caused by a dysregulated
host response to infection.
– Organ dysfunction can be identified as an acute change in
total SOFA score 2 points consequent to the infection.
• The baseline SOFA score can be assumed to be zero in patients not
known to have preexisting organ dysfunction.
– A SOFA score 2 reflects an overall mortality risk of
approximately 10% in a general hospital population with
suspected infection.

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

JAMA. 2016;315(8):801-810.
 Definition
• Septic shock
– Adult patients with septic shock can be identified
using the clinical criteria of
1. Clinical of sepsis
2. Hypotension requiring vasopressor therapy to maintain
mean BP 65 mmHg or greater
3. Having a serum lactate level greater than 2 mmol/L
after adequate fluid resuscitation.
– Hospital mortality > 40%

JAMA. 2016;315(8):801-810.
 How to make diagnosis of
sepsis/septic shock?
• Sepsis
– Fever or hypothermia
– Documented or suspected infection
– Organ dysfunction
• Tachypnea, hypoxemia
• Hypotension
• Alteration of consciousness
• Low platelet, elevated creatinine or bilirubin
• Serum lactate >2 mmol/L
 Definition
• Septic shock
– qSOFA should be used to identified patients at risk
1. Alteration in mental status
2. Systolic blood pressure 100 mmHg
3. Respiratory rate 22/min

JAMA. 2016;315(8):801-810.
Pathophysiology of septic shock
 Septic shock management
• Get rid of source of infection
– Appropriate antibiotic
– Appropriate drainage
• Hemodynamic management
– Fluid therapy
– Vasopressors & inotrope
– Hemodynamic target
• Organs support
– Metabolic supports
– Ventilator support
– Adjunctive therapies
 Recommendation 1
• Source identification and control

– Appropriate specimen(s) collection for gram stain

and culture
– Hemoculture
– Initiate appropriate antibiotic within the 1st hour
– Appropriate drainage when suitable
Delayed initiation of antibiotic
increases mortality

Kumar A. Crit Care Med 2006;34(6):1589–96

 Recommendation 2
• Adequate volume resuscitation

– Initiate crystalloid resuscitation 30 mL/kg

– Start within the 1st hour after septic shock
diagnosis
– To be completed within 3 hours
– Frequent re-evaluate patient’s respond
– Fluid responsive test
EGDT (USA) ProCESS (USA) ARISE (AUS) ProMISe (UK)
2001 2014 2014 2015
263 septic shock 1341 septic shock 1600 pts 1260 septic shock
APACHE II 21.4+6.9 20.7+7.5 15.4+6.5 18.7+7.3
SBP 106 mmHg 100 mmHg 79 mmHg 78 mmHg
Lactate 7.7 mmol/L 4.9 mmol/L 6.7 mmol/L 7 mmol/L
Usual care vs EGDT EGDT 439 EGDT 796 EGDT 625
-CVP 8-12 mmHg Standard 446 -Monitor ScvO2 -Monitor ScvO2
-MAP 65-90 mmHg -Fluid 1L in 20min Usual care 804 Usual care 626
-ScvO2 > 70% -Fluid 2L in 1 hr -No ScvO2 -No ScvO2
-Hct > 30% Usual care 456
Decrease mortality Not improve Not improve Not improve
60 d:56.9 vs 44.3 %P=0.03 60 d: 21vs18vs19% 90 d: 18.6 vs 18.9 90 d: 29.5vs29.2%

Fluid before <20mL/Kg >30mL/Kg >30mL/Kg >30mL/Kg

Fluid 6hrs 3.5 vs 5 L 4.3 vs 3.8 vs 3.3 L 4.5 vs 4.2 L 4 vs 3.8 L
Vasopressor 57.3 vs 36.8% 55 vs 52 vs 44% 66.6 vs 57.8 % 53.3 vs 46.6%
PRC 64.5 vs 68.4% 15 vs 8 vs 7% 13.6 vs 7% 8.8 vs 3.8%
Dobutamine 9.2 vs 15.4% 8 vs 2 vs 1% 15.4 vs 2.6% 18.1 vs 3.8%
 When to stop fluid therapy?
• Achieve hemodynamic goal
– Mean arterial pressure > 65 mmHg
– Urine output > 0.5mL/kg/hours
– Decrease serum lactate
• No fluid respond
– Rapid increasing of CVP
– Unable to increase BP, SV after fluid therapy
• Complication of fluid therapy
– Hypoxemia & increasing lung crepitation
 When to stop fluid therapy?
มาลี มพ่ววงง,
มาลี อ่อ่ววมพ่ SIRIRAJ HOSP

• Achieve hemodynamic goal

MALEE AOMPON
53151627 28/10
23/12/1945
Age: 67 YEAR
F

– Mean arterial pressure > 65 mmHg

– Urine output > 0.5mL/kg/hours
– Decrease serum lactate
• No fluid respond
– Rapid increasing of CVP
– Unable to increase BP, SV after fluid therapy
• Complication of fluid therapy
– Hypoxemia & increasing lung crepitation
Page: 1 of 1
cm
 Guideline for fluid resuscitation
• Initial fluid resuscitation
– 20-30 mL/kg crystalloid solution
• 800-1,000 mL in 1st hour
• Total 1,500-2,500 mL in 3rd hours
– Consider colloid if unable to achieve hemodynamic goal and
evidence of fluid responsive
• Albumin is the most preferable colloid
• Avoid hydroxyethyl starch in septic shock patients
• Maintenance fluid after achieve macro &
microcirculation goal
– Increase rate as need
• Invasive vs non-invasive test
 Type of colloid resuscitation and outcome
SAFE study Critically ill patients, N =
NEJM 2004 6,997
-Mean BP 74 mmHg
43% surgical patients
19% severe sepsis
17% trauma
ALBIOS study Severe sepsis, N = 1,818
NEJM 2014 -Mean BP = 74 mmHg
62% septic shock
Hydroxyethyl starch Critically ill patients, N =
NEJM 2012 7,000
-Mean BP = 74 mmHg
45% required vasopressor
29% severe sepsis
8% trauma
Hydroxyethyl starch Severe sepsis, N = 798
NEJM 2012 55% lung infection
33% abdominal infection
CRISTAL trial Shock patients, N = 2,857
JAMA 2013 -SBP = 92 mmHg
54% septic shock
40% hypovolemic shock
6% trauma
4% albumin vs NSS 28 d mortality
34% vs 35%, P = 0.96
Sepsis 30.7% vs 35.3%, P = 0.09
Trauma 13.6% vs 10%, P = 0.06
20% Albumin vs 28 d mortality 31.8% vs 33.2%, P = 0.97
Crystalloid 90 d mortality 41.1% vs 43.6%, P = 0.29
Septic shock 43.6% vs 49.9%, P = 0.03
6% HES vs NSS 90 d mortality
18% vs 17%, P = 0.26
CHF 36.5% vs 39.9%, P = 0.03
RRT 7% vs 5.8%, P = 0.04
Sepsis 25.4% vs 23.7%, P = 0.38
6% HES vs RLS 90 d mortality
51% vs 43%, P = 0.03
Bleed 10% vs 6%, P = 0.09
RRT 22% vs 16%, P = 0.04
Colloid vs Crystalloid 28 d mortality
645 HES 25.4% vs 27%, P = 0.26
281 Gelatin 90 d mortality
80 Albumin 30.7% vs 34.2%, P = 0.03
 Data from our patients
• 686 septic shock
– Mean BW = 58.5+13.5 kg Fluid 0-3 hour (mL/kg)
• Hospital mortality = 30%
– 23%, 19%, 34.9%

Fluid 1st hour (mL/kg)

 Data from our patients
Fluid day 1-3 (L)

• 686 septic shock

– Mean BW = 58.5+13.5 kg
• Hospital mortality = 30%
 Recommendation 3
• Acceptable blood pressure

Goal of septic shock hemodynamic management

• 1st goal: Restore blood pressure
– Mean arterial pressure > 65 mmHg
– Need higher target blood pressure among previously
hypertension
– Norepinephrine is the first choice vasopressor
 Result

• Include 776 severe

sepsis/septic shock patients
– Mean ABP = 74 mmHg
– Mean HR = 104/min
– Lactate =3.7 mmol/L
– Received fluid 2,900 mL
– Norepinephrine 94% • Low BP VS High BP
– 28d mortality 34 vs 36.7, P=0.57
• Randomized into – 90d mortality 42.3vs43.8, P=0.74
– Low mean ABP > 65 mmHg – Median dose NE 0.45vs0.58, P<0.001
– High mean ABP > 80 mmHg – Renal replacement 35.8vs33.5, P=0.5
– RRT in chronic HT 42.2vs31.7,P=0.046
 Septic shock survival rate:
According to MAP at 6 hours after treatment

60-65
Study Vasopressors regimens Outcome
Lancet 2007 Mortality
RCT Norepinephrine + dobutamine 28 d: 34% vs 40%,P=0.31
330 septic shock vs Adrenaline 90 d: 50% vs 52%,P=0.73
MAP 69, SAPS 53 Target MAP > 70 mmHg, CI > 2.5 Arrhythmia
Lactate 3.2 Mean NE 1.1, AD 0.9 mcg/kg/min SVT 12%, VT/VF 6%
NEJM 2008 Overall mortality
RCT Norepinephrine vs Vasopressin 28 d: 39.3% vs 35.4%,P=0.26
778 septic shock Target MAP 65-75 mmHg 90 d: 43.9% vs 49.6%,P=0.11
APACHE II = 27 Less severe NE<15mcg/min
MAP 73 mmHg 28 d: 35.7% vs 26.5%,P=0.05
Lactate 3.5 90 d: 46.1% vs 35.8%,P=0.04
Arrhythmia 2%
NEJM 2010 Mortality
RCT Norepinephrine vs Dopamine 28 d: 48.5% vs 52.5%,P=0.1
1,679 shock pts Target MAP 65 mmHg Hosp:56.6% vs 59.4%,P=0.24
1,000 septic pts Arrhythmia
APACHE II = 20 12.4% vs 24%, P=0.001
MAP 58 mmHg Significant decrease
Lactate 2.2 cardiogenic shock mortality
 Outcome

• 330 septic shock

– RCT to
• NE 0.2mcg/kg/min + Dobu
• AD 0.2mcg/kg/min + Placebo
• 28 day mortality
• Mean age 63 (50-73) years – 34 vs 40%, P = 0.31
• SAPS II 53 (40-65) • Similar adverse effects

• 778 septic shock
– Require > 5mcg/min NE
– RCT to
• Vasopressin 0.01-0.03U/min
• NE 5-15 mcg/min
• Mean age 61 years
• APACHE 27+7
Outcome
• 28 day mortality
– 35.4 vs 39.3%, P = 0.26
• NE < 15mcg/min
– 26.5 vs 35.7%, P = 0.05
• NE > 15mcg/min
– 44 vs 42.5%, P = 0.76
 Outcome

• 1679 shock patients

– 1044 septic shock
– 280 cardiogenic shock • 28 day mortality
– 263 hypovolemic shock – 52.5 vs 48.5%, P = 0.1

• Mean age 68 years • Arrhythmia

– 24.1 vs 12.4%, P<0.001
• APACHE 20 (15-28) – Atrial fibrillation 20.5 vs 11%
– VT/VF 3.6 vs 1.5%
 Dopamine vs Norepinephrine

• 28 days mortality 40.7% vs 38%, RR 1.07 (0.99-1.16)

• Arrhythmia 17.7% vs 7.6%, RR 2.33 (1.45-3.85)
Cochrane Database of Systematic Reviews 2016
 Vasopressors
• Current recommendation

– Target MAP > 65 mmHg

• Norepinephrine is the first-choice vasopressor
• Dopamine is an alternative vasopressor
• Especially in non-tachycardia patient
• Vasopressin or adrenaline can be added to
norepinephrine to keep MAP in acceptable range
• Hydrocortisone should be considered in septic shock,
refractory to fluid and conventional vasopressors
 • Corticosteroid use was
associated with
– Lower 28-day mortality
• Meta-analysis • RR, 0.90; 95% CI, 0.82-0.98; I2 = 27%
– Lower intensive care unit (ICU)
• 37 RCT, 9,564 patients mortality
• RR, 0.85; 95% CI, 0.77-0.94; I2 = 0%
– Lower in-hospital mortality
• RR, 0.88; 95% CI, 0.79-0.99; I2 = 38%
– Increased shock reversal at day 7
– Increase vasopressor-free days
– Increased risk of hyperglycemia
• RR, 1.19; 95% CI, 1.08-1.30
– Increase hypernatremia
• RR, 1.57; 95% CI, 1.24-1.99
 Recommendation 4
• Adequate tissue perfusion

Goal of septic shock hemodynamic management

• 2nd goal: Restore tissue (organ) perfusion
– Urine output > 0.5 mL/kg/hr continuously for 2-3 hr
– Lactate decreasing > 10% in 2-3 hr
– Lactate < 2 mmol/L
 Septic shock survival rate:
According to urine output at 6 hours
Goals achievement and
septic shock outcome
• Good correlation of
serum lactate from
capillary, venous and
arterial blood

– A lactate = V lactate

– C lactate = A lactate + 1
 Recommendation 4
• Adequate tissue perfusion
– For patients who can not achieve tissue perfusion
target
• Re-evaluate volume status
• Re-evaluate blood pressure
– Keep mean BP 60-90 mmHg
• Check hematocrit
– Keep > 30%
• Consider dobutamine to improve cardiac output
 Inotrope
Dosage
Drugs Pharmacology Effect
(mcg/kg/min)
Strongly increase
Dobutamine  adrenergic 0.02-0.5
BP>>HR
Increase CO via
Phosphodiesterase lower SVR
Milrinone 0.5-0.75
inhibitor type III
Mild increase HR
Increase CO
Levosimendan Ca2+ sensitizer Hope not 0.02-0.5
increase HR
 Inotrope
• Dobutamine
– Standard inotrope
– Evidence of inadequate tissue perfusion after
• Adequate fluid resuscitation
• Achieve target MAP > 65, < 90 mmHg
– Evidence from EGDT 2000 study
– No RCT comparing dobutamine vs placebo
 Inotropes
• Current recommendation

– Dobutamine is recommended in patients with

evidences of persistent hypoperfusion despite
adequate fluid loading and the uses of
vasopressor agents.
 Recommendation 5
• Organs and metabolic support
– Respiratory system
• Mechanical ventilator
• Low tidal volume strategy
• Appropriate PEEP
– Renal system
• Appropriate renal replacement therapy
– Nutrition and blood sugar control
• Start enteral nutrition when suitable
• Target blood sugar 140-180 mg/dL
 Conclusion
• Early diagnosis sepsis and early treatment
• Get rid source of infection and hemodynamic
resuscitation
– Monitoring tissue perfusion together with mean BP
– Early resuscitation with fluid therapy
• Crystalloid first
• Albumin is colloid of choice
– Norepinephrine is the 1st line vasopressor
– Hydrocortisone can improve BP