Sepsis

SUDIRMAN KATU
DIVISI PENYAKIT TROPIK INFEKSI
DEPARTEMEN ILMU PENAYKIT DALAM
FAKULTAS KEDOKTERAN UNIVERSITAS HASANUDDIN
MAKASSAR 2018
 OBJECTIVES

• To understand and be able to identify the differences between SIRS, Sepsis, Severe
Sepsis, and Septic Shock.
• To understand the morbidity and mortality of Sepsis in relation to length of stay,
current guidelines, cost to health care systems.
• To understand modalities of treatment which include management, such as fluid
resuscitation and pharmacological interventions.
 In-hospital death 8X higher
compared to other diagnoses
.http://www.cdc.gov/nchs/data/databriefs/db62.pdf accessed August 7, 2015
 CASE
• At 17:00 noon, Mirza , a 19 year old on the soccer team, arrives at the Emergency
Department (ED) a few days after cutting his foot at practice. The area on his foot
around the wound has progressively gotten red, tender, hot to the touch, and has
some drainage. Today it caused pain when walking and he was feeling weak and
had a temperature. His only medical history is a mild case of asthma for which he
occasionally uses an inhaler.
The ED Technician takes Mirza’s vital signs. Mirza’s vital signs are:
• Heart Rate (HR) 98
• Respiratory Rate (RR) 24
• Temperature (T) 38.2° C
• Systolic Blood Pressure (SBP) 100 (normal for Mirza = 125 – 135)

• Level of Consciousness Alert & oriented to time, place and person

• Weight 90 kg
Using the Sepsis Algorithm, answer the following
questions:
• Does Mirza have 2 or more Systemic Inflammatory Response Syndrome (SIRS)
criteria?
• If yes, what criteria?
• Is there an actual or potential infection?
• If so, what is the source?
• What should happen next?
 The Sepsis Continuum
Severe Septic
Infection/Trauma SIRS Sepsis
Sepsis Shock

 A clinical response arising Sepsis with > 1 sign of Sepsis-induced

from a nonspecific insult, organ failure hypotension
with 2 of the following:
SIRS with a • Cardiovasculer
presumed Despite adequate
(refracter hypertension)
 T >38oC or <36oC or confirmed • Renal fluid Resuscitation,
• Respiratory with perfusion
 HR >90 beats/min infectious • Hepatic abnormalities
 RR >20/min process • Hematologic
• CNS
 WBC >12,000/mm3 or • Unexplain metabolic
<4,000/mm3 or >10% immature acidosis
neutrophils
SIRS = systemic inflammatory
response syndrome Bone, et al. 1992 Chest 101:1644-1655
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.
Crit Care Med 2012; 36(1): 296-327
AJN ▼ February 2018 ▼ Vol. 118, No. 2
SIRS = 3 Ts white with sugar
• Temperature ( > 38 or < 36ºC) : 38,2 0C
• Tachycardia ( > 90 bpm) : 98 bpm
• Tachypnoea ( > 20 breaths per min.) : 24 bpm
• White blood cell count (< 4 × 109 cells/L or > 12 × 109 cells/L)
• Sugar – blood glucose (> 7.7 mmol in the absence of diabetes
mellitus)
 Clinical criteria of severe sepsis

BP (ideal = 90 + age x 2; Min = 70+ age x 2)

 SURVIVING SEPSIS CAMPAIGN
• STEP 1: Identify SEPSIS
• STEP 2: Categorize SEPSIS
• STEP 3: Initiate TREATMENT
 NEW SEPSIS DEFINITION
• Guidelines were revised in 2008, 2012, and most
recently updated in 2015, and revised 2018.
• These guidelines have shaped how hospitals must
identify and treat patients who are identified as having
sepsis, severe sepsis, and septic shock.
 Sepsis ; Defining a Disease Continuum
Severe
Infection/Trauma SIRS Sepsis
Sepsis
Sepsis ;
• Life-threatening organ
dysfunction caused by a
dysregulated host response
infection
• Suspected or documented
infection and an
• Acute increase of > 2 SOFA
points (proxy for organ
dysafunction)
• Hospital mortality > 10%
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.
Septic
Shock
Sepsis with persistent
hypotension:
• Requiring vasoppressors to
maintain MAP > 65 mmHg
• And having a serum lactate
level > 2 mmol/L (18mg/dL)
despite adequate fluid
resuscitation
• Hospital mortality >40%
Bone, et al. 1992 Chest 101:1644-1655
Crit Care Med 2012; 36(1): 296-327
 SEPSIS SCORING TOOL
Quick SOFA / qSOFA

> 22/ min SBP

≤100mmHg

In patients with infection a qSOFA score >

2 is associated with higher mortality and
prolonged ICU stay.
SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) SCORE
 Identifying Acute Organ Dysfunction as
a Marker of Severe Sepsis
Cardiovascular
Respiratory
Tachycardia
PaO2/FiO2 200 if lung SBP<90mmHg
only dysfunction/site of MAP < 70mmHg
infection (despite fluid)
PaO2/FiO2 250 with Need for Vasopressors
other organ
dysfunction/lung not site Renal
of infection UO <0.5 ml/kg per hr
(despite fluid)
Metabolic
Unexplained Hematologic
metabolic acidosis
•Lactate > 1.5 times Platelets <80,000/mm3
upper normal Decline in platelet
count of 50% over 3
days
IN-HOSPITAL MORTALITY PREDICITION
THE MODIFIED EARLY WARNING (MEWS) SCORE
DIFFERENCE IN THE SURVIVING SEPSIS CAMPAIGN BUNDLES
Table 6. SURVIVING SEPSIS CAMPAIGN BUNDLE 2016
Table 7. SURVIVING SEPSIS CAMPAIGN GUIDELINES COMPARING 2012 & 2016
Table 8. STRONG RECOMENDATIONS FROM THE SURVIVING SEPSIS CAMPAIGN 2016 GUIDELINES
Using the Sepsis Algorithm, answer the following
questions:
• Does Mirza have 2 or more Systemic Inflammatory Response Syndrome
(SIRS) criteria?
• If yes, what criteria?
• Is there an actual or potential infection?
• If so, what is the source?
• What should happen next?
Source infection of sepsis in Internal Medicine

• BLOOD STREAM INFECTION (BSI)

• RESPIRATORY TRACT INFECTION (RTI)
• INTRA ABDOMINAL INFECTION (IAI)
• URINARY TRACT INFECTION (UTI)
• SKIN AND SOFT TISSUE INFECTION
Sepsis?
• Temperature ( > 38 or < 36ºC) :
• Tachycardia ( > 90 bpm) :
• Tachypnoea ( > 20 breaths per min.) :
• Focus Infection :
• qSOFA ;
• Respiratory Rate (RR)
• Systolic Blood Pressure (SBP)
• Level of Consciousness
Sepsis?
• Temperature ( > 38 or < 36ºC) : 38,2 0C
• Tachycardia ( > 90 bpm) : 98 bpm
• Tachypnoea ( > 20 breaths per min.) : 24 bpm
• Focus Infection : SSTI
• qSOFA ;
• Respiratory Rate (RR) 24
• Systolic Blood Pressure (SBP) 100 (normal for Mirza = 125 – 135)
• Level of Consciousness Alert & oriented to time, place and person
 Causative organisms associated with sepsis
• Beta-haemolytic streptococcus/group A Streptococcus pyogenes (GAS)
• Haemophilus infl uenzae
• Staphylococcus aureus
• Methicillin-resistant Staphylococcus aureus (MRSA)
• Streptococcus pneumoniae
• Morganella morganii
• Escherichia coli (E. coli)
• Pseudomonas aeruginosa
• Klebsiella
• Clostridium sordelli
• Clostridium diffi cile
• Clostridium septicum
 Source control
Two new best practice statements are included in the 2016 guidelines
recommending prompt source control of infection as quickly as
possible:
1. We recommend that a specific anatomic diagnosis of infection
requiring emergent source control beidentified or excluded as
rapidly as possible in patients with sepsis or septic shock, and that
any required source control intervention be implemented as soon as
medically and logistically practical after the diagnosis is made (BPS).
2. We recommend prompt removal of intravascular access devices that
are a possible source of sepsis or septic shock after other vascular
access has been established (BPS).
 Source Control: By the Guidelines
1. Find the source and get definitive control within 12 hours (grade 1C)
2. Exception peripancreatic necrosis: (grade 2B)
• definitive intervention best delayed until demarcation nonviable tissues has
occurred
3. Get control in the severely ill with least physiologically insulting method (UG)
• percutaneous drainage rather than surgery
4. Remove possible vascular access sources AFTER establishing additional access
(UG)

Dellinger et. al. (2012). Surviving Sepsis Campaign: International Guidelies for Management of Severe Sepsis and Septic Shock:
2012. 41(2). pp. 580-637
 Surviving sepsis campaign guidelines for management of
severe sepsis and septic shock

A. Initial Resuscitation L. Sedation, Analgesia, and

B. Diagnosis Neuromuscular Blockade in Sepsis
M. Glucose Control
C. Antibiotic therapy
D. Source Control N. Renal Replacement
E. Fluid Therapy O. Bicarbonate therapy
P. Deep Vein Thrombosis Prophylaxis
F. Vasopressors
G. Inotropic Therapy Q. Stress Ulcer Prophylaxis
H. Steroids R. Consideration for Limitation of Support
S. Pediatric consideration
I. Recombinant Human Activated Protein C
J. Blood Product Administration
K. Mechanical Ventilation of Sepsis-Induced
Acute Lung Injury

Dellinger RP - Crit Care Med 2012;

 THREE Clocks

3 hour

1 hour
 6 Hour Resuscitation Bundle

• Early Identification
• Early Antibiotics and Cultures
• Early Goal Directed Therapy
6 - hour Severe Sepsis/Septic Shock Bundle
• Early Detection:
• Obtain serum lactate level.
• Early Blood Cx/Antibiotics:
• within 3 hours of
presentation.
• Early EGDT:
• Hypotension (SBP < 90, MAP <
65) or lactate > 4 mmol/L:
• initial fluid bolus 20-40 ml of
crystalloid (or colloid equivalent)
per kg of body weight.
• Vasopressors:
– Hypotension not
responding to fluid
– Titrate to MAP > 65
mmHg.
• Septic shock or lactate > 4
mmol/L:
– CVP and ScvO2 measured.
– CVP maintained >8 mmHg.
– MAP maintain > 65 mmHg.
• ScvO2<70%with CVP > 8
mmHg, MAP > 65 mmHg:
– PRBCs if hematocrit < 30%.
– Inotropes.
 Rhode Island Hospital EGDT Data
Time from Entering ED
Time from Entering ED
to Receiving Antibiotics to Catheter Insertion Time from Entering ED
to Transfer to MICU
Reduced by 60%
Reduced by 42% Reduced by 51%
200 350
185 500

180
450
300
160
148 400

140 250
350

120 11 300
106 200

100 95
90 250

150
80 200

60 150
100

100
40
50
50
20

0
0 0 1 2 3 4 5 6
Month
1 2 3 4 5 6 1 2 3 4 5 6
Month Month
24 - hour Severe Sepsis and Septic Shock Bundle
• Glucose control:
• maintained on average <150 mg/dL (8.3 mmol/L)
• Drotrecogin alfa (activated):
• administered in accordance with hospital guidelines
• Steroids:
• for septic shock requiring continued use of vasopressors
for equal to or greater than 6 hours.
• Lung protective strategy:
• Maintain plateau pressures < 30 cm H2O for
mechanically ventilated patients
Hour-1 bundle

Intensive Care Med (2018) 44:925–928

Bundle elements with strength of recommendations
and under-pinning quality of evidence
 “Time Zero”
• Time Zero = time of presentation
• ED, Medical Floors, ICU
• Both bundles time based
• Most important time based elements:
• Antibiotic timing
• Resuscitation timing (EGDT)
 THREE CLOCKS

EARLY MANAGEMENT BUNDLE

0 hr.

3 hr.

6 hr.
Severe
Sepsis

Time Zero
Interventions Required:
 Blood culture before Interventions Required:
antibiotics  Lactate level repeated (If
 Antibiotics elevated)
 Lactate level

Set Measure ID # SEP-1-8; Early Management Bundle, Severe Sepsis/Septic Shock

CASE continue
• Based on Mirza’s condition and vital signs, here are the steps the ED staff
take:
• They place Mirza into a bed at 17.30 pm.
• The nurse starts an intravenous (IV) line in case fluids or IV medications
need to be given
• The doctor orders the following labs: Lactate, Blood Culture and Complete
Blood Count (CBC) (the phlebotomist draws the labs at 17.55 pm)
• The doctor orders 1 Liter (L) of intravenous fluid [normal saline (NS)] and
the nurse gives the fluid starting at 18:20 pm, at the time she hangs the
fluid bag the SBP = 88 and the HR = 102
CASE continue
• In the meantime, Mirza is starting to shiver. Some lab results come back
from the lab at 18:40 pm. The lab results are:
• Lactate = 4.2
• CBC: White Blood Cell (WBC) count = 15 thousand; Hematocrit (Hct) = 42
• The blood culture is pending
• The ED technician takes Mirza’s vital signs (VS) again at 18:45 pm after the
liter of fluid has been given to him. Mirza’s vital signs are now:
• SBP = 80
• HR = 114
• RR = 28
• T = 39° C
• Mirza looks very pale
Septic shock?
• Temperature ( > 38 or < 36ºC) :
• Tachycardia ( > 90 bpm) :
• Tachypnoea ( > 20 breaths per min.) :
• Leucocyte :
• Focus Infection :
• qSOFA ;
• Respiratory Rate (RR)
• Systolic Blood Pressure (SBP)
• Level of Consciousness
 Sepsis ; Defining a Disease Continuum
Severe
Infection/Trauma SIRS Sepsis
Sepsis
Sepsis ;
• Life-threatening organ
dysfunction caused by a
dysregulated host response
infection
• Suspected or documented
infection and an
• Acute increase of > 2 SOFA
points (proxy for organ
dysafunction)
• Hospital mortality > 10%
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.
Septic
Shock
Sepsis with persistent
hypotension:
• Requiring vasoppressors to
maintain MAP > 65 mmHg
• And having a serum lactate
level > 2 mmol/L (18mg/dL)
despite adequate fluid
resuscitation
• Hospital mortality >40%
Bone, et al. 1992 Chest 101:1644-1655
Crit Care Med 2012; 36(1): 296-327
Septic shock?
• Temperature ( > 38 or < 36ºC) : 39 0C
• Tachycardia ( > 90 bpm) : 114 bpm
• Tachypnoea ( > 20 breaths per min.) : 28 bpm
• Leucocyte : 15.000
• Focus Infection : SSTI
• qSOFA ;
• Respiratory Rate (RR) 28
• Systolic Blood Pressure (SBP) 80 after fluid ressucitation
• Level of Consciousness Alert & oriented to time, place and person
• Lactate : 4,2
Answer the following questions:
• Is Mirza’s condition improving?
• What do you think needs to happen now?
CASE continue
• Because Mirza’s condition is not improving:
• The doctor orders another liter (L) of fluid (NS) and IV antibiotics and
asks the nurse to get VS again as soon as the fluid is administered
• 1 L fluid is given at 19:10 pm
• The antibiotic is started at 19:20 pm and takes 30 min to give
• The doctor calls the nurse at 19:25 pm and tells her that he wants to
start Early Goal Directed Therapy (EGDT) on Mirza
Protocolized Care
FLUID RESUSCITATION
RESEARCH SUPPORTING FLUID RESUSCITATION BUNDLE
CHOICE OF FLUIDS

Crystalloids Colloids

Ringers Normal Gelatins Albumin

Lactate Saline Hetastarch
 IV FLUID COMPOSITIONS
Crystalloids
mEq/L
Na+ Cl- Lactate Acetate
0.9% NaCl 154 154 0 0
Lactated Ringer's (LR) 130 111 29 0
Hartman's 131 109 29 0
Ringer's Acetate (RA) 130 112 0 27
Plasma-Lyte®/Normosol-R ® 140 98 0 27
 2012: IVF recommendation
• Initial fluid challenge ≥ 1000 mL of crystalloids or
minimum of 30 mL/kg of crystalloids in the 1st 4-6
hours
• (Strong recommendation; Grade 1C).
• Crystalloids is the initial fluid for resuscitation
• (Strong recommendation; Grade 1A).
• Adding albumin to the initial fluid resuscitation
• (Weak recommendation; Grade 2B).
• Against hydroxyethyl starches (hetastarches) with
MW >200 dalton
• (Strong recommendation; Grade 1B).
FLUID REPLACEMENT CHALLENGES

End Stage Renal

Disease on Dialysis

Compensated
Congestive
Heart Failure
HEMODYNAMIC CHANGES IN SEPTIC SHOCK
Interstitial Edema in Septic Shock

Lungs Brain Kidney

 During Septic Shock

End End
Diastole Systole

10 Days Post Shock

End End
Diastole Systole

Courtesy of Joe Parrillo Hackensack NJ

 RESEARCH RECOMMENDATION

SCCM recommends that, in the resuscitation of sepsis-

induced hypoperfusion, at least 30 ml/kg of IV
crystalloid fluid be given within the first 3 hours
(strong recommendation, low quality of evidence).
Passive Leg raising
Adequate fluid resuscitation …
ANTIBIOTIC THERAPY

• Started within 3 hrs after

severe sepsis
presentation
• Monotherapy vs.
Combination Therapy
Administer IV antibiotics
 Septic Shock: Timing of Antibiotics
Percent
1.00 14 ICUs; n = 2,731
% Survival
.80 % Total receiving antibiotics

.60 50% of patients in Septic Shock

Only
received antibiotics w/in 6 hrs.
.40

.20

0.0

Time, hrs Kumar Crit Care Med 2006

 Choice of VASOPRESSORS

First Norepinephrine
Line

Second Epinephrine Low Dose

Line Vasopressin
(.01-.03 units/min)

Niche Dopamine Phenylephrine

Drugs (sinus (high cardiac output
bradycardia) or serious
tachyarrhythmias
and salvage)
 Management
Establish a 2nd IV line for Dopamine infusion
 Surviving sepsis campaign 2016
• We suggest against using IV hydrocortisone to treat septic shock patients if
adequate fluid resuscitation and vasopressor therapy are able to restore
hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a
dose of 200 mg per day
• No ACTH stimulation tests or serum cortisol testing
• No additional mineralocorticoid
• 7 days
• Taper
 WHAT DO WE KNOW?
• Hydrocortisone provides adequate glucocorticoid and mineralocorticoid
effects so fludrocortisone is not needed.
• Tapering of steroids is recommended.
• Although the current hypothesis for the use of steroids in septic shock is to
treat relative adrenal insufficiency, current evidence suggests no value in
measuring this with a corticotropin response test.
• Steroids are of no benefit in the treatment of severe sepsis in the absence
of shock.
• Low dose steroid therapy reduces time to reversal of septic shock
• Still controversial as to whether or not there is a meaningful reduction in
mortality.
• The more severely ill and hemodynamically unstable the patient is the
more likely to benefit from stress-dose steroids.
Correct metabolic derangement
• Metabolic acidosis.
• Hyper or hypoglycemia : always correct
hypoglycemia.
 Management of DIC:

• Restoration of normovolemia reverses abnormal activation.

• ‘Component replacement’
(Goal - Normal PT, PTT, fibrinogen, PC = 40,000 to 1
Lakh/cumm.)
a. FFP - most beneficial in early stages.
b. Cryo- consider 1 unit/3 units of FFP transfused.
c. Platelet concentrate
 Recognize and manage organ failure
a. Cardiovascular support:
Rate & rythm- correct 02, acidosis, Ca, Mg, K variations
Stroke volume - fluid correction & replace losses
Ionotrope support.

b. Renal: Volume replacement

Low dose dopamine
?diuretic with vol expansion
Indications for dialysis:
Hyperkalemia
refractory metabolic acidosis
Anuria despite diuresis
BUN>100mg%
 Recognize and manage organ failure
c. Respiratory support:
Supplement 02,
Early intubation and PPV ( PEEP)

d. GI: Antacids, sucralfate, early enteral nutrition.

CASE continue
• The start time for EGDT is 18:40 pm when the lactate result of 4.2 came back from
the lab. All interventions related to his care that have time frames associated with
them are based on this start time.
• The liter of fluid has been administered and at 19:30 the nurse checks Mirza’s VS again
as the doctor ordered. Mirza’s vital signs are:
• SBP = 85
• HR = 105
• RR = 25
• T = 38.7° C
• The sepsis catheter is inserted at 20:05 pm and the nurse starts monitoring the
measurements from the catheter that give information that helps guide treatment for
Mirza. The doctor orders a chest X-ray to make sure the catheter is inserted correctly
and makes arrangements to transfer Mirza to the Intensive Care Unit (ICU) as soon as
possible.
Septic shock  improve?
• Temperature ( > 38 or < 36ºC) : 39 0C  38,7 0C
• Tachycardia ( > 90 bpm) : 114 bpm  105 bpm
• Tachypnoea ( > 20 breaths per min.) : 28 bpm  bpm25
• Leucocyte : 15.000
• Focus Infection : SSTI
• qSOFA ;
• Respiratory Rate (RR) 28  25
• Systolic Blood Pressure (SBP) 80  85
• Level of Consciousness Alert & oriented to time, place and person
• Lactate : 4,2
 TO SAVE LIVES.....

Early identification

Early antibiotics

Early fluid resuscitation

Here are the values recorded from the sepsis
catheter:
Time CVP MAP ScvO2
20:15 pm 4 56 60
20:40 pm 5 57
21:10 pm 5 56 62
21:45 pm 6 59
22:10 pm 8 60 65
22:40 pm 8 59
23:00 pm 10 62 64
23:30 pm 9 64
23:55 pm 9 67 66
00:15 am 8 68
00:40 pm 9 68 68
01:15 am 8 70
01:45 am 10 69 69
02:10 am 9 68
02:45 am 9 72 72
CASE continue
• The ED staff takes another lactate draw at 00:05 am. The results from that draw
arrive at 00:57 am and are 2.3.

• Based on this information, did the ED staff meet the EGDT goals outlined in the Sepsis
Algorithm? Which of these were met?
• Antibiotics given at the right time?
• Sepsis catheter inserted at the right time?
• CVP, MAP, ScvO2 targets?
• Decreased repeat lactate?

• Mirza slowly improves over the next 2 days while in the ICU. He remains on IV
antibiotics and is transferred to the Medical Surgical unit until he is discharged home
2 days later.
Septic shock  improve?
• Temperature ( > 38 or < 36ºC) : 39 0C  38,7 0C
• Tachycardia ( > 90 bpm) : 114 bpm  105 bpm
• Tachypnoea ( > 20 breaths per min.) : 28 bpm  bpm25
• Leucocyte : 15.000
• Focus Infection : SSTI
• qSOFA ;
• Respiratory Rate (RR) 28  25
• Systolic Blood Pressure (SBP) 80  85
• Level of Consciousness Alert & oriented to time, place and person
• Lactate : 4,2  2,3
 SEPTIC SHOCK ONLY
Severe

3 hr.

6 hr.
Sepsis
Time Zero
Interventions Required:
Interventions Required: Persistent Hypotension
ALL of Severe Sepsis +  Within 1 hour of fluid add
 Fluid 30 ml/kg VASOPRESSOR
(NO exclusionary Persistent Hypotension
criteria) OR Lactate > 4
 Shock Assessment (1 of 2)
Shock Assessment

Physical Exam (ALL) Hemodynamics (2 of 4)

• Vital Signs (T, HR, RR, BP)
• Cardiopulmonary exam
• Capillary refill evaluation
• Peripheral Pulse evaluation
• Skin evaluation
• CVP
• SVO2
• Bedside cardiovascular ultrasound
• Passive leg raise / fluid challenge
 “Delays in administering all four
guidelines recommendations, even
when they did not exceed 3 hours,
were associated with a significant
increase in in-hospital mortality.”

SCCM journal April 2018. Volume 46. Number 4

TERIMAKASIH