Diagnosing & Managing Sepsis Syndrome: 

Statement of Need

Sepsis kills more than 210,000 Americans each year and is becoming more common, especially in the hospital. Sepsis is a medical emergency that can be difficult to define, diagnose, and treat, but every minute counts in the effort to save lives.

Introduction to Sepsis

Definition, Etiology, Morbidity and Mortality

Definition of Sepsis

• Sepsis

ACCP/SCCM Consensus Conference. Crit Care Med. 1992;20(6):864-74.

– Systemic response to infection

– Manifested by two or more SIRS criteria as a result of proven or suspected infection

• Temperature ≥ 38C or ≤ 36C

• HR ≥ 90 beats/min

• Respirations ≥ 20/min

• WBC count ≥ 12,000/mm3 or ≤ 4,000/mm3

or > 10% bands

• PaCO2 < 32 mmHg

Case Study

Case Study: Mr. Z

• He tells you “My tooth is killing me! You can pull it if you need to. I feel like it is going to explode.”

• His tooth pain is severe and he cameto the emergency department since he could not see his dentist until themorning. He has drainage from tooth #20, for which a culture has been obtained and sent to the lab.

• Mr. Z is a 47 year-old male who was admitted to the emergency department. He is complaining of a toothache that has been present for 7 days.

Case Study: Mr. Z

• He is started on Cefoxitin (Mefoxin®) 2 g IV q6h.

• Mr. Z is alert and oriented.

• He has a history of hypertension and had a hemorrhagic stroke 10 years ago but has had no major health issues since this time.

• His heart and lung sounds are normal and his skin is cool and moist. He has good capillary refill, abdomen soft and non-tender.

Case Study: Mr. Z

Admission

Heart Rate 111

Temperature 38.7

SPO2 0.96

NIBP 128/88 (101)

Respiratory Rate 22

Questions

1) Does Mr. Z have signs of sepsis? Yes

2) What is a blood test that would be useful? Lactate

SPO2: Pulse oximetry oxygen saturation; NIBP: Non-invasive blood pressure

Case Study: Mr. Z

AdmissionHeart Rate 111

Temperature 38.7

SPO20.96

NIBP 128/88 (101)

Respiratory Rate 22

Serum Lactate 3.5

After 20 mg/kg normal saline (10 minutes)

Heart Rate 104

Temperature 38.6

SPO20.96

NIBP 130/88 (102)

Respiratory Rate 22

Case Study: Mr. Z

After 4 Hours

Heart Rate 88

Temperature 38.1

SPO2 0.98

NIBP 133/78 (94)

Respiratory Rate 17

Serum Lactate 1.8

• Often, vital signs are normal when lactates are elevated.

• The use of the lactate allowed the clinician to better evaluate the seriousness of the situation.

• If the lactate had remained elevated, more fluids could have been given.

• A decrease in lactate shows improved perfusion.

Sepsis is Serious.

• Sepsis is a serious medical condition caused by an overwhelming immune response to infection.

http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

• Complex chain of events:

– Inflammatory and anti-inflammatory processes

– Humoral and cellular reactions

– Circulatory abnormalities

• Results in impaired blood flow, which damages organs by depriving them of nutrients and oxygen.

The Intracellular Immune Response to Infection

Adapted from Holmes CL, Russell JA, Walley KR. Chest. 2003;124:1103-15.

Symptoms of Sepsis

• Sepsis can begin in different parts of the body and can have many different symptoms.

• Rapid breathing and a change in mental status, may be the first signs of sepsis.

• Other symptoms include:

– Chills/hypothermia

– Decreased urination

– Tachycardia

– Nausea and vomiting

– Fever

Clinical Manifestations of Shock

Delirium and Encephalopathy

Acute Lung Injury or ARDS Oliguria

Anuria CreatinineMetabolic acidosis

Platelets PT/APTT Protein C D-dimer

Adrenal Dysfunction

Altered Glucose Metabolism

Jaundice Enzymes Albumin PT

Gut Dysfunction

Hyperpyrexia or Hypothermia

ARDS: Acute respiratory distress syndrome; PT: Prothrombin time; APTT: Activated partial thromboplastin time

The Sepsis Continuum

Adapted from Bone RC, Balk RA, Cerra FB et al. Chest. 1992;101:1644-55.

Infection/Trauma

SIRS SepsisSevere Sepsis

A clinical response arising from a nonspecific insult, including ≥ 2 of the following:

• Temperature > 38ºC or < 36ºC

• Heart rate > 90 beats/min

• Respiratory rate > 20 breaths/min or PaCO2 < 32 Torr

• WBC > 12,000 cells/mm3, < 4,000 cells/mm3, or > 10% immature

SIRS with a presumed or confirmed infection

Sepsis with ≥ 1 sign of organ failure:

• Cardiovascular (refractory hypotension)

• Renal

• Respiratory

• Hepatic

• Hematologic

• CNS

• Unexplained metabolic acidosis

Local or systemic infection or traumatic injury

SevereSepsis

Bone RC, Balk RA, Cerra FB et al. Chest. 1992;101:1644-55.

Trauma

Infection

SepsisOther

Pancreatitis

Burns

SIRS

The Relationship Between SIRS, Sepsis, and Severe Sepsis

Locations for Common Infection

Lungs

Urinary Tract

Abdomen

Vascular Catheters(endovascular)

Appendix

http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

Skin and soft tissue

Microbes

• Many different types of microbes can cause sepsis:

http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

CDC/ Matthew J. Arduino CDC/ Robert Simmons

Staphylococcus sp. (Bacteria) Aspergillus sp. (Fungi) Influenza (Virus)

CDC/ Erskine. L. Palmer, PhD; M. L. Martin

• Severe cases often result from a localized infectionbut sepsis can also spread throughout the body.

– Bacteria (most common)

– Fungi

– Viruses

Mortality Rates

• Sepsis remains the leading cause of death in critically ill patients in the United States.

• Each year 750,000 people will develop sepsis.

Angus DC, Linde-Zwirble WT, Lidicker J et al. Crit Care Med. 2001;29(7):1303-10.

National Center for Health Statistics, 2001. American Cancer Society, 2001.

0

50,000

100,000

150,000

200,000

250,000

Dea

ths

Per

Year

AIDS SevereSepsis

Breast Cancer

Sepsis Incidence in Men and Women

Martin GS et al. N Engl J Med. 2003;348:1546-54.

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001

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Martin GS, Mannino DM, Eaton S et al. N Engl J Med. 2003;348:1546-54.

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001

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300

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Sepsis Incidence by Race

Sepsis Incidence in the United States: 2000

Martin GS, Mannino DM, Eaton S et al. N Engl J Med. 2003;348:1546-54. SEER Cancer Statistics Review. National Cancer Institute. www.cancer.gov. 2007. HIV/AIDS Surveillance Report. Centers for Disease Control. 2001;11.Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. NHLBI, NIH. 2006. Turabelidze G. J Neurol Sci. 2008;269:158-62.

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Sepsis Morbidity and Mortality

• In severe cases, one or more organs fail.

http://www.nigms.nih.gov/Education/factsheet_sepsis.htm

• Worst case scenario:– Blood pressure drops

– Septic shock

– Multiple organ system failure

– Death

• The number of sepsis cases per year has been on the rise:

– Aging population, the increased longevity of people with chronic diseases, the spread of antibiotic-resistant organisms, an upsurge in invasive procedures and broader use of immunosuppressive and chemotherapeutic agents.

How Do I Decide Who is Really Sick With an Infection?

Sepsis Biomarkers

Use in Diagnosis, Risk, and Response

Utility of Biomarkers

1. Diagnosis/differentiation

– Value of baseline

2. Prognostication

– Value of change over time

3. Following success/failure of therapy

Diagnosis of Sepsis

• Bacteria in the blood or other body fluids

– Source of the infection

– A high or low white blood cell count

– A low platelet count

– Low blood pressure

– Too much acid in the blood (acidosis)

– Altered kidney or liver function 

• Biomarkers

• Diagnosis of sepsis and evaluation of its severity is complicated by the highly variable and non-specific nature of signs and symptoms.

Sepsis Biomarkers: Screening

Lever A, Mackenzie I. Br Med J. 2007;335:879–83.

• Distinguishing patients with localized infections or SIRS from those with sepsis is challenging.

• SIRS is not specific to sepsis and can result from other conditions such as acute pancreatitis and immunodeficiencies.

• Biomarkers of sepsis may improve diagnosis and therapeutic decision making.

Sepsis Biomarkers

• More than 170 biomarkers have been assessed for sepsis prognosis and diagnosis

Pierrakos C, Vincent JL. Crit Care. 2010,14:R15.

• Some common biomarkers include:

– White blood cell count

– Procalcitonin (PCT)

– Procoagulant factors– Lactate

– Interleukins and other cytokines

– C-reactive protein (CRP)

Lactic Acidosis

Mizock BA, Falk JL. Crit Care Med. 1992;20:80-95.

Glycogen

Glucose Pyruvate

Lactate

CitricAcidCycle

CO2

H2O

(Cytoplasm) (Mitochondria)

Anaerobic Glycolysis

1 Glu + 2 ADP + 2 Pi

2 Lactate + 2 ATP

1 Glu + 6 O2 + 38 ADP + 38 Pi

6 CO2 + 6 H20 + 38 ATP

O2

Aerobic Glycolysis

Diagnostic and Therapeutic Markers

SvO2

60-80% Normal

50% Lactic Acidosis (≥ 4 mmol/L)

80

60

40

38-40%

28 day in-hospital mortality Death within 3 days

Lactate1

30

25

20

15

10

5

00-2.4 2.5-3.9 > 4.0

% o

f M

ort

alit

y R

ate

% o

f M

ort

alit

y R

ate

0-2.4 2.5-3.9 > 4.0N = 827 N = 238 N = 112

Initial Lactate (mmol/L)2

50

40

30

20

10.0

0.0

Serum Lactate as a Predictor of Mortality

1 Trzeciak S, Dellinger RP, Chansky ME et al. Intensive Care Med. 2007;33:970-7.2 Shapiro NI, Howell MD, Talmor D et al. Ann Emerg Med. 2005; 45:524-8.

28%

Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

Serum Lactate as a Predictor of Mortality

Mea

n L

acta

te L

evel

(m

mo

l/L)

7

6

5

4

3

2

1

0

Arrival Scene (T1) Emergency Department (T2)

Non-survival

Survival

p = 0.001p < 0.001

Adapted from Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

8/66 (12%)

Mortality

24/58 (41%)

Mortalityp < 0.001

7 Missing (4 Died)

11 Missing (0 Died)

First Lactate Measurement

Second Lactate Measurement

N = 55

8/54 (15%)

Mortality

0/1(0%)

Mortality

p = 1.00

N = 51

2/14 (14%)

Mortality

18/37(49%)

Mortality

p = 0.025

N = 106

10/68 (15%)

Mortality

18/38 (47%)

Mortalityp < 0.001

N = 124

< 3.5 mmol/l ≥ 3.5 mmol/l

< 3.5 mmol/l ≥ 3.5 mmol/l < 3.5 mmol/l ≥ 3.5 mmol/l

< 3.5 mmol/l ≥ 3.5 mmol/l

Second Lactate Cumulative

Value of Blood Lactate Levels

Jansen TC, van Bommel J, Mulder PG et al. Crit Care. 2008,12:R160.

Mo

rtal

ity

(%)

SBP (mmHg)

Lactate (mmol/l)< 100

> 100

> 3.5

< 3.5

60

50

40

30

20

10

0

Lactate, SBP, and Mortality

Serum Lactate and Mortality in Severe Sepsis

• Initial serum lactate evaluated in 839 adults admitted with severe sepsis.

Mikkelsen ME, Miltiades AN, Gaieski DF et al. Crit Care Med. 2009;37:1670-7.

Low Int High

ShockNon-Shock

28-D

ay M

ort

alit

y (%

)

50

45

40

35

30

25

20

15

10

5

0

p < 0.001

p = 0.001

p = 0.022

p = 0.024• High initial serum

lactate associated with ↑ mortality regardless of presence of shock or MODS.

Low Int High

Improving Lactate a Good Prognostic Sign

Bakker J, Gris P, Coffernils M et al. Am J Surg. 1996;171:221-6.

8

6

4

2

0

INITIAL +8h +16h +24h FINAL

Time

La

cta

te (

mm

ol/L

)

Survivors

Non-survivorsp < 0.05

p < 0.05p < 0.01

You have to go to the disease instead of waiting for it to come to you!

Hospital Origin and Mortality

Origin Mortality

Surviving Sepsis Campaign. http://ssc.sscm.org.

ED 52.4% 27.6%

ICU 12.8% 41.3%

Wards 34.8% 46.8%

Risk Stratification of Sepsis

Surviving Sepsis Campaign. http://ssc.sscm.org.

Hypotension, vasopressors 36.7%

Lactate > 4 mmol/L only 30.0%

SBP < 90 mmHg and lactate > 4 mmol/L 46.1%

Sepsis Testing and Results

Guidelines, Algorithms, and Protocols

• Blood gases

Factors to Consider When Evaluating Sepsis

• Electrolytes

• Glucose

• Hematocrit

• Lactate

Sepsis Resuscitation Bundle

The Sepsis Resuscitation Bundle is published by the Surviving Sepsis Campaign and is used by multiple hospitals across the country.

The goal is to perform all indicated tasks 100% of the time within the first 6 hours of identification of severe sepsis.

Surviving Sepsis Campaign. http://ssc.sscm.org.

Sepsis Resuscitation Bundle

Surviving Sepsis Campaign. http://ssc.sscm.org.

3. Administer broad-spectrum antibiotic, within 3 hours of emergency department (ED) admission and within 1 hour of non-ED admission.

2. Obtain blood cultures prior to antibiotic administration.

1. Measure serum lactate.

4. In the event of hypotension and/or a serum lactate > 4 mmol/L:a. Deliver an initial minimum of 20 ml/kg of crystalloid or an equivalent.

b. Apply vasopressors for hypotension not responding to initial fluid resuscitationto maintain mean arterial pressure (MAP) > 65 mmHg.

5. In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L:a. Achieve a central venous pressure (CVP) of > 8 mmHg.

b. Achieve a central venous oxygen saturation (ScvO2) > 70% or mixed venous oxygen saturation (SvO2) > 65%.

Sepsis Treatment Guidelines

• Antibiotic therapy

Surviving Sepsis Campaign. http://ssc.sscm.org.

– Begin intravenous antibiotics as early as possible

• Always within the first hour of recognizing severe sepsis (1D) and septic shock. (1B)

– Broad-spectrum

• One or more agents active against likely bacterial/fungal pathogens and with good penetration into presumed source. (1B)

– Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, & minimize costs. (1C)

– Consider combination therapy in Pseudomonas infections. (2D)

Sepsis Treatment Guidelines

• Antibiotic therapy

Surviving Sepsis Campaign. http://ssc.sscm.org.

– Consider combination empiric therapy in neutropenic patients. (2D)

– Combination therapy no more than 3-5 days and de-escalation following susceptibilities. (2D)

– Duration of therapy typically limited to 7-10 days

• Longer if response slow, undrainable foci of infection, or immunologic deficiencies. (1D)

– Stop antimicrobial therapy if cause is found to be non-infectious. (1D)

Applications

Identification, Treatment, and Outcomes

Are any two of the following SIRS criteria present and new to the patient?

Heart rate > 90 beats/min Respiratory rate > 20/min

Temperature < 36.0 or > 38.3C Acutely altered mental state

Blood glucose > 7.7 mmol/L (in absence of diabetes) White cell count < 4 or > 12 x 109/L

Is there a clinical suspicion of new infection?

Cough/sputum/chest pain Dysuria

Abdominal pain/distension/diarrhea Headache with neck stiffness

Line infection Cellulitis/wound/joint infection

Endocarditis

Is there evidence of any organ dysfunction?

Systolic BP < 90/mean < 65 mmHg Urine output < 0.5 mL/kg/h for 2 h

Lactate > 2 mmol/L after initial fluids Creatinine > 177 umol/L

INR > 1.5 or aPTT > 60 s Platelets < 100 x 109/L

Bilirubin > 34 umol/L SpO2 > 90% unless O2 given

Identification of Sepsis

If YES, patient has SIRS

If YES, patient has Sepsis

If YES, patient has Severe Sepsis

Daniels R. J Antimicrob Chemother. 2011;66(Suppl 2):ii11–ii23.

Improve Patient Outcomes

• Lactate clearance is associated with improved patient outcome.

Nguyen HB, Rivers EP, Knoblich BP et al. Crit Care Med. 2004;32(8):1637-42.Afessa B, Keegan MT, Schramm GE et al. Crit Care Med. 2011;15(Suppl 1): P286. Boldt J, Kumle B, Suttner S et al. Acta Anaesthesiol Scand. 2001;45:194–9.

• Lactate measurement is associated with increased risk of death independent of other aspects of sepsis bundle guidelines.