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
300
200
100
0
MenWomen
Po
pu
lati
on
-Ad
just
ed I
nci
den
ce
of
Sep
sis
(No
./10
0,00
0)
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
OtherBlackWhite
Po
pu
lati
on
-Ad
just
ed I
nci
den
ce
of
Sep
sis
(No
./10
0,00
0)
500
400
300
200
100
0
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.
0
50
100
150
200
250
Sepsis BreastCancer
AcuteMyocardial
Infarction
MultipleSclerosis
LungCancer
ColonCancer
AIDS
Inci
den
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er 1
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00
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.
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