Sepsis &Septic Shock
Mario M. Panaligan, MD, FPCP, FPSMID
REFERENCES • Harrison’s Principles of Internal Medicine, 17th ed
– Severe Sepsis and Septic Shock (Chapter 265, pp. 1695-1702)– Treatment and Prophylaxis of Bacterial Infections (Chapter 127, pp.
851-864)– Antiviral Chemotherapy, Excluding Antiretroviral Drugs (Chapter
171, pp. 1087-1095)– Diagnosis and Treatment of Fungal Infection (Chapter 191, pp.
1242-1244)– Agents Used to Treat Parasitic Infections (Chapter 201, pp. 120-
1275)
Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Med 2008; 36 (1): 296-327
“Sepsis is a disease of
medical progress…”
SEPSIS
• 10th leading cause of death in the US • Estimated 751, 000 cases of severe sepsis
each year in the US– With a mortality rate of 28.6% and an annual cost
of US$16.7 billion
• Worldwide, 18 million cases of severe sepsis occur annually, killing approximately 1400 people each day and incurring a healthcare cost of US$9.4 billion in Europe alone
Nguyen HB, Rivers EP. The Clinical Practice of Early Goal-Directed Therapy in Severe Sepsis and Septic Shock. Adv Sepsis 2005;4(4):126–33.
Sepsis
• Prospective observational study at UP-PGH in 1998 involving 1,270 patients– Prevalence rate: 25%– Mortality rate: 34%
• Sepsis-related: 77%• Septic shock: 42%
Alejandria MM, Phil J Microbiol Infec Dis, 2000
Risk Factors for Progressing to Severe Sepsis and Poor Outcome
Progression RR
Physiologic variables 1.45
Pneumonia 1.47
Abdominal Infection 1.51
Primary bacteremia 1.81
Aerobic gram - bacilli 1.38
Outcome RR
Initial Severity 1.41
Renal dysfunction 1.31
ICU-acquired Infection 1.53
Aerobic gram - bacilli 1.49
Alberti C et al. Am J Respir Crit Care Med 2005; 171: 461Alberti C et al. Am J Respir Crit Care Med 2003; 168: 77
SIRSSIRS
OtherOther
TraumaTrauma
BurnsBurnsSEPSISSEPSIS
INFECTIONINFECTION
BacteremiaBacteremia
FungemiaFungemia
ParasitemiaParasitemia
ViremiaViremia
OthersOthers PancreatitisPancreatitis
• A clinical response arisingfrom a nonspecific insult, including 2 of the following:
– Temperature >38oC or <36oC
– HR >90 beats/min– Respiratory rate >20/min
or PaCO2 < 32 mmHg– WBC count >12,000/mm3
or <4,000/mm3 or >10% immature neutrophils
SIRS = systemic inflammatory response SIRS = systemic inflammatory response syndrome.syndrome.
Bone et al. Bone et al. Chest.Chest. 1992;101:1644. 1992;101:1644.
SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis
SIRS = systemic inflammatory response SIRS = systemic inflammatory response syndrome.syndrome.
• SIRS with a presumed or
confirmed infectious process
SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis
Bone et al. Chest. 1992;101:1644.
• A clinical response arisingfrom a nonspecific insult, including 2 of the following:
– Temperature >38oC or <36oC
– HR >90 beats/min– Respiratory rate
>20/min or PaCO2 < 32 mmHg
– WBC count >12,000/mm3 or <4,000/mm3 or >10% immature neutrophils
Bone et al. Bone et al. Chest.Chest. 1992;101:1644; Wheeler and Bernard. 1992;101:1644; Wheeler and Bernard. N Engl J MedN Engl J Med. 1999;340:207. . 1999;340:207.
SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis
• Sepsis with ≥1 sign of organ failure
– Cardiovascular (refractory hypotension)
– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic
acidosis
ShockShock
Severe Sepsis
WITH
Hypoperfusion abnormalities
AND
Persistent Hypotension
Despite adequate fluid resuscitation
Bone RC, Chest 1992;101:1644-1655 Rangel-Frausto M, JAMA, 1995; 273: 117
SEPTIC SHOCKSEPTIC SHOCK
SEPTIC SHOCK
PLUS
Altered organ function
such that homeostasis cannot be
maintained without intervention
Bone RC, Chest 1992;101:1644-1655 Rangel-Frausto M, JAMA, 1995; 273: 117
MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS)
MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS)
Multiple Organ Dysfunction Multiple Organ Dysfunction Syndrome (MODS)Syndrome (MODS)
SEPTIC SHOCKSEPTIC SHOCK
SEPSIS-INDUCEDSEPSIS-INDUCEDHYPOTENSIONHYPOTENSION
SEVERE SEVERE SEPSIS SEPSIS
SEPSISSEPSIS
Sepsis: A Disease Continuum
PathogenesisTrigger (organism-derived, e.g. endotoxin)
Release of tumor necrosis factor α / other proinflammatory cytokines
Inflammatory cascade
Hypothalamus Capillary endothelial cell Vessel wall
FeverTachycardiaTachypnea
Neutrophil migrationPlatelet adherence
DICDepletion of intravascular vol
Nitric oxide synthesis
Vasodilatation
Cellular hypoxia
Organ dysfunction/hypoperfusion HypotensionDeath
Signs and symptoms suggestive of sepsis
• Primary– Fever and chills– Hypothermia– Hyperventilation– Skin lesions– Change in mental
status
• Complications– Hypotension– Bleeding– Leukopenia– Organ failure
• Lungs: cyanosis, acidosis
• Kidney: oliguria, acidosis
• Heat: congestive heart failure
Management of Patients with Sepsis
DIAGNOSTIC WORK-UP
• HISTORY• Thorough PE
– Search for source/s of infection– Identify signs of systemic organ dysfunction
• Diagnostic tests– Ancillary laboratory exams
• ABGs, Renal and liver function tests, CBC
– Appropriate microbiologic examinations• Specimens are obtained before antibiotic therapy• Consideration for immediate administration of antibiotic/s
Dellinger RP, et al. Crit Care Med, 2008
Biomarkers of sepsis?
• Utility?– Ability to influence or affect a
diagnostic or therapeutic decision• To identify a subgroup of patients who
are more likely to benefit from a given intervention and to maximize clinical benefit of that therapy
To predict response to therapy
Biomarkers of sepsis?
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
The PIRO Model
Marshall JC, Current Infect Dis Reports 2006, 8: 351Levy MM, Intensive Care Med 2003, 29: 530
Surviving Sepsis Campaign: International Guidelines for
Management of Severe Sepsis and Septic Shock: 2008
Dellinger RP, Levy MM, Carlet JM, et al. Critical Care Med 2008; 34: 17-60.
Issues in Improving Outcome of Patients with Severe Sepsis
• The surviving sepsis guidelines– Early goal-directed therapy (EGDT)
– Low-dose intravenous steroids
– Strict blood glucose level control
– Recombinant activated protein C
– Appropriate early antimicrobial therapy
Dellinger RP et al. Crit Care Med 2008; 32, Suppl
GRADE System of Recommendations
• Quality of Evidence (Grade)– A (High quality): RCT– B (Moderate): Downgraded RCT or upgraded
observational studies– C (Low): Well done observational studies– D (Very Low): Case series or expert opinion
• Strength of Recommendation– 1: Strong– 2: Weak
CURRENT MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK
• Immediate stabilization procedures
• Definitive therapeutic intervention
Dellinger RP, et al. Crit Care Med, 2008
Recognition Initial Resuscitation
Diagnosis ManagementSupportive Management
INITIAL RESUSCITATION
INITIAL RESUSCITATION
• First 6 hours– Begin resuscitation immediately in patients with
hypotension or elevated serum lactate >4mmol/l; do not delay pending ICU admission (1C)
– Resuscitation goals: (1C) • Central venous pressure (CVP) 8 - 12 mm Hg • Mean arterial pressure > 65 mm Hg• Urine output > 0.5 mL/kg/hr• Central venous (superior vena cava) oxygen saturation >
70%, or mixed venous > 65%
Dellinger RP, et al. Crit Care Med, 2008
IMMEDIATE STABILIZATION
• Reversal of life-threatening abnormalities• Special attention for the ABCs
– Airway protection for patients with depressed level of consciousness
• MV support
– Circulatory support to optimize organ perfusion• Aggressive fluid management• Inotropics or vasopressors when necessary• Hemodynamic monitoring • Urine output
Dellinger RP, et al. Crit Care Med, 2008
FLUID THERAPY
• Fluid-resuscitate using crystalloids or colloids (1B)– Target a CVP of > 8 mmHg (>12 mmHg if
mechanically ventilated) (1C)– Use a fluid challenge technique while associated
with hemodynamic improvement (1D)• Give fluid challenges of 1000 ml of crystalloids or 300-
500 ml of colloids over 30 minutes
– Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement (1D)
Dellinger RP, et al. Crit Care Med, 2008
VASOPRESSORS / INOTROPIC SUPPORT
• Maintain MAP > 65mmHg (1C)• Norepinephrine (NE) or dopamine (DOP)
centrally administered are the initial vasopressors of choice (1C)
• Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock (2C)– Use epinephrine as the first alternative agent in
septic shock when BP is poorly responsive to NE or DOP (2B)
Dellinger RP, et al. Crit Care Med, 2008
VASOPRESSORS / INOTROPIC SUPPORT
• Use dobutamine (DOB) in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output (1C)
• Do not increase cardiac index (CI) to predetermined supranormal levels (1B)
• Do not use low-dose dopamine for renal protection (1A)
• In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D)
Dellinger RP, et al. Crit Care Med, 2008
DIAGNOSIS AND MANAGEMENT
DIAGNOSIS
• Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C)– Obtain two or more blood cultures (BCs)
• One or more BCs should be percutaneous • One BC from each vascular access device in place > 48
hours
– Culture other sites as clinically indicated– Perform imaging studies promptly in order to
confirm; and– Sample any source of infection; if safe to do so
Dellinger RP, et al. Crit Care Med, 2008
Antimicrobial Therapy
• Mainstay of treatment for patients with infection and sepsis
Dellinger RP, et al. Crit Care Med, 2008
EMPIRIC ANTIMICROBIAL THERAPY
• Broad-spectrum– Selection based on the presumed site of infection
and the likely pathogens involved• Gram stain result if available• Local susceptibility patterns
– To be started within an hour after performance of important microbiologic exams
• Other factors to consider include– Host’s immune status– Allergies– Renal or hepatic dysfunction
Dellinger RP, et al. Crit Care Med, 2008
Definitive Antibiotic Therapy
• Pathogen-directed
• Pharmacokinetic – pharmacodynamic properties of the antibiotic
• Site of Infection
Dellinger RP, et al. Crit Care Med, 2008
PREDICTORS OF POOR OUTCOME
• Age
• Severity of the underlying condition
• Presence of complications at the onset of treatment
• Grade (severity) of bacteremia
• Source of infection
• Inappropriate antimicrobial therapy
Mandell GL, Principles of Infectious Diseases, 2005
Impact of Inadequate Antibiotic Treatment on All-Cause Mortality
• All-cause mortality: more than twice as high among patients who received inadequate antibiotic treatment compared to those who received adequate antibiotic treatment
52.1
23.5
-5
5
15
25
35
45
55
65
All-cause Mortality (%)
P<0.001
Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality. Chest 1999; 115: 462-474
Inadequate AntibioticTreatment
(n=169 patients)
Adequate AntibioticTreatment
(n=486 patients)
• Infection-related mortality: more than twice as high among patients who received inadequate antibiotic treatment compared to those who received adequate antibiotic treatment
Impact of Inadequate Antimicrobial Treatment on Infection-related Mortality
Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality. Chest 1999; 115: 462-474
42
17.7
05
10
1520253035
404550
Infection-related Mortality (%)
P<0.001
Adequate AntibioticTreatment
(n=486 patients)
Inadequate AntibioticTreatment
(n=169 patients)
Risk factors for mortality
• Non-modifiable– Presence of
malignancy– Severe underlying
condition (High MSOF and MPM scores)
– Gram-negative bacteremia
• Modifiable– Inappropriate
antimicrobial therapy– Use of alternative
antibiotics– Nosocomial
acquisition of infection
Alejandria MM, Phil J Microbiol Infect Dis, 2000
Timing of antimicrobial therapy• Review of 3 cohorts of adult patients with septic shock
(N=2731)– 58% community-acquired; 42% nosocomial– Documented infection seen in 78%
• 50% received effective antimicrobial treatment within 6 hours of documented hypotension
– Overall mortality was 56%– Survival rate: 82.7% in patients receiving effective
antimicrobials within 30 minutes VS 42% in patients receiving antimicrobials 6 hours after the onset of septic shock
• Mean 7.6% decrease in survival for every hour of delay in the initiation of antibiotic therapy
Kumar A, Crit Care Med 2006; 34: 1589
Source Control
• Definite identification of site of infection– Drainage of an abscess or local focus of
infection– Debridement of infected necrotic tissue– Removal of a potentially infected device– Definitive control of a source of ongoing
microbial contamination
Dellinger RP, et al. Crit Care Med, 2008
Sou
rce
Con
trol
Source Control Technique
Examples
DRAINAGE Intraabdominal abscess
Thoracic empyema
Septic arthritis
Cholangitis
DEBRIDEMENT Necrotizing fasciitis
Infected pancreatic necrosis
Intestinal infarction
Mediastinitis
DEVICE REMOVAL Infected vascular catheter
Urinary catheter
Colonized endotracheal tube
Infected intrauterine contraceptive device
DEFINITIVE CONTROL
Sigmoid resection for diverticulitis
Cholecystectomy for gangerenous cholecystitis
Amputation for clostridial myonecrosis
Supportive ManagementAdjunctive Measures
Glucose Control
• Use of IV insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B)– Aim to keep blood glucose < 8.3 mmol/L (150
mg/dl) using a validated protocol for insulin dose adjustment (2C)
– Provide a glucose calorie source and monitor blood glucose values every 1-2 hrs (4 hrs when stable) in patients receiving IV insulin (1C)
Dellinger RP, et al. Crit Care Med, 2008
Renal Replacement and Bicarbonate Therapy
• Intermittent hemodialysis (HD) and continuous veno-venous hemofiltration (CVVH) are considered equivalent (2B)
• CVVH offers easier management in hemodynamically unstable patients (2D)
• Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-induced lactic acidemia with pH > 7.15 (1B)
Dellinger RP, et al. Crit Care Med, 2008
Use of Steroids• Do not use steroids to treat sepsis in the absence
of shock unless the patient’s endocrine or hydrocortisone history warrants it (1D)
• IV hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressors (2C)– Hydrocortisone dose is usually < 300 mg/day (1A)– Hydrocortisone is preferred to dexamethasone (2B)– Fludrocortisone (50 ug orally OD) may be included if an
alternative is being used which lacks significant mineralocorticoid activity (2C)
Dellinger RP, et al. Crit Care Med, 2008
Annane D, BMJ Aug 2004
Use of Steroids
• Meta-analysis of 16 trials (n=2063) on the effects of corticosteroids on mortality in patients with severe sepsis or septic shock– Analysis of 15 trials (n=2022)
• No reduction of all cause mortality in 28 days (RR=0.92, 95% CI 0.75, 1.14)
– Subgroup analysis of 5 trials (long duration > 5 days and low dose corticosteroid therapy)
• All cause mortality: RR=0.8, 95% CI 0.67, 0.95)
• ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone (2B)
• Steroid therapy may be weaned once vasopressors are no longer required (2D)
Use of Steroids
Dellinger RP, et al. Crit Care Med, 2008
DVT prophylaxis
• Use either low dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contraindicated (1A)
• Use a mechanical prophylactic device such as compression stockings or an intermittent compression device, when heparin is contraindicated (1A)
• Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for DVT (2C)
• In patients at very high risk, LMWH should be used rather than UFH (2C)
Dellinger RP, et al. Crit Care Med, 2008
Stress Ulcer Prophylaxis
• Provide stress ulcer prophylaxis using H2 blocker (1A) or PPI (1B)* Benefits of preventing UGIB must be
weighed against the potential for development of VAP
Dellinger RP, et al. Crit Care Med, 2008
Blood Product Administration
• Give red blood cells when hgb decreases to < 7 g/dl to target a hgb of 7-9 g/dl in adults (1B)
• Do not use erythropoietin to treat sepsis-related anemia (1B)
Dellinger RP, et al. Int Care Med, 2008
Blood Product Administration
• Only when bleeding leads to hemodynamic compromise
• Potential deleterious effects– Increased viscosity impede blood flow– Decreased unloading of oxygen due to reduced 2,3-DPG
levels in transfused cells– Tissue ischemia due to decreased deformability of
transfused cells– Depress immune status
• No difference in outcome between patients maintained on Hgb levels > 7 g/dl OR 10 g/dl
(Herbert PC, JAMA 1995; 273:1439)
Blood Product Administration
• Do not use FFP to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures (2D)
• Do not use antithrombin therapy (1B)• Administer platelets when: (1B)
– Counts are < 5,000/mm3 regardless of bleeding– Counts are 5,000 to 30,000/mm3 and there is
significant bleeding risk– Higher platelet counts > 50,000/mm3 are typically
required for surgery or invasive procedures
Dellinger RP, et al. Crit Care Med, 2008
Drotrecogin alfa activated (recombinant activated protein C)
• Significantly reduced mortality in patients with severe sepsis (30.8% vs 24.7%) based on an RCT involving 1690 patients– Higher rate of serious bleeding (3.5% vs 2 %)
• Recommended in patients at high risk of death (APACHE II 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced ARDS) and no absolute contraindication related to bleeding risk (2B; 2C for post-operative patients)
• Adult patients with severe sepsis and low risk of death should not receive rhAPC (1A)
Dellinger RP, et al. Crit Care Med, 2008
Prevention of Sepsis
Preventive Measures
• Appropriateness of the antibiotics
Mandell GL, Principles of Infectious Diseases, 2005
Preventive Measures
• Risk identification
• Modify host factors for infection– Control underlying illness– Improve immune status through
immunization
EBCPG, ASCO, J Clin Oncol 1996; 14: 1957 Mandell GL, Principles of Infectious Diseases, 2005
Preventive Measures
• Prevent acquisition or transmission of pathogens– Adherence to infection control policies– Appropriate isolation procedures– Chemoprophylaxis for high risk individuals
Mandell GL, Principles of Infectious Diseases, 2005
SUMMARY
• Early clinical suspicion• Assessment of disease severity• Rigorous diagnostic work-up• Immediate administration of appropriate
antibiotic therapy• Comprehensive supportive care• Preventive measures particularly for high risk
individuals
Top Related