Transcript Sepsis & Nosocomial Infections

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. 16951702)
– 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 UPPGH 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
Outcome
RR
Physiologic variables
1.45
Initial Severity
1.41
Pneumonia
1.47
Renal dysfunction
1.31
Abdominal Infection
1.51
ICU-acquired Infection
1.53
Primary bacteremia
1.81
Aerobic gram - bacilli
1.49
Aerobic gram - bacilli
1.38
Alberti C et al. Am J Respir Crit Care Med 2005; 171: 461
Alberti C et al. Am J Respir Crit Care Med 2003; 168: 77
Bacteremia
Other
Fungemia
Trauma
INFECTION
Parasitemia
SIRS
SEPSIS
Burns
Viremia
Others
Pancreatitis
Infection/
Trauma
SIRS
• A clinical response
arising
from 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
syndrome.
Bone et al. Chest. 1992;101:1644.
Sepsis Severe Sepsis
Infection/
Trauma
SIRS
• A clinical response arising
from 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
Sepsis Severe Sepsis
• SIRS with a
presumed or
confirmed
infectious
process
SIRS = systemic inflammatory response
syndrome.
Bone et al. Chest. 1992;101:1644.
Infection/
Trauma
SIRS
Sepsis Severe Sepsis
• Sepsis with ≥1 sign of
organ failure
– Cardiovascular (refractory
hypotension)
– Renal
– Respiratory
– Hepatic
– Hematologic
– CNS
– Unexplained metabolic
acidosis
Shock
Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.
SEPTIC SHOCK
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
MULTIPLE ORGAN DYSFUNCTION
SYNDROME (MODS)
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
SEPSIS
SEVERE
SEPSIS
SEPSIS-INDUCED
HYPOTENSION
SEPTIC SHOCK
Multiple Organ Dysfunction
Syndrome (MODS)
Sepsis: A Disease Continuum
Pathogenesis
Trigger (organism-derived, e.g. endotoxin)
Release of tumor necrosis factor α / other proinflammatory cytokines
Inflammatory cascade
Hypothalamus
Capillary endothelial cell
Fever
Tachycardia
Tachypnea
Neutrophil migration
Platelet adherence
DIC
Depletion of intravascular vol
Vessel wall
Nitric oxide synthesis
Vasodilatation
Cellular hypoxia
Death
Organ dysfunction/hypoperfusion
Hypotension
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?
The PIRO Model
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Marshall JC, Current Infect Dis Reports 2006, 8: 351
Levy 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
Supportive Management
Diagnosis 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 300500 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
65
All-cause Mortality (%)
55
P<0.001
52.1
45
35
23.5
25
15
5
-5
Inadequate Antibiotic
Treatment
(n=169 patients)
Adequate Antibiotic
Treatment
(n=486 patients)
Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for
hospital mortality. Chest 1999; 115: 462-474
• All-cause mortality: more than twice as high among
patients who received inadequate antibiotic treatment
compared to those who received adequate antibiotic
treatment
Infection-related Mortality (%)
Impact of Inadequate Antimicrobial
Treatment on Infection-related Mortality
50
45
40
35
30
25
20
15
10
5
0
P<0.001
42
17.7
Inadequate Antibiotic
Treatment
(n=169 patients)
Adequate Antibiotic
Treatment
(n=486 patients)
Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for
hospital mortality. Chest 1999; 115: 462-474
• Infection-related mortality: more than twice as high
among patients who received inadequate antibiotic
treatment compared to those who received adequate
antibiotic treatment
Risk factors for mortality
• Non-modifiable
• Modifiable
– Presence of
malignancy
– Severe underlying
condition (High
MSOF and MPM
scores)
– Gram-negative
bacteremia
– 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
Source Control
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
Management
Adjunctive 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
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)
Annane D, BMJ Aug 2004
Use of Steroids
• 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)
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 2,3DPG 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 postoperative 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
Mandell GL, Principles of Infectious Diseases, 2005
EBCPG, ASCO, J Clin Oncol 1996; 14: 1957
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