SIRS and Severe Sepsis

1
SIRS and Severe Sepsis

• Mark M. Huycke, M.D.
• Professor of Medicine
• Infectious Diseases Section
• Department of Internal Medicine, and
• Chief of Staff
• Dept. of Veterans Affairs Medical Center

May 2013
2
Definitions

• Infection
• Inflammatory response to pathogenic or
  potentially pathogenic (e.g., commensals)
  microorganisms at normally sterile host tissues
• Bacteremia
• Presence of viable bacteria in the blood
• Systemic inflammatory response syndrome (SIRS)
• Widespread inflammatory response to a variety of
  severe clinical insults
• temperature gt38oC or lt36oC
• heart rate gt90 beats/min
• hyperventilation with rate gt20 bpm or pCO2 lt32
  mmHg
• WBC gt12,000 cells/mm3, lt4000 cells/mm3, or gt10
  bands

3
Definitions

• Sepsis
• SIRS caused by an infection (not necessarily
  bacteremia)
• Severe sepsis
• sepsis with organ dysfunction (e.g., CNS,
  cardiovascular, pulmonary, renal, hematological
  or metabolic)
• Septic shock
• sepsis with hypotension/hypoperfusion despite
  adequate fluid resuscitation
• lactic acidosis, oliguria, or acute alteration in
  mental status
• Multiple organ failure (MOF)
• at the end of spectrum of severity

4
Definitions

• Clinical continuum
• Incidence of positive blood cultures increases
  down the continuum
• 17 with sepsis to 69 with septic shock
• Mortality rate within a category is not
  influenced by culture results
• Mortality rate increases progressively down the
  continuum
• 7 with SIRS alone
• 16 with sepsis
• 20 with severe sepsis
• 46 with septic shock

Am J Respir Crit Care Med 1996 Sep154(3 Pt
1)617-24
5
Diagnostic Criteria for Sepsis

• infection (documented or suspected) and some of
  the following
• inflammatory measures (leukocytosis, leukopenia,
  fever, hypothermia)
• tachycardia
• tachypnea
• altered mental status
• hemodynamic instability (hypotension, hypoxemia,
  acute oliguria, hyperbiliruginemia,
  hyperlactatemia, decreased capillary refill or
  mottling)
• coagulopathy (thrombocytopenia, elevated INR or
  PTT, DIC)
• ileus

Intensive Care Med 200329530-8.
6
Epidemiology
Population-adjusted incidence of sepsis by gender
and race
N Engl J Med 2003 3481546-54.
7
Epidemiology
No. of cases of sepsis in U.S. by etiology
N Engl J Med 2003 Apr 17348(16)1546-54.
8
Common Sites of Infection in Severe Sepsis
N Engl J Med 1997336912-8
9
Pathogenesis

• Loss of balance between pro-inflammatory and
  anti-inflammatory elements, leading to remote and
  systemic inflammation
• exaggeration of normal inflammatory responses
• uncontrolled, unregulated, and self-sustaining
• blood-borne spread

10
Pathogenesis

• microcirulatory and mitochondrial dysfunction
• activation and injury to vascular endothelium
• demargination of neutrophils gt leukocytosis
• circulating cytokines and mediators
• pro-inflammatory TNF, IL-1b, IL-6, IL-12, etc.
• anti-inflammatory IL-4, IL-10, IL-1Ra, etc.
• complement activation and coagulopathy
• bacterial virulence factors

11
Bacterial virulence factors leading to shock

• Streptococcus pyogenes
• pyrogenic exotoxins (speA and speC)
• Staphylococcus aureus
• pyrogenic exotoxins (e.g., TSST)
• Gram-negative bacilli (e.g., GNRs like E. coli,
  Neisseria meningitidis)
• lipid A in lipopolysaccharide (i.e., endotoxin)

12
Lipid A in LPS activates cells via Toll-like
receptor 4 (TLR4), MD-2 and CD14 on the cell
surface and acts as potent stimulant for innate
immunity.
Lipid A (component of LPS)
13
TCR a
MHC ß
TCR ß
MHC a
speA
FEBS J 2784649-7, 2011
14
Classification of Shock

• Hypovolemic shock
• Decreased preload
• Cardiogenic shock
• Pump failure
• Distributive (vasodilatory) shock
• Decrease in systemic vascular resistance (e.g.,
  septic, SIRS-related, anaphylaxis, neurogenic)

15
Organs Affected by Sepsis

• Vascular
• Vasoactive substances (prostacyclins, nitric
  oxide)
• Impaired compensatory secretion of vasopressin
• Initial increase in the cardiac output
• Maldistribution of systemic blood flow
• Decrease in number of functional capillaries
• Hypotension
• Lung
• ARDS with significant V/Q mismatch

16
Organs Affected by Sepsis

• GI tract
• Loss of normal barrier function with
  translocation of bacteria and endotoxin into
  systemic circulation
• Liver dysfunction impairs elimination of
  enteric-derived endotoxin and bacterial products
• Kidney
• Acute tubular necrosis and renal failure
• Nervous system
• Encephalopathy
• Peripheral sensorimotor polyneuropathy

17
Characteristics that influence Outcome in Sepsis

• Age
• Abnormal host response (e.g., hypothermia or
  leukopenia)
• Comorbidities (AIDS, hepatic disease,
  immunosuppression)
• Site of infection
• Infecting microorganism
• hospital-acquired?
• enterococci, pseudomonas, candida?
• Antibiotics and supportive therapy

18
Management Principles

• Septic shock is a medical emergency
• SIRS vs. Sepsis vs. Severe Sepsis
• Consider differential diagnosis
• acute myocardial infarction
• pulmonary embolism (PE)
• acute pancreatitis
• fat or amniotic fluid emboli
• adrenal insufficiency
• transfusion or drug reactions
• gastrointestinal hemorrhage

19
Management Principles

• Assess airway, respiration, and perfusion
• Start supplemental oxygen
• Intubate and mechanically ventilate as needed
• Early and complete resuscitation of circulation
• aggressive monitoring of blood pressure
• look for signs of decreased perfusion/O2 delivery
• Act fast!

20
Monitor, Culture, Support, and Find the Source

• Admit to ICU
• Monitor BP, pulse, RR, temp, O2 sat
• Complete HP
• Obtain cultures as appropriate
• blood, urine, sputum with Gram stain,
  wounds/drainage, CSF, other sterile sites
• CBC with differential, blood chemistry, CXR,
  other x-rays as needed, EKG
• Find source of infection!

21
Examples of Source Control

• Drain
• abscesses
• thoracic empyema
• septic arthritis
• Debride
• intestinal infarction
• mediastinitis
• necrotizing fasciitis

• Devices and lines
• remove infected vascular catheters
• change urinary drains
• remove prosthetic heart valves
• Definitive
• sigmoid resection for diverticulitis
• cholecystectomy for gangrenous cholecystitis

• Appropriate, early antimicrobial therapy
• MRSA and Gram-positive cocci
• Gram-negative bacilli
• anti-pseudomonal coverage if pseudomonas
  suspected
• anti-fungal therapy if fungi suspected

22
Inadequate Antibiotic Therapy Increases
Mortality!
Ibrahim1
Leibovici2
Alvarez-Lerma4
Luna3
Rello5
Nosocomial Pneumonia/VAP
Bloodstream Infections
In septic shock, each hour delay in starting
effective antibiotic therapy decreases survival
by 8!6
4Intensive Care Med. 199622387394. 5AJRCCM.
1997156196200.
1Chest. 2000118146155. 2J Intern Med.
1998244379386. 3Chest. 1997111676685.
6Crit. Care Med. 200634158996.
23
Initial Resuscitation

• Goals during the first 6 hours
• Mean arterial pressure ?65 mmHg
• Central venous pressure 812 mmHg
• Urine output ??0.5 mL/kg/hr
• Central venous (superior vena cava) or mixed
  venous oxygen saturation SvO2 ?70

24
Fluids?

• Give rapidly and in boluses
• Think large (in liters, not ccs)
• Continue aggressive hydration until
• BP, tissue perfusion, and O2 delivery acceptable,
  or
• Pulmonary edema develops, or
• Wedge pressure gt18 mmHg

25
Vasopressors

• Second line agents - fluids first!
• Primary goal is to increase SVR
• No good trials comparing different agents
• Few trials that document improved outcomes
• Problems
• tachyphylaxis
• hypoperfusion/ischemia
• arrhythmia

26
Vasopressors in Sepsis
Drug Heart rate Contractility Arterial constriction
Dobutamine -
Dopamine
Epinephrine
Norepinephrine
Phenylephrine 0 0
Amrinone --
27
Early Goal-directed Therapy (EGDT) for
Sepsis-induced Hypoperfusion
57
49
47
44
33
31
N Engl J Med 20013451368-77.
28
Other therapies

• Hydrocortisone for refractory hypotension
• Insulin to control hyperglycemia
• Adequate and early nutrition
• Transfusion (when lt7.0 gm/dL to maintain Hgb at
  7.0 - 9.0 gm/dL)
• gastric acid prophylaxis
• deep vein thrombosis (DVT) prophylaxis

29
Clinical Scenario

• 32 yo male admitted to OU trauma service via
  air-ambulance from Germany
• 10 days PTA pt suffered bilateral lower extremity
  trauma from IED explosion in Afghanistan
• extensive debridement at Landstuhl AMC with IV
  antibiotics (cefazolin and pipericillin-tazobactam
  )
• now febrile (103ºF), HR 122 bpm, RR 26 bpm, BP
  81/50, and SaO2 84 on RA
• exam reveals anxious male, diaphoretic, clear
  lungs, RRR with murmur, benign abd, both LEs with
  extensive packed wounds with copious drainage and
  exposed fractured bones from mid-thigh to feet

30
Work-up

• CXR clear
• EKG ? sinus tachycardia
• LE x-rays ? multiple bilateral communited
  fractures of humerus, fibula, tibia, tarsals and
  metatarsals no evidence for osteomyelitis
• WBC 18,500 (80 segs, 10 bands)
• Hgb 13.2 gm/dL plt ct 148,000
• electrolytes normal
• RA ABG ? pH 7.49, pCO2 28, pO2 76
• UA ? 2 protein, neg for glc, 4 WBCs and 2 epi
  cells
• blood, wound, and urine cultures obtained

31
The next day

• patient becomes severely hypotensive
• no response to 6 liters of NS
• vasopressor started
• intubated due to confusion and worsening
  oxygenation
• WBC ? 33,000 and plt ct ? 50,000
• BUN 28, Cr 2.1, K 5.8, HCO3 14, bili 2.4
• urine culture negative
• wound and blood cultures are growing GNRs

32
Management

• presumed sepsis ? source - leg wounds
• transferred to MICU
• placed in contact isolation
• 3 liters of NS ? BP to 95/60 and HR to 98 bpm
• O2 by mask at 10 lpm ? SaO2 now 98
• empiric IV antibiotics started (vancomycin and
  imipenem) for nosocomial wound infection

33
Microbiology

• multi-drug resistant Acinetobacter baumanii
  recovered from blood cultures and wounds
• isolate is resistant to cephalosporins,
  amino-glycosides, carbapenems, and extended
  spectrum penicillins
• IV colistin added
• trauma team amputates both legs

34
SIRS and Severe Sepsis

• Septic shock is a medical emergency
• SIRS vs. sepsis vs. severe sepsis
• Consider differential diagnosis
• Remember the mechanisms for bacterial virulence
• Immediately start appropriate empiric antibiotics
  and goal-directed therapies