SEPSIS AND MULTIORGAN DYSFUNCTION SYNDROME

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SEPSIS AND MULTIORGAN DYSFUNCTION SYNDROME

• Dr. Randula Samarasinghe
• Senior registrar in medicine
• Sri Jayawardenapura General hospital

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Background

• Septiceamia is a state of microbial invasion
  from a portal of entry into the blood stream
  which causes sign of illness
• - Schottmueller 1914

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History

• Severe sepsis and single organ failure 1960
• Multiple progressive system failure By Baue
• 
  1975

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Systemic inflammatory response syndrome( SIRS )

• The presence of 2 or more of the following
• Temperature gt 38 C or lt 36 C
• Heart rate gt 90 per minute
• Respiratory rate gt 20 breaths per minute or PaC02
  lt 32 mmHg
• WBC gt 12000 / or lt 4000 / or greater than 10
  band forms

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Definitions

• Sepsis - SIRS due to proven or suspected
  microbial aetiology
• Septicemia - The presence of microbes or their
  toxins in the blood
• Bacteremia the presence of bacteria in the
  blood as evidenced by positive blood culture

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Severe sepsis ( sepsis syndrome )

• Sepsis with one or more signs of organ
  dysfunction
• (1) SBP lt 90 mmHg (MAP lt 70 mmHg )
• (2) UOP lt 0.5 ml / Kg / hr despite adequate
  fluids
• (3) Pa02 /Fio2 lt 250
• (4) Platelet lt 80,000 / µl
• (5) Unexplained metabolic acidosis ( pH lt 7.3
  )
• base deficit gt 5 meq /l and plasma
  lactate gt 1.5
• upper limit of normal

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• Septic shock
• Sepsis with hypotension (SBP lt 90 mmHg
• or 40 mmHg lt than patients normal BP
  for
• at least one hour despite fluids
• Refractory septic shock
• Septic shock for gt 1 hr despite fluids
  and
• vasopressors

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MODS ( multiorgan dysfunction syndrome )

• A clinical syndrome in which the development
• of progressive and potentially reversible
• physiological dysfunction in two or more organ
• or organ systems induced by a variety of insults
  

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PATHOPHYSIOLOGY

• 
  Severe sepsis
• Infection SIRS(sepsis)
  Septic shock
• 
  MODS

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PATHOPHYSIOLOGY

• Aseptic triggers
• Pancreatitis SIRS Complications
• Burns
• Vasculitis
• Thromboembolism

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• 
  
• Infection SIRS(sepsis)
  Complications of
• 
  sepsis
  
• Microbial factors Host
  factors
• High burden of infection Excessive or
  poorly regulated
• Virulent factors immune
  response
• Antibiotic resistance
• 
  
  

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Organisms causing sepsis syndrome

• Most causes of severe sepsis are caused by
  bacteria or fungi that do not cause systemic
  disease in immunocompetent host
• Commonest cause of sepsis worldwide is malaria

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Organisms causing sepsis syndrome

• Gram negative bacteria - Enterobactericiea
• -
  Pseudomonas sp.
• -
  Haemophilus sp.
• -
  Other gram neg.
• Gram positive bacteria - Staph. aureus
• -
  Coagulase negative Staph.
• -
  Enterococci
• -
  Streptococcus pneumonea

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Organisms causing sepsis syndrome

• Fungi
• Protozoa
• Classical pathogens - Neisseria meningitides
• -
  Streptococcus Pneumonea
• -
  Haemophilus influenzea
• -
  Streptococcus Pyogenes

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IMMUNE MODULATORS OF SEPSIS

• The inflammatory response that results in the
  sepsis syndrome is generated both by the innate
  and adaptive immune system.
• This mediated via a multitude of cellular
  mediators
• The immediate response is via the innate immunity
  with amplification of that response via the
  adaptive immune system

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N Engl J Med 20063551699-713.
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Cellular mediators
Cell wall / cellular molecules of bact./ fungi
LPS Bact. Peptidoglycans
Lipoteichoic acid DNA
Toll like receptor ( TLR ) of cells of innate imm

Cellular mediators
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Innate immunity cont.

• cellular mediators
• Anti inflammatory Pro
  inflammatory
• Interleukin 10 TNF
  a
• 
  interleukin 1 ß
• Activate endothelial
  cells

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• Activated
  endothelial cells
• Upregulation of cell
  adesion molecules
• Endothelium Neutrophils
  platelets
• Release of cell mediators - Protease,
  oxidents,
• 
  PG and leucotriens
• Endothelial cell injury
  and release of NO and cytokines
• Permeability
  Vasodilation Procoagulant
  

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N Engl J Med 20063551699-713.
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Role of adaptive immunity in sepsis

• Microorganisms stimulate specific cell
• mediated and humoral adaptive immune
• responses that amplify the innate immunity

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Multiorgan dysfunction in sepsis

• The precise mechanisms of organ dysfunction is
  not known
• Proposed mechanisms
• - Hypoxic hypoxia - microcirculatory and
• mitochondrial distress syndrome (
  MMDS )
• - Direct cytotoxicity - Endotoxin and mediators
• - Apoptosis Delayed in inflammatory cells and
  
• hastened in other tissues

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Involved organ systems

• Central and peripheral nervous systems
• Cardiovascular system
• Respiratory system
• Renal dysfunction
• Gastrointestinal system
• Hepatobiliary system
• Coagulopathy
• Musculoskeletal system
• Alterations in acid base balance

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Central and peripheral nervous system

• Sepsis associated encephalopathy ( SAE )
• -A diffuse cerebral dysfunction induced
  by the systemic response to infection without
  clinical or laboratory evidence of direct
  involvement of the central nervous system
• Septic encephalopathy
• - A septic state induced by an infectious
  process in the central nervous system

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Sepsis associated encephalopathy
(SAE )

• Incidence of SAE ? Seen in 70 of septic
  patients
• Mortality increased
• Encephalopathic features may precede classical
  clinical features of sepsis
• SAE is considered a reversible state

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Pathophysiology of SAE

• Multifactorial
• - Effects of inflammatory mediators on CNS
• - Metabolic alterations
• - Breakdown of BBB
• - Altered neurotransmitter synthesis
• - Altered receptorial distribution
• - Impaired auto regulation of circulation

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Pathological changes of brain in SAE

• - Ischaemic lesions
• - Disseminated micro-infarcts
• - Perimicrovessels oedema
• - Brain purpura
• - Central pontine myelinolysis
• - Multifocal necrotizing leucoencephalopathy
  

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Clinical features of SAE

• Acute altered mental state
• - Cognitive disorders
• - Impaired consciousness
• Cognitive disorders seen in
• Early sepsis
• - Confusional state
• - Lack of attension
• - Inappropriate behavior
• Late sepsis
• - Delirium
• - severe agitation

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Clinical features of SAE

• Impaired consciousness somnolence, stupor and
  coma
• Severity assessed by GCS
• Mortality increases with lower GCS
• Other features - Asterixis, myoclonus, tremors
  seen but rare
• Signs of lateralisation are exceptional

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Investigations

• Laboratary findings - EEG the test of choice
• Changes seen when neurological examination is
  normal
• Findings not specific
• Five EEG patterns seen
• 1. normal EEG
• 2. Excessive theta
• 3. Predominant delta
• 4. Triphasic waves
• 5. Suppression or burst suppression

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Treatment

• No specific treatment

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Cardiovascular system

• Sepsis associated cardiomyopathy
• - Myocardial dysfunction is common in severe
• sepsis
• - Prevalence variable
• - Cardiac contractility reduced

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Pathophysiology
Myocardial depressant factors
Myocardial perfusion abnormalities
Oxygen reactive species
Calcium homeostasis derangements
Sepsis associated cardiomyopathy
Apoptosis
Adhesion molecules
Nitric oxide
Impaired high energy metabolism
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Sepsis associated cardiomyopathy

• Left ventricular dysfunction Systolic and
  diastolic
• Systolic dysfunction may be associated with an
  acutely dilated left ventricle
• Right ventricular dysfunction Systolic and
  diastolic
• RV systolic dysfunction independent of pulmonary
  vascular resistance
• RV systolic dysfunction may be associated with
• RV dilatation

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Diagnosis of sepsis associated cardiomyopathy

• Clinical evaluation, echocardiographic studies
  and pulmonary artery catheterisation may be
  unreliable due to masking of myocardial
  depression as a result of enhanced inotropism and
  chronotropism in initial phase of sepsis.
• Biochemical markers used as diagnostic tools

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Biochemical markers of myocardial damage

• Troponin I
• - Relates to myocardial dysfunction in severe
  sepsis and septic shock
• - TnI gt 0.6 ng/ml associated with an LVEF lt 50
• Brain natriuretic peptide ( BNP )
• -BNP levels increases in all forms of shock
• - In severe sepsis BNP gt 190 pg / ml

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Clinical features of sepsis syndrome

• Signs and symptoms are highly variable
• Focal or localising signs maybe abesn
• Look for signs of systemic inflammation
• Thorough examination for focus of infection and
  organ function
• Considerable organ hypoperfusion may be present
  despite of normal BP

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Investigations

• No test to distinguish septic from aseptic SIRS
• except microbial studies
• Blood , urine and CSF studies along with imaging
  studies
• - Establish SIRS
• - Focus of infection
• - Responsible organism
• - Assess organ function
• Blood cultures negative in more than 50

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Management of severe sepsis and organ dysfunction

• Initial resuscitation Hypotension or serum
  lactate gt 4 mmol / l
• - Immediate ( lt 6 hours )
• - Type of fluid - Crystalloids or Colloids

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Fluid resuscitation

• Volume of fluids
• - Administered in fluid challenges- 1000 ml or
  gt crystalloids / 300 500 ml colloids over 30
  mts
• - Further fluid Guided by resuscitation end
  points
• - Fluid loading reduced when increased cardiac
  filling pressure not associated with haemodynamic
  improvement
• - Blood transfusion to maintain Hct gt 30

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Resuscitation end points

• CVP 8 - 12 mmHg
• Mean arterial pressure gt 65 mmHg
• Urine output gt 0.5 ml / Kg / hr
• Central Venous oxygen saturation gt 70
• Other paramters
• Fall in heart rate
• Fall in base deficit
• Fall in blood lactate levels

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Vasopressor therapy

• When fluids not adequete
• Agents of choice
• 1. Noradrenaline
• 2. Dopamine
• 3. Adrenaline to be used when not
  responding to 1 and 2

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Ventilation

• In ARDS - 9 increase in survival with low tidal
  volumes ( 6 ml / Kg ideal body weight )
• Respiratory support may be needed in the absence
  of ARDS or pulmonary sepsis
• - Increase ventilatory demand
• - Respiratory muscle dysfunction

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Continuous renal replacement therapy ( CRRT )

• CRRT is used to treat sepsis associated ARF and
  to remove proinflammatory mediators
• Net effect on survival yet to be established

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• Nutrition
• - Early enteral nutrition is recommended
• - No value in Immune boosting suppliments
• ( L - arginine , omega 3 fatty acids )

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Hyperglycemia

• Potentially harmful
• studies in septic patient scarce
• In critically ill surgical and medical patients
• Tight control ( Glucose 4.4 - 6.1 mmol / l )
• - Reduced mortality in surgical
  patients
• - Reduced morbidity in medical
  patients

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Deep vein thrombosis prophylaxis

• Combination of pharmacological and mechanical
  methods can be used
• Avoid heparin in coagulopathy
• Both UFH and LMWH can be used
• Benefit shown in clinical trials ivolving ICU
  patients

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Stress ulcer prophylaxis

• Studies show reduction in GI bleeding
• Drugs - H2 receptor blocker
• - Proton pump inhibitor

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Corticosteroids

• Hydrocortisone in low doses ( Daily dose lt 300 mg
  )
• can be used in patients with septic shock not
  
• responding to adequate fluids and vasopressor
  
• therapy ( Relative adrenal insuficiancy )

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Antibiotics

• Prompt empirical antibiotic treatment required
• - Treatment within 4 hours of admission reduces
  stay mortality
• - Delay in hypotensive pateints increases
  mortality by 7.6 an hour

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Choice of antibiotics

• Though empirical may be Guided by history and
  examination
• Broad spectrum agents measurements of drug
  concentrations may be useful
• Antifungal agents

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Recombinant Human Activated
protein C

• Action
• - Natural anticoagulant
• - Promotes fibrinolysis
• - Inhibits thrombosis and inflammation
• - Modulates coagulation and inflammation in
  severe sepsis
• Major side effect is bleeding

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Recombinant Human Activated
protein C

• May be used in patients with severe sepsis and
  high risk of death
• - APACHE score gt 25
• - Multi organ failure
• Not recommended for patients with severe sepsis
  with low risk of death
• - APACHE score lt 20
• - single organ failure

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Recombinant Human Activated
protein C

• For patients with APACHE score 21 - 24 ?
• For patients APACHE score lt 20 and multi organ
  failure ?
• Evidence gained from 2 RCT
• PROWESS and ADDRESS trials

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• THANK YOU