Sepsis : Pathophysiology and Treatment

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Sepsis Pathophysiology and Treatment

• Zainab Abdulla
• April 25, 2006

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• Definitions
• Epidemiology
• Pathophysiology
• Treatment
• Future directions

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Definitions

• Systemic Inflammatory Response
• Syndrome (SIRS)
• Systemic inflammatory response to various
  stresses.
• Meets 2 or more of the following criteria
• Temperature of gt38C/lt36degree C
• Heart rate of more than 90 beats/min
• RR gt20 breaths/min or PaCo2 lt32mmHg
• WBC gt12,000/mm3 or lt4000/mm3

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Definitions

• SEPSIS
• Evidence of SIRS accompanied by known or
  suspected infection.
• Severe SEPSIS
• Sepsis accompanied by hypoperfusion or organ
  dysfunction.
• Cardiovascular
• SBPlt90mmhg/MAPlt70 for at least 1 hr despite
  adequate volume resuscitation or the use of
  vasopressors to achieve the same goals.
• Renal
• Urine output lt0.5ml/kg/hr or Acute Renal Failure.
• Pulmonary
• PaO2/FiO2 lt250if other organ dysfuncton is
  present or lt200 if the lungs is the only
  dysfunctional organ.

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Definitions

• Severe SEPSIS (contd)
• Gastrointestinal
• Hepatic dysfunction (hyperbilirubinemia,Elevated
  transaminases
• CNS
• Alteration in Mental status (delirium)
• Hematologic
• Platelet count of lt80,000/mm3 or decreased by 50
  over 3 days/DIC
• Metabolic
• PHlt7.30 or base deficit gt5.0mmol/L
• Plasma lactate gt1.5 upper limit of normal.
• Septic Shock
• Severe Sepsis with persistent hypoperfusion or
  hypotension despite adequate fluid resuscitation

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Epidemiology

• Current estimates suggest that over 750,000 cases
  of Sepsis are diagnosed annually, resulting in
  more than 200,000 deaths.
• The incidence rate for Sepsis has been increasing
  over the past two decades, driving an increase in
  the number of deaths despite a decline in
  case-fatality rates.
• Sepsis is the tenth leading cause of death in the
  United States and accounts for more than 17
  billion dollars in direct healthcare
  expenditures.
• Risk factors include age gt 65 years, male,
  non-whites.
• A primary site of infection cannot be established
  in 10 of patients with severe Sepsis/SIRS.

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Epidemiology
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Epidemiology Mortality rate
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Epidemiology Causative organism
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Pathophysiology of Sepsis
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Pathophysiology of Sepsis

• Disorder Due to Uncontrolled Inflammation?
• Increased inflamatory mediators like IL-1, TNF,
• IL-6.
• Based on animal studies.
• In a study in children with meningococcemia, TNF
  levels directly correlated with mortality.
• Clinical trials involving TNF anagonist,
  antiendotoxin antibodies, IL-1 receptor
  antagonists, cortocosteroids failed to show any
  benefits.
• Patients with RA treated with TNF antagonist
  develop infectious complications.

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Pathogenesis of Sepsis
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Pathophysiology of Sepsis

• Failure of Immune System to Eliminate
• Microorganism?
• Shift from inflammatory (ThI) to antiinflammatory
  response (Th2).
• Anergy.
• Apotosis of B cells, T cells, Dendritic cells.
• Loss of macrophage expression of MHC Class I and
  co-stimulatory molecules.
• Immunosuppressive effect of apoptotic cells.

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Pathogenesis of Sepsis
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Pathogenesis of Sepsis
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Pathogenesis of Sepsis
The dark stained regions are concentrations of B
cells in lymphoid follicles that are visible to
the naked eye. The patients with Sepsis have
dramatically smaller and fewer lymphoid follicles
than the patients with trauma.
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Pathogenesis of Sepsis

• Factors that influence Immune Response
• Genetic factors, polymorphisms in cytokine genes,
  TLR4 mutations, MBP.
• Type of organism, virulence, size of inoculum.
• Host Factors
• Age, Nutritional status, Coexisting illness,
  COPD, CHF, Cancer, DM, Immunodeficiency.
• Therapeutic efforts to modify the host immune
  response in critical illness will require a more
  thorough understanding of the cytokine milieu and
  the factors that determine their production.

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Multiple Organ Dysfunction Syndrome (MODS)

• MODS occurs late and is the most common cause of
  death in patients with Sepsis.
• Lactic acidosis led investigators to think that
  this is due to tissue ischaemia.
• Minimal cell death in postmortem samples taken
  from the failed organs of patients with Sepsis.
• Recovery from Sepsis is associated with near
  complete recovery of organ function, even in
  organs whose cells have poor regenerative
  capacity.
• Increased tissue oxygen tensions in various
  organs (muscle, gut, bladder) in animals and
  patients with Sepsis.

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MODS Possible Explanations

• Mitochondrial Dysfunction
• Mitochondria use gt 90 of total body oxygen
  consumption for Adenosine TriPhosphate (ATP)
  generation, a bioenergetic abnormality is
  implied.
• Cell and animal data have shown that nitric oxide
  (and its metabolites peroxynitrite), produced in
  considerable excess in patients with Sepsis, can
  affect oxidative phosphorylation by inhibiting
  several of its component respiratory enzymes.
• In cell models, the antioxidant GSH has a
  protective role against mitochondrial inhibition,
  particularly for complex I. Human data are scarce
  but supportive of these findings.

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MODS Possible Explanations

• Increased cellular apoptosis
• Extensive apoptosis of lymphoid cells is a
  prominent feature of Sepsis in both human
  patients and mice.
• Neither apoptosis nor necrosis are prominent
  features in other organs (notably the lungs,
  liver or kidneys) that are commonly involved in
  cases of MODS.

• Derangements in epithelial
• cellular physiology
• Derangements in epithelial cellular physiology
  lead to organ dysfunction responsible for
  late-phase mortality in Sepsis (e.g., membrane
  pumps, TJs, cytoskeletal proteins, and
  cell-surface receptors).

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MODS Possible Explanations

• Late acting mediators of Sepsis
• HMGB1 (high mobility group box 1) was identified
  as a late-acting, cytokine-like mediator of
  inflammation and lethality in an animal model of
  endotoxemia and Sepsis.
• Neutralizing antibodies against HMGB1 confer
  significant protection against LPS- or
  Sepsis-induced mortality.
• It is elevated in late phase of Sepsis,
  suggesting that this may play a role in
  pathogenesis of MODS.
• Ethyl pyruvate and certain cholinergic agonists,
  which inhibits HMGB1 are therapeutic in various
  animal models of Sepsis even when given well
  after the onset of symptoms.
• Increased levels of MIF have been demonstrated in
  both the plasma and alveoli of patients with
  ARDS, suggesting that it may play a role in the
  pathogenesis of Sepsis induced organ dysfunction.
• Although it is unlikely that any single mechanism
  can account for all forms of organ failure in
  MODS, it is plausible that some key molecular
  events are common factors contributing to
  cellular dysfunction in multiple tissues.

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MODS
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Treatment of Sepsis

• Early recognition of the Sepsis syndrome.
• Prompt administration of broad-spectrum
  antibiotics.
• Surgical intervention when indicated.
• Aggressive supportive care in intensive care
  units.
• Steroids
• Tight glycemic control.
• Activated protein C
• Newer therapies.

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Eradication of Infection

• Identification of septic focus (history, physical
  examination, imaging, cultures). Blood cultures,
  urine culture, sputum culture, abscess culture.
• I.V. antibiotics should be initiated as soon as
  cultures are drawn.
• Patients with severe Sepsis should receive
  broadspectrum antibiotic covering both gram
  positive and gram negative organism.
• Empiric antifungal drug if patient had received
  antimicrobial treatment. Neutropenic patients,
  DM, Chronic steroids.
• There is limited evidence to support the use of
  combination therapy except in neutropenic
  patients.
• Many experts would also consider extended
  spectrum beta-lactamase inhibitor to be
  effective.
• In centers with high prevalence of MRSA,
  Vancomycin should be added if they have IV
  catheter and develop severe Sepsis.

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Choice of Antibiotics

• If pseudomonas is an unlikely pathogen, combine
• vancomycin with one of the following
• Cephalosporin, 3rd or 4th generation (e.g.,
  ceftriaxone, cefotaxime, or cefepime).
• Beta-lactam/beta-lactamase inhibitor (e.g.,
  ampicillin-sulbactam).
• Fluroquinolones (eg., Levofloxacin, gatifloxacin,
  moxifloxacin.)
• If pseudomonas is suspected, combine vancomycin
  with two
• of the following
• Antipseudomonal cephalosporin (e.g., cefepime,
  ceftazidime, or cefoperazone).
• Antipseudomonal carbapenem (eg, imipenem,
  meropenem).
• Antipseudomonal beta-lactam/beta-lactamase
  inhibitor (e.g., pipercillin-tazobactam,ticarcilli
  n-clavulanate).
• Aminoglycoside (e.g., gentamicin, amikacin,
  tobramycin).
• Fluoroquinolone with good anti-pseudomonal
  activity (e.g., ciprofloxacin).
• Monobactam (e.g., aztreonam).

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Antibiotics dosing

• Dosage for intravenous administration (normal
  renal function).
• Imipenem-cilastin 0.5g q 6h
• Meropenem 1.0g q 8h
• Piperacillin-tazobactam 3.375gq 4h or 4.5 g q 6h
• Cefepime1-2 q 8hr
• Gatifloxacin 400mg iv q d
• Ceftriaxone 2.0g q 24hr
• Levofloxacin500mg q d

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Airway

• Assess the airway, respiration, and perfusion
• ARDS/ALI causes respiratory failure in patients
  with severe Sepsis.
• Supplemental oxygenation, Ventilator for
  respiratory failure, airway protection.
• Etomidate can cause adrenal insufficiency via
  inhibition of glucocorticoid synthesis, which may
  contribute to increased mortality in patients
  with Sepsis.

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Treatment of Hypotension

• Volume Resuscitation
• Hypotension in severe Sepsis and septic shock
  results from a loss of plasma volume into the
  interstitial space, decreases in vascular tone,
  and myocardial depression.
• An arterial catheter may be inserted if blood
  pressure is labile.
• Intravenous fluids Crystalloids vs. Colloids.
• Goals for initial resuscitation include
• Central venous pressure 8 to 12 mmHg.
• Mean arterial pressure 65 mmHg.
• Urine output 0.5 mL per kg per hr.
• Central venous or mixed venous oxygen saturation
  70.
• Pulmonary capillary wedge pressure exceeds 18
  mmHg.
• Volume status, tissue perfusion, blood pressure,
  and the presence or absence of pulmonary edema
  must be assessed before and after each bolus.
• Pressors, if above measures fail.
• PRBCs.

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Coticosteroids

• Anti-inflammatory actions such as inhibiting the
  production of proinflammatory cytokines,
  enhancing the release of anti-inflammatory
  mediators.
• Decreasing the function and migration of
  inflammatory cells.
• Maintains BP by upregulation of adrenergic
  receptors.
• Patients with Septic shock has relative adrenal
  insufficiency despite elevated levels of
  cortisol.
• Cosyntropin stim test Cortisol of lt 9mcg/dl
  identifies patients with relative adrenal
  insufficiency.
• In 2001, studies showed that physiologic doses of
  steroids are useful in patients with refractory
  shock.
• Administration of replacement-dose
  corticosteroids(50mg of Hydrocortisone IV q 6hrs
  with fludrocortisone 50mcg NGTfor 7 days)
  improved refractory hypotension and (63 vs 73
  mortality P 0.02),in patients with relative
  adrenal insufficiency.
• But only in patients with relative adrenal
  insufficiency (defined as an increase of serum
  cortisol in response to the corticotropin
  stimulation test of 9 mg/dL or less).

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Role of Coticosteroids

• Unanswered questions
• What defines adrenal dysfunction? High dose ACTH,
  Low dose ACTH test?
• How long should treatment continue once shock has
  resolved?
• Taper Steroids?
• Role of Fludrocortisone?

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Treatment

• Tight Glycemic control
• A decreased release of insulin, increased release
  of hormones with effects countering insulin, and
  increased insulin resistance combine to produce
  stress hyperglycemia in many critically ill
  patients.
• Hyperglycemia diminishes the ability of
  neutrophils and macrophages to combat infections.
  Also insulin possesses antiapoptotic effects.
• A large, single-center, randomized trial of more
  than 1500 critically ill patients demonstrated
  that, maintaining serum glucose levels between 80
  and 110 mg/dL (mean morning glucose of 103 mg/dL)
  through the use of a continuous insulin infusion
  decreased mortality (4.6 vs 8 P lt 0.04),
  development of renal failure (P 0.04),
  and episodes of septicemia (P 0.003), compared
  with conventional treatment (mean morning glucose
  of 153 mg/dL.
• Physicians liberalize their insulin treatment to
  keep blood glucose levels less than 150 mg/dL due
  to concerns of hypoglycemia.
• Studies are needed to determine whether less
  tight control of blood glucose for example, a
  blood glucose level of 120 to 160 mg per
  deciliter (6.7 to 8.9 mmol per liter) provides
  similar benefits.

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Activated Protein C
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Activated Protein C

• Mechanism of action
• antithrombotic, antiinflammatory,
  profibrinolytic.
• PROWESS Trial
• 1690 randomly assigned to placebo or DAA, 28-day
  mortality rate was significantly lower in the
  drotrecogin-treated group (24.7 vs. 30.8).
• rhAPC decreased mortality rates consistently
  across all demographic subgroups defined by age,
  sex, race, and geographic region of treatment,
  compared with placebo.
• In 2001, FDA approved the use of drotrecogin alfa
  (activated DAA ) for the treatment of severe
  Sepsis.
• DAA produced the largest benefit in the sickest
  subgroups, with an absolute mortality reduction
  of 7.4 in patients with more than one organ
  dysfunction and 13 (P 0.0002) in patients with
  APACHE II scores totaling more than 24.
• The treatment was effective regardless of age,
  severity of illness, the number of dysfunctional
  organs or systems, the site of infection
  (pulmonary or extrapulmonary), and the type of
  infecting organism (gram-positive, gram-negative,
  or mixed.

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Activated Protein C

• Drawbacks
• Change in study protocol, drug preparations,
  APACHE scoring.
• Increased risk of bleeding including fatal
  intracranial hemorrhage, in patients receiving
  DAA.
• The study excluded these groups of patients
• Higher risk of bleeding, INR gt 3.0, hypercoaguble
  states.
• Chronic liver disease, pancreatitis.
• Chronic renal failure who were dependent on
  dialysis.
• Recent surgery, organ-transplant recipients, HIV
  with CD4 lt 50 cells.
• Patients with thrombocytopenia (defined as a
  platelet count of less than 30,000 per cubic mm).
  
• Those who had taken acetylsalicylic acid at a
  dose of gt 650 mg per day within three days before
  the study.
• Age lt18 years, weight gt 135kg.
• Many patients with severe Sepsis meet one or more
  of these criteria.
• Further studies will be needed to assess the
  safety of activated protein C in these groups of
  patients.

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Adjunctive therapies

• TNF antagonist.
• Murine anticlonal antibody.
• NORASEPTII RCT 1879 patients randomly assigned to
  murine monoclonal antibodies (40.7 vs42.8),
  effective in patients with a IL-6 gt 1000pg/ml.
• Two large phase III studies are currently
  underway to determine the effects of the murine
  IgG3 monoclonal antibody to TNF-a and of the p55
  TNF receptor fusion protein construct in patients
  with Sepsis.
• Pentoxyphylline.
• Inhibits synthesis of TNF.
• Inhibits neutrophil activation and downregulates
  adhesion molecules.
• Randomized placebo controlled trial 51 patients
  pentoxyphylline vs saline infusion (30 vs. 33)
• A decrease in the multiple organ dysfunction
  score, which was noted at day 4 and reached
  statistical significance (P lt 0.05) at day 14 in
  the patients who received pentoxifylline.
• Pentoxifylline significantly affects the
  synthesis of TNF and IL-6 as well as reduces the
  mortality rate in premature infants with Sepsis.

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Adjunctive therapies

• IL -1 receptor Antagonist
• IL-1 induces fever, constitutional symptoms, and
  hypotension.
• An initial trial of IL-1 receptor antagonist in
  99 human subjects demonstrated a dose-dependent
  improvement in 28-day mortality (44 vs. 16 )
  correlated with IL-6 levels.
• A subsequent trial with 893 patients with Sepsis
  syndrome revealed a trend towards improved 28-day
  mortality that did not achieve statistical
  significance, although a retrospective analysis
  of the data suggested that those patients with
  the highest predicted mortality (24 or greater)
  benefited most from the treatment and experienced
  a significant reduction in mortality at 28 days
  (45 in the placebo group versus 35 in the
  patients receiving 2 mg/kg/h of IL-1 receptor
  antagonist P 0.005).

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Adjunctive therapies

• Interleukin-10
• Interleukin-10 is a prominent mediator of the
  anti-inflammatory cascade
• Decrease serum concentrations of TNF and IL-1.
• In experimental animal models, administration of
  exogenous IL-10 protected against death in the
  setting of endotoxemia and staphylococcal
  enterotoxin injection .Alternatively, antibodies
  directed against IL-10 will increase mortality in
  a similar clinical situation.
• Further studies are needed to define the utility
  of IL-10 in the treatment of Sepsis.

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Adjunctive therapies

• HA-1A
• Multicenter trials involving more than 1500
  patients randomly assigned to HA-1A or placebo
  within six hours of the onset of septic shock,
  the antibody had no effect upon 14-day mortality.
• Monoclonal antibody TLR-2Inhibition of toll-like
  receptor (TLR)-2 with a neutralizing antibody
  successfully prevented lethal septic shock in a
  murine model, even when given three hours after
  initiation of systemic inflammation.

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Adjunctive therapies

• Cytokine agents
• Interferon-gamma
• In patients with defective monocyte functions,
  shown benefit, needs larger trials.
• Granulocyte colony stimulating factor
• Studies not shown benefit in RCT of non
  neutropenic patients.
• Granulocyte-macrophage colony stimulating factor
• Small phase 11 trial in 18 septic patients did
  not show any benefit.

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Adjunctive therapies

• Anti-MIF antibody
• MIF levels correlate with outcome among patients
  with Sepsis, and human trials of anti-MIF
  antibody therapy are underway.
• Antithrombin
• There was no significant benefit in mortality in
  patients receiving AT at 28, 56, or 90 days, or
  in survival time within the intensive care unit.
• Tissue factor pathway inhibitor
• Serine protease inhibitor that impairs the
  ability of tissue factor (thromboplastin) to
  initiate the coagulation cascade large
  multicenter randomized controlled trial
  (OPTIMIST) failed to show any improvement in
  outcome when patients treated with tifacogin were
  compared to control patients.

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Potential Therapies

• Antibodies against complement-activation product
  C5a decreased the frequency of bacteremia,
  prevented apoptosis, and improved survival.
• Antibodies against macrophage migration
  inhibitory factor protected mice from
  peritonitis.
• Strategies that block apoptosis of lymphocytes or
  gastrointestinal epithelial cells have improved
  survival in experimental models of Sepsis.
• Mice with Sepsis that are deficient in
  polyADPribose polymerase 1 (PARP) have improved
  survival, and administration of a PARP inhibitor
  was beneficial in pig models.
• Electrical stimulation of the vagus nerve
  protects against endotoxic shock.
• HMGB1, neutralizing antibodies against HMGB1
  confer significant protection against LPS- or
  Sepsis-induced mortality.

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Conclusions

• The incidence of Sepsis is increasing.
• Possible contributing factors
• Use of antibiotics leading to microbial
  resistance
• More invasive procedures
• Increasing use of immunosuppressants.
• There have been new insights into the
  pathogenesis of Sepsis which could be potential
  therapeutic targets in the future.
• Treatment of Sepsis includes early institution of
  antibiotics, volume resuscitation, tight
  glycemic control, steroids protein C when
  indicated.

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Discussion