Septicaemia

LS 508
M.Sc. III (Monsoon Semester - 2016)
Sepsis and Society
Sepsis, the most
expensive condition
treated in U.S.
hospitals spent more
than $20 billion in
2011, increasing on
average annually by
11.9%
 Incidence of the Disease
India currently tackles 750,000 cases of Sepsis every year of which overall
mortality rate in ICU patients is 12.08% and in the severe stage Sepsis patients it is
59.26%.
In India, the number of deaths from Sepsis each year has almost doubled since
1980
Approx. 1 Lakh People die of Sepsis per Year.
The US Center for Disease Controls National Center for Health Statistics estimates
that number of times people were in the hospital with sepsis increased from
621,000 in the year 2000 to 1,141,000 in 2008.
In the developing world sepsis accounts for 60-80% of lost lives per year, affecting
more than 6 million new borns and children annually
Over 100,000 women contract sepsis in the course of pregnancy and childbirth
Incidence of the Disease

The three major factors responsible for this are:

Rise in the number of organ transplants and other surgical
procedures that require suppressing the patient's immune
system;
Increase in the number of elderly people in the population; and
Overuse of antibiotics to treat infectious illnesses, resulting in
the development of drug-resistant bacteria.
 Sepsis Definition
Sepsis: A systemic response to infection manifested by 2 of
following:
Temp > 38oC or < 36oC
HR > 90 bpm
RR > 20 bpm or PaCO2 < 32 mmHg
WBC > 12 x 109/L, < 4 x 109/L or >10% band form
Septic Shock: Sepsis with hypotension despite adequate fluid
resuscitation, with perfusion abnormalities that could include, but
are not limited to, lactic acidosis, oliguria, and/or acute mental
status.
 Sepsis Definition

Four progressive stages of

Sepsis:
SIRS (Systematic Inflammatory
Response Syndrome),
SEPSIS,
Septic Shock,
MODS (Multiple Organ
Dysfunction Syndrome).
Sepsis Definition
Systemic Inflammatory Response Syndrome (SIRS):
Systemic inflammatory response to various stresses.
Meets 2 or more of the following criteria :
Temp > 38oC or < 36oC
HR > 90 bpm
RR > 20 bpm or PaCO2 < 32 mmHg
WBC > 12 x 109/L, < 4 x 109/L or >10% band form
Sepsis Definition
SEPSIS:
Evidence of SIRS accompanied by known or suspected infection.

Severe SEPSIS:

Sepsis accompanied by hypo-perfusion or organ dysfunction.

Cardiovascular :
SBP<90mmhg/MAP<70 for at least 1 hr despite adequate volume resuscitation or the
use of vasopressors to achieve the same goals.
Renal :
Urine output <0.5ml/kg/hr or Acute Renal Failure.
Pulmonary :
PaO2/FiO2 <250if other organ dysfunction is present or <200 if the lungs is the only
dysfunctional organ.
Sepsis Definition
Severe SEPSIS (contd):
Gastrointestinal:
Hepatic dysfunction (hyperbilirubinemia,Elevated transaminases
CNS:
Alteration in Mental status (delirium)
Hematologic:
Platelet count of <80,000/mm3 or decreased by 50% over 3 days/DIC
Metabolic:
PH<7.30 or base deficit >5.0mmol/L
Plasma lactate >1.5 upper limit of normal, acidosis.

Septic Shock:
Severe Sepsis with persistent hypo-perfusion or hypotension despite adequate fluid
resuscitationwith perfusion abnormalities that could include, but are not limited to, lactic
acidosis, oliguria, and/or acute mental status.
Infection sites in Sepsis

Bernard & Wheeler NEJM 336:912, 1997

Severe Sepsis incidence & mortality
with Age

Mortality

Incidence

Angus Crit Care Med 29:1301, 2001

Organ dysfunction in severe sepsis

Disseminated
Intravascular
Coagulation

Bernard NEJM 344:699, 2001

Risk Factors for Sepsis

Sepsis
 Steps in Sepsis and Septic shock
Bacterial infection HOST PARASITE

Excessive host response

PRR PAMP
Host factors lead to Pathogen
cellular damage Pathogen
recognition associated
receptor Molecular pattern
Organ damage

Death
Pathogenesis of Sepsis

Disorder Due to Uncontrolled

Inflammation?
Pathogenesis of
Sepsis

Cohen, Nature: 2002 420:885

Pathogenesis of Sepsis
Pathogenesis of Sepsis
Failure of Immune System to Eliminate
Microorganism?

Shift from inflammatory (Th-1) to anti-

inflammatory response (Th-2).
Anergy: absence of the normal immune
response to a particular antigen
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.
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
ischemia.
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.
Multiple Organ Dysfunction Syndrome
(MODS)
MODS : Possible Explanations
Mitochondrial Dysfunction
Mitochondria use > 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.
 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 cell 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).
 MODS : Possible Explanations
Late acting mediators of Sepsis
HMGB1 (high mobility group box 1) identified as a late-acting, cytokine-like mediator
of inflammation and lethality in an animal model of Sepsis.
Neutralizing antibodies against HMGB1 confer significant protection against LPS- or
Sepsis-induced mortality.
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 Macrophage migration inhibitory factor (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 No 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.
 END DAY 1
Next Day:
Management and treatment of Sepsis
Alternated and adjuvant Therapies of sepsis
Management of Sepsis

Recognition
Supportive care
Source control
Antibiotics
Specific (adjunctive) therapy
Treatment of Sepsis
Early diagnosis 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
Need of Newer therapies
Treatment of Sepsis: Limitations

No specific treatment available to control the inflammation

Available therapies are directed to achieve the secondary
goals of Sepsis management
Antibiotics are prescribed to control the infection, and
Fluid therapy to stabilize the patient's condition
No primary therapy available to control the series of
inflammatory events induced by multiple infections
Initial Resuscitation: Therapeutic Goals

Central venous pressure: 8 12 mmHg

Mean arterial pressure: 65 mmHg
Urine output: 0.5 mL/kg/h
Central venous (SVC) or mixed venous
oxygen saturation: 70%
Rational Choice of Antibiotics

EFFICACY
Spectrum of activity
Pharmacokinetics & pharmacodynamics
Patterns of resistance
TOXICITY
COST
Choosing antibiotics in sepsis

There is no single, Best regimen

Site of the infection guides the selection
Which Organisms usually cause infection at that site
Choose antibiotic(s) with the appropriate spectrum
After obtaining cultures, Administer antibiotics quickly and
empirically at appropriate dose
Non-Antibiotic therapy for sepsis

Low dose steroids

Intensive insulin therapy
tight glycaemic control
Activated protein C
Goal directed therapy
 Non-Antibiotic therapy for sepsis
Tight Glycemic control
A decreased release of insulin, increased release of hormones with effects countering
insulin (Cortisol, Cytokines), and increased insulin resistance combined to produce
stress hyperglycemia in many critically ill patients.
Hyperglycemia diminishes the ability of neutrophils and macrophages to combat
infections.
Insulin therapy shows anti-inflammatory and 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 < 0.04), renal failure incidence (P =
0.04), and episodes of septicemia (P = 0.003), compared with
conventional treatment (mean morning glucose of 153 mg/dL.
Physicians liberalize insulin treatment to keep blood glucose levels less than 150
mg/dL due to concerns of hypoglycemia.
 Activated Protein C
Protein C is a vitamin K-dependent
glycoprotein, synthesised in liver. It
circulates in an inactive form.
Activated by the thrombin-
thrombomodulin complex on
endothelial cells.
Activated protein C degrades the
activated clotting factors Va and
VIIIa
APC plays an important role in
regulating anticoagulation,
inflammation, cell death, and
maintaining the permeability of
blood vessel walls
 Activated Protein C
PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) 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 >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.
Acute Physiology and Chronic Health Evaluation
Acute Physiology and Chronic Health Evaluation
APACHE II scores
 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, hypercoagulable states.
Chronic liver disease, pancreatitis.
Chronic renal failure who were dependent on dialysis.
Recent surgery, organ-transplant recipients, HIV with CD4 <50 cells.
Patients with thrombocytopenia (platelet count of less than 30,000 per cubic mm).
Those who took acetylsalicylic acid at a dose of >650 mg per day within three days.
Age <18years, weight >135kg.
Many patients with severe Sepsis meet one or more of these criteria.
Further studies needed to assess the safety of activated protein C in these
groups of patients.
 Adjunctive therapies
TNF antagonist:
NORASEPTII RCT 1879 patients randomly assigned to murine monoclonal antibodies
(40.7% vs42.8%), effective in patients with a IL-6 > 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 < 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.
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).
Adjunctive therapies

Interleukin-10

A prominent mediator of 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.
Adjunctive therapies
Anti-endotoxin antibody HA-1A (Centoxin)

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-2 Inhibition 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.
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.
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.
 Other 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.
THE END