Septicemia and Shock:
Pathogenesis and Novel Therapeutic Strategies
Authored By
Pranab kumar Bhattacharya[ 1] Rupak Bhattacharya[2]; UpasanaBhattacharya[1]; Ritwik Bhattacharya[2]; RupsaBhattacharya[2]; Dalia Mukherjee[3] ; Ayeshi Mukherjee[3]; Debasis Mukherjee[3]; HindoleBanerjee[2] Runa Mitra[4]
Beharampore, Murshidabad, West Bengal, India
2] 7/51 Purbapalli PO -Sodepur District 24 Parganas(north) West Bengal Kolkata-70001 India
[3] Swamiji Road , South habra District 24 Parganas(north) West Bengal Kolkata-70001 India
[4] B K Mitra Palliative care unit Barrackpore District 24 Parganas(north) West Bengal Kolkata-70001 India
[4] B K Mitra Palliative care unit Barrackpore District 24 Parganas(north) West Bengal Kolkata-70001 India
Corresponding author: Professor Dr Pranab kumar Bhattacharya MD( calcutta univ) FIC path
Professor Department of Pathology, Murshidabad District Medical College,
Beharampore, Murshidabad, West Bengal, India and Professor of Pathology on Deatilment at calcutta School of Tropical Medicine 108 CR Avenue Kolkata-700073 West Bengal India
Beharampore, Murshidabad, West Bengal, India and Professor of Pathology on Deatilment at calcutta School of Tropical Medicine 108 CR Avenue Kolkata-700073 West Bengal India
Email-: profpkb@yahoo.co.in Mobile -9231510435
Abstract and research data/ result and analysis not given for this article here much intentionally to prevent plagiarism unless and untill published in a high index journal
[ NEJM] sent and in review process now t
The overall mortality in patients with sepsis
is approximately 30%; this figure increases to 50% or greater in patients with
septic shock, and sepsis continues to be seen as a major clinical challenges in
ITU or ICU or CCU . Sepsis is usually associated with exacerbated
production of both pro- and anti-inflammatory cytokines, which are detectable
within blood .These “half-angel/half-devil” properties are fully illustrated in
sepsis. While the cytokines are a prerequisite to fight infection, their
overzealous production is also deleterious for patients. The highest levels of
cytokines are found in plasma of non-surviving
patients from sepsis : can they be markers and causative agents of poor outcome
in severe sepsis? . Only, the level of the chemokine “RANTES” is inversely
considered as associated with the APACHE
II score and with poor outcomes. The link, interplay and network of cytokines
taking place during sepsis are illustrated by the correlations between the
levels of most pro- and anti-inflammatory cytokines. Excessive release of
anti-inflammatory cytokines may be according to myself associated also with the immune dys-regulation observed in
sepsis. However, despite the presence of huge amounts of anti-inflammatory
cytokines and molecules targeting specifically interleukin-1 (IL-1) (i.e. IL-1
receptor antagonist) and tumor necrosis factor (TNF) (i.e. soluble TNF
receptors), there is no indication that their levels are sufficient to fully
counteract these pro-inflammatory cytokines. TNF was initially thought to be
the “hub of the cytokine network”. Although TNF contributes to favor the
production of many other cytokines within a complex cascade, there are numerous
examples, which illustrate that its presence is not a prerequisite for these productions. It is acknowledged that severe sepsis/ or septic
shock is a major problem in clinical bed
side medicine, and yet the extent of the
problem and its basic immunology remains poorly defined to us. The problem of sepsis is further
complicated by the remarkably diverse spectrum of illness encompassed under the
term “sepsis”. Sepsis may range in
severity from mild systemic inflammation without significant clinical
consequences to multi system failure(MODS)
as in septic shock with an exceedingly high mortality rate. Sepsis also
connotes a clinical syndrome that may occur in any age group, in markedly
different patient populations, and in response to a multitude of microbial
pathogens from multiple different anatomic sites within the human body.
Although protocols could
be tailored by each hospital, all the protocols a required to include a 3-hour
bundle consisting of receipt of the following care within 3 hours: obtaining of
a blood culture before the administration of antibiotics, measurement of the
serum lactate level, and the administration of broad-spectrum antibiotics.
Protocols are also required to include a 6-hour bundle, consisting of the
administration of a bolus of 30 ml of intravenous fluids per kilogram of body
weight in patients with hypo tension or a serum lactate level of 4.0 mmol or
more per liter, the initiation of vasopressors for refractory hypotension, and
the re measurement of the serum lactate level within 6 hours after the
initiation of the protocol. An
association between time to treatment and outcome among patients with sepsis or
septic shock treated in the emergency department during a state wide initiative
mandating protocolized care. It is found
that a longer time to completion of a 3-hour bundle of care for patients with sepsis
and the administration of broad-spectrum antibiotics were each associated with
higher risk-adjusted in-hospital mortality.
A recent meta-analysis of 11 observational studies, however, showed no
significant mortality benefit of the administration of antibiotics within 3
hours, as compared with after 3 hours, after triage in the emergency department
(odds ratio, 1.16; 95% CI, 0.92 to 1.46) or within 1 hour after the recognition
of shock (odds ratio, 1.46; 95% CI, 0.89 to 2.40).[1].
There
may be several biologic explanations for the association between the
time to completion of a 3-hour treatment bundle and outcome of sepsis. First,
more rapid the administration of antibiotics it reduces pathogen burden,
modifies the host response, and could reduce the incidence of subsequent organ
dysfunctions. Second, clinicians who decide more quickly to measure the serum
lactate level may identify heretofore unrecognized shock and are more prepared
to deliver lactate-guided resuscitation than clinicians who are slower to
measure the serum lactate level — a strategy that may improve outcome in
randomized trials.[2] Third, physicians have broad variation in how
they identify sepsis, even when they are presented with similar cases.[3] Fast delivery of sepsis treatment, even within
the structure of mandated protocols, requires a prompt clinical suspicion of
both infection and worsening organ dysfunction.
Broad spectrum Antibiotics are essential to
the treatment of bacterial sepsis as they reduce the bacterial burden. The
impact of bacterial resistance found to be very important in a range of
conditions. Resistance to antibiotics can be defined genotypically,
phenotypically and clinically through pharmacokinetic/pharmacodynamic studies
and their correlations with clinical outcomes. Although the kinetics of
antibiotics has been shown to be favorably altered in sepsis, a range of
studies in sepsis has revealed that for most pathogens resistance contributes
to significant increases in mortality. This has been clearly demonstrated in
bacteraemia, including community- and hospital-acquired infections, and with
bacteraemia caused by vancomycin-resistant enterococci, methicillin-resistant
staphylococci, and extended-spectrum producing gram-negative bacterias. Significant
mortality increases have also been seen with ventilator-associated pneumonia
and serious infections requiring admission to intensive care. Gentotypic and
phenotypic resistance in coagulase-negative staphylococci causing bacteraemia,
and in invasive pneumococcal disease has not shown differences in mortality. In
the latter case, dosage regimens have to date been adequate to overcome
laboratory-defined resistance. Early indications are that de-escalating therapy
from broad-spectrum initial coverage after results of cultures and
susceptibility tests become available does not jeopardise outcomes, and further
prospective studies are warranted. There is now convincing evidence that
broad-spectrum initial therapy to cover the likely pathogens and their resistances pending
culture results is mandatory in sepsis to minimise adverse outcomes.
Monocytes/macrophages
play also a key role in host defense
mechanism by phagocytosing invaded
pathogens, or in presenting antigens to
immune cells, and producing numerous inflammatory cytokine mediators. Expression of many
proteins and genes is up regulated
in activated human monocytes, a whole picture of pathophysiologic
function of activated human monocytes has not yet been drawn. Serial analysis
of gene expression (SAGE) procedure when
are used to lipopolysaccharide
(LPS)-stimulated human monocytes more
than 12,000 different transcripts can be sequenced. In addition, the Long SAGE
can be used in LPS-stimulated monocytes to increase the accuracy of
corresponding gene identification. Comparison of gene expression profile with
that of resting monocytes revealed the whole LPS-inducible gene expression
profile. The functional classifications of LPS-inducible genes( greater than 8
fold increase compared with resting monocytes) in monocytes showed that 25% of
inducible genes were identified to encode cytokines and chemokines, followed by
proteins related to metabolism (11%), cell surface antigens (9%), nuclear
proteins (8%), proteases (6%), proteins related to extracellular transport (4%)
and intracellular transducers (4%). Moreover, 14% of LPS-inducible genes still
encode proteins with unknown function.
HMGB1 is a member of the
high mobility group protein super family that had been widely studied as
nuclear proteins that bind DNA, stabilize nucleosomes, and facilitate gene
transcription. Surprisingly, a series of recent discoveries revealed a cytokine
activity of HMGB1, that when secreted into the extracellular milieu, mediates
downstream inflammatory responses in endotoxemia, arthritis, and sepsis. HMGB1
is properly defined as a "cytokine" because it stimulates pro inflammatory
responses in monocytes/macrophages, is produced during inflammatory responses in
vivo in standardized models of systemic and local inflammation,
mediates delayed endotoxin lethality, and is required for the full expression
of inflammation in animal models of endotoxemia, sepsis, and arthritis. HMGB1
is either actively secreted by monocytes/macrophages or passively released from
necrotic cells from any tissue. These pathways are central for the biology of
HMGB1 as a cytokine, since they provide key mechanisms that integrate the
inflammatory response to infectious and non-infectious cell injuries. Receptor
signal transduction of HMGB1 occurs in part through the receptor for advanced
glycation end-products (RAGE) expressed on monocytes/ macrophages, endothelial
cells, neurons, and smooth muscle cells. HMGB1 is a “late-acting” cytokine,
because it first appears in the extracellular milieu 8-12 hours after the
initial macrophage response to pro-inflammatory stimuli. Knowledge of the
cytokine role of HMGB1 has implications for understanding
"downstream" cytokine cascades, regulation of delayed innate immune
responses, and targeting treatment towards these processes. Effectiveness of
delayed treatment with HMGB1 blockade up to 24 hours after induction of
experimental sepsis offers a unique window of opportunities to allow rescue
from lethal sepsisHMGB1 is a
member of the high mobility group protein super family that has been widely
studied as nuclear proteins that bind DNA, stabilize nucleosomes, and
facilitate gene transcription. Surprisingly, a series of recent discoveries
revealed a cytokine activity of HMGB1, that when secreted into the
extracellular milieu, mediates downstream inflammatory responses in
endotoxemia, arthritis, and sepsis. HMGB1 is properly defined as a
"cytokine" because it stimulates proinflammatory responses in
monocytes/macrophages, is produced during inflammatory responses in
vivoin standardized models of systemic and local inflammation,
mediates delayed endotoxin lethality, and is required for the full expression
of inflammation in animal models of endotoxemia, sepsis, and arthritis. HMGB1
is either actively secreted by monocytes/macrophages or passively released from
necrotic cells from any tissue. These pathways are central for the biology of
HMGB1 as a cytokine, since they provide key mechanisms that integrate the
inflammatory response to infectious and non-infectious cell injuries. Receptor
signal transduction of HMGB1 occurs in part through the receptor for advanced glycation
end-products (RAGE) expressed on monocytes/ macrophages, endothelial cells,
neurons, and smooth muscle cells. HMGB1 is a “late-acting” cytokine, because it
first appears in the extracellular milieu 8-12 hours after the initial
macrophage response to pro-inflammatory stimuli. Knowledge of the cytokine role
of HMGB1 has implications for understanding "downstream" cytokine
cascades, regulation of delayed innate immune responses, and targeting
treatment towards these processes. Effectiveness of delayed treatment with
HMGB1 blockade up to 24 hours after induction of experimental sepsis offers a
unique window of opportunities to allow rescue from lethal sepsis
The recent success of
several important trials has fuelled interest in further therapeutic developments.
Here, I review the many different strategies that are being investigated,
focusing in particular on those that are in late pre-clinical, or early
clinical development. These can be broadly divided into three groups:
strategies aimed at bacterial targets, strategies aimed at disorders of immune
regulation in the host, and finally, other novel strategies based on modifying
host response like super antigens . Which, if any, of these will prove
successful in large clinical trials is unknown. Nevertheless, the fact that
sepsis has finally proved tractable as a target for new drug development lends
support to those who believe that at least some of the compounds identified in
this paper will prove to have clinical benefit..........(continued but not published in the blog for safety purpose)
Reference
1] , , , , . The impact of timing of
antibiotics on outcomes in severe sepsis and septic shock: a systematic review
and meta-analysis. Crit Care Med 2015;43:1907-191
2] , , , et al. Early lactate-guided
therapy in intensive care unit patients: a multicenter, open-label, randomized
controlled trial. Am J Respir Crit Care Med 2010;182:752-761
3] , , , et al. Diagnosing
sepsis is subjective and highly variable: a survey of intensivists using case
vignettes. Crit Care 2016;20:89-89
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