Septicemia and Shock: Pathogenesis and Novel Therapeutic Strategies

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]

[1] ¹Department of Pathology, Murshidabad District Medical College,

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 

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 

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] Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. 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] Jansen TC, van Bommel J, Schoonderbeek FJ, 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] Rhee C, Kadri SS, Danner RL, 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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