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Hayk Minasyan
PII: S0883-9441(16)31053-X
DOI: doi: 10.1016/j.jcrc.2017.04.015
Reference: YJCRC 52482
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Please cite this article as: Hayk Minasyan , Sepsis and septic shock: Pathogenesis and
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Hayk Minasyan
Address for correspondence:
Mamikonyanz 38-38, Yerevan, Armenia, 0014
Tel: [+374] 77255295
E-mail address: haykminasyan@rambler.ru
Abstract
The majority of bacteremias do not develop to sepsis: bacteria are cleared from the bloodstream.
Oxygen released from erythrocytes and humoral immunity kill bacteria in the bloodstream.
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Sepsis develops if bacteria are resistant to oxidation and proliferate in erythrocytes. Bacteria
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provoke oxygen release from erythrocytes to arterial blood. Abundant release of oxygen to the
plasma triggers a cascade of events that cause: 1. oxygen delivery failure to cells; 2. oxidation of
plasma components that impairs humoral regulation and inactivates immune complexes; 3.
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disseminated intravascular coagulation and multiple organs failure. Bacterial reservoir inside
erythrocytes provides the long-term survival of bacteria and is the cause of ineffectiveness of
antibiotics and host immune reactions. Treatment perspectives that include different aspects of
sepsis development are discussed.
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Keywords: bacteremia, sepsis, septic shock, pathogenesis, treatment.
Introduction
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Sepsis is both best known yet most poorly understood medical disorders [1]. Sepsis leads to
shock, multiple organ failure and death if not recognized early and treated promptly [2]. It is a
serious clinical condition that represents a patients response to infection and has a high mortality
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rate [3]. Sepsis remains the dominant challenge in the care of critically ill patients [4]. More than
30 million cases of sepsis worldwide per annum are estimated. The incidence of sepsis increases
9-13% annually, a mortality rate is 33-35% (Tab. 1). The most common sites of infection are the
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lungs (40%), abdomen (30%) and urinary tract (10%) [13]. Sepsis may be caused by gram-
positive, gram-negative and poly microbial infection [14, 15]. Gram-negative infection most
often occurs in the lungs [16]. Staphylococcus aureus and Streptococcus pneumoniae are gram-
positive isolates, whereas Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa
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predominate among gram-negative isolates [17, 18]. Gram-positive organisms cause sepsis by
producing exotoxins and by their cell wall components [19]. Gram-negative bacteria cause
sepsis by their membrane lipopolysaccharides (endotoxins) [20]. Bacterial toxins play a pivotal
role in the pathophysiology of sepsis, however, the literature illustrates that no single
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whereas intravasal defense is fulfilled by erythrocytes. The humoral immunity events take place
in pre-septic stage and interfere with the study of sepsis per se. As a result, the pathogenesis
and pathophysiology of some pivotal aspects of sepsis remain unclear.
Bacteria proliferate in the tissues being resistant to complement. Blood natural resistance factors
(complement, lysozym, etc.) are not effective if infection enters the blood from the tissues. Sepsis
develops when bacteria in the bloodstream survive oxidation on the surface of erythrocytes [32-
36].
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the outer cell wall is compensated for by the presence of exposed peptidoglycan and a range of
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other toxic secreted products. Cell wall components of gram-positive bacteria may signal via the
same receptor as gram-negative endotoxin [37]. Gram-negative organisms are associated with
poorer outcomes in first-hit infections; an inverse relationship between Gram status and mortality
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is observed in second-hit infections [38].
The majority of sepsis causing bacteria is facultative anaerobes [39]. This type of respiration is
the most flexible and it facilitates pathogen survival, proliferation and dissemination in the
variety of environmental conditions. The pathogens that are not facultative anaerobes, may
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express additional respiratory mechanisms that make their respiration close to facultative
anaerobes [40, 41].
All sepsis causing bacteria produce superoxide dismutase (SOD), catalase and glutathione
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peroxidases (tab.2), that protect them against oxidative stress caused by reactive oxygen species.
The primary source of oxidative stress for sepsis causing bacteria is the attack by host phagocytic
cells. All successful pathogens have evolved effective systems for defense against oxidative
stress [42]. Phagocytes utilize the cytotoxic effects of the reactive oxygen species, such as
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superoxide, hydrogen peroxide, and the highly toxic hydroxyl radical. Sepsis causing bacteria
have evolved effective enzymatic pathways of oxidant inactivation, including those catalyzed by
superoxide dismutase (SOD), catalase/peroxidase, and glutathione in combination with
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glutathione peroxidase and glutathione reductase [43]. The same pathways may protect sepsis
causing bacteria from oxidation and killing on the surface of erythrocytes [34].
Sepsis causing bacteria may be either oxidase positive or oxidase-negative. The production of
cytochrome c oxidase has no critical role in causing sepsis.
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Certain structures of bacteria are indispensable for causing sepsis. All sepsis causing bacteria
have S-layer and produce capsules, slime layer and biofilm (tab. 2). These structures protect the
bacteria in the tissues against phagocytosis, ROS, lytic enzymes, immune complexes, etc.,
whereas in the bloodstream capsule and slime layer prevent triboelectric charging, attraction and
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fixation on the surface of erythrocytes, oxidation and killing by the oxygen released from
erythrocytes [33 ].
Sepsis causing bacteria produce hemolysins . Erythrocytes are the main bactericidal cells in the
bloodstream and hemolysins are necessary for bacterial survival in the bloodstream. If the speed
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of bacterial growth in the tissue is limited by host immune reactions, bacteria produce a capsule,
slime layer and biofilm for surviving. After entering the bloodstream, bacterial capsule and slime
layer prevent triboelectric charging and fixation on the surface of erythrocytes. If bacteria
rapidly proliferate in the tissues, they are short of time to produce a capsule and slime layer and
after entering the bloodstream, they are caught and fixed on the surface of erythrocytes. If
bacteria survive oxidation on the surface of erythrocytes, they produce hemolysins that destroy
erythrocytes or provide bacterial penetration into the inner space of erythrocytes. Hemolysins are
important for the development of sepsis to advanced stages.
Motility is not a crucial factor for causing sepsis (tab 2.). Sepsis causing bacteria may be either
motile or not motile organisms.
intracellular granules to form a phagolysosome [44]. In the phagolysosome the bacteria are
killed after exposure to enzymes, antimicrobial peptides and reactive oxygen species (ROS) [45].
Neutrophils undergo an oxidative burst during which the NADPH oxidase complex assembles
at the phagosomal membrane and produces O2-, which is rapidly converted to hydrogen peroxide
by the enzyme superoxide dismutase. In turn, a constituent of the azurophil granules,
myeloperoxidase, generates hypochlorous acid (HOCl) from hydrogen peroxide. HOCL is the
most effective bacterial killer [46].
Neutrophils can degranulate and release antimicrobial factors into the extracellular space [47].
They can also generate neutrophil extracellular traps (NETs), which are composed of granule and
nuclear constituents that kill bacteria extracellularly [48]. NETs disarm pathogens with elastase,
cathepsin G and histones that have a high affinity for DNA [49]. NETs may serve as a physical
barrier that prevents further spread of the pathogens [50].
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Platelets activate neutrophils to trap bacteria. Platelets rapidly localize to sites of injury and
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infection [51]. Both platelets and neutrophils have the potential to trap microbial pathogens
independently of each other; however, together platelet-neutrophil interactions induce
transcellular synthesis and hyperactivation of neutrophils to produce increased pro-inflammatory
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molecules [50, 52]. Platelets have the ability to bind and internalize bacteria through engulfing
endosome-like vacuoles that fuse with the -granules of the platelet and allow the granular
proteins to have access to the pathogens [53]. As a result, thrombocytopenia correlates with the
severity of the sepsis and the rate of mortality [54].
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4.Survival of sepsis causing bacteria in phagocytes
After phagocytosis by macrophages, bacteria are located in a membrane-bound vacuole
(phagosome), but the ensuing trafficking of this vacuole and subsequent bacterial survival
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strategies vary considerably [55]. If the ingested bacteria have no intracellular survival
mechanisms, the bacteria-containing phagosomes fuse with the lysosomal compartment, and
bacteria are digested within 1530 min. The metabolic burst in activated phagocytes results in
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production of nitric oxide and reactive oxygen species, such as chloramines, hydroxyl radicals,
and hydrogen peroxide, which are usually converted into the potent oxidant hypochlorous acid
[56]. The cascade of these events is the following (see fig. 1). After phagocytosis lysosomes fuse
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with the phagosome, forming a phagolysosome and proteases are introduced into the phagosome.
In addition, a membrane protein phagocyte oxidase (NADPH oxidase) winds up in the membrane
of the phagolysosome. Phagocyte oxidase takes an electron from NADPH and transfers it to O 2,
forming the superoxide radical, O2-. . The superoxide radical is converted to hydrogen peroxide
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by superoxide dismutase. Hydrogen peroxide can damage microbes, but it is converted to more
effective bactericidal (HOCl) by myeloperoxidase. Hypochlorite is the most effective
intracellular bactericidal.
Sepsis causing bacteria protect themselves against the oxygen-dependent bactericidal mechanism
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oxygen (02) that is relatively non toxic for facultative anaerobes. This conversion rapidly
depletes all converted hydrogen peroxide to innocuous water and oxygen and prevents formation
of extremely harmful for bacteria hydrochloride.
oxidation on the membrane of erythrocytes, they enter erythrocytes by making holes in the
membrane. Inside erythrocytes bacteria may be killed by higher concentration of oxygen.
However, bacteria may survive inside erythrocytes if there is lack of oxygen or bacteria are
resistant to oxidation (Fig. 2, scenario 3). Surviving, bacteria proliferate in erythrocyte and the
latter bacterial incubator and reservoir [34, 35]. Bacteria inside erythrocytes have nutrients for
proliferation, besides, they are out of reach of antibiotics, immune complexes and other
antibacterial factors. Bacterial proliferation tears erythrocyte membrane and bacteria, being
released back into the plasma, infect new erythrocytes.
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consequences of these two events determine the course of sepsis and its deterioration to septic
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shock. Oxidation of blood plasma components and lack of oxygen in erythrocytes cause distant
injury of the tissues.
6.1.Oxidation of blood plasma components
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The oxidation of blood plasma components, including regulatory hormones, proteins, peptides
and other active substance is one of ignored factors of sepsis and septic shock. Oxidation of
plasma components destroys humoral regulation. Human body comprises two separate but
interacting compartments: (a) compartment of blood circulation (pulmonary and systemic
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circulation); (b) compartment out of blood circulation. In the majority of cases, bacterial infection
proliferates in the compartment out of blood circulation and then enters into the compartment of
blood circulation. It has different consequences: from innocuous bacteremia to fatal septic shock.
Bacteremia, sepsis, severe sepsis and septic shock may be interpreted as a continuum different
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amount of oxygen released by erythrocytes into plasma. Bacterial stimulation of the surface
receptors of erythrocytes causes the release of oxygen. The more oxygen is released from
erythrocytes to the arterial blood, the more severe is sepsis. The consequences of oxygen release
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are multiple. First, erythrocytes become unable to supply oxygen and perform their respiratory
(oxygen transportation) function. As a result, general multi-organ hypoxia develops. Second,
released oxygen activates platelets and causes disseminated intravascular coagulation. Third,
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released oxygen is highly reactive and destroys and transforms plasma proteins, peptides,
immune complexes, hormones, amino acids, fatty acids, vitamins and many other substances
necessary for cell nutrition, proliferation, protection, energy production, functioning, etc.
Proteins are substrates for biological oxidation [57]. Oxidative changes to proteins lead to
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pathway of hGH degradation [59]. The Growth Hormone and Insulin-like Growth Factor-1
(IGF-1) axis play a pivotal role in critical illness. Protein wasting with skeletal muscle loss,
delayed wound healing, and impaired recovery of organ systems are some of the most feared
consequences [60]. Growth hormone administration reduces nitrogen production and improves
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nitrogen balance in patients with severe sepsis [61]. Oxidative inactivation of other proteins, for
example, insulin, impairs the ability of cells to uptake glucose, amino acids and other essential
substances. Dityrosine formation and other oxidative chemical changes of insulin due to its
oxidation decrease and abolish its biological activity [62]. Deactivation of insulin causes
hyperglycemia - one of the metabolic derangements that influence sepsis outcome [63-66].
The oxidation of blood components may cause hypothalamic-pituitary-adrenal insufficiency [67].
Primary and secondary adrenal insufficiency occurs in patients with sepsis and is associated with
a poor outcome [68 - 71]. Blood oxidation also affects the hypothalamo-pituitary-thyroidal axis,
inactivating thyrotropin, thyroid gland hormones (triiodothyronine(TT3), thyroxine (TT4) and
their binding proteins. Thyroid hormone regulates metabolism and has an impact on sepsis
prognosis. The level of TT4 is lower in patients with septic shock than in patients without septic
shock [72-74]. De-iodinations of iodothyronines play key roles in metabolic regulation [75, 76].
Vasopressin (Antidiuretic hormone) is oxidized as well. Oxytocin and vasopressin are
oxidized with the formation of dityrosine [77]. Its oxidation and depletion cause vasodilatory
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shock - a syndrome with high mortality [78-81]. Low expression levels of Angiotensin II and
ACE (angiotensin converting enzyme) are valuable in predicting the mortality of patients with
severe sepsis. Systemic vasodilatation and arterial hypotension are landmarks of septic shock
[82].
Albumin oxidation causes hypoalbuminemia in sepsis [83,84]. Even mild oxidation of human
serum albumin (HAS) impairs HSA functional properties including protease susceptibility,
ligand-binding affinity and antioxidant activity [85-87]. The major structural change in oxidized
HSA is a disulfide-bonded cysteine at the thiol of Cys34 of reduced HAS [88].
Oxidative damage results in protein modification. [89]. Hypoalbuminemia is an independent
mortality predictor [90]. Albumin is recommended as the resuscitation fluid in sepsis [91, 92],
although it is still unclear whether the use of albumin decreases mortality or not [93,94].
Oxygen released from erythrocyte destroys also immune complexes and immunoglobulins,
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particularly IgG and IgM . The oxidation of IgG significantly changes the immunoreactivity and
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specificity of IgG fractions [95]. Oxidized immunoglobulins have autoimmune and
proinflammatory activity [96-98].
Low levels of immunoglobulins are frequent in severe sepsis and septic shock [99-101].
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However, intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have not shown
the benefit for the treatment of sepsis [102,103]. It may be explained by the destruction
(oxidation) of injected immunoglobulins, besides, bacteria inside erythrocytes are out of reach of
immunoglobulins.
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Thus, oxygen release to blood plasma from erythrocytes destroys humoral regulation. This may
be one of the causes of the development of multiple organ dysfunction syndrome (known as
multiple organ failure or multisystem organ failure) [104-107].
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6.2. Anemia, cell hypoxia and lactate production
The release of oxygen to arterial blood (before erythrocytes enter to capillaries) causes failure of
oxygen delivery to cells and hypoxia [33-36]. Another co-factors of hypoxia is anemia caused by
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hemoglobin pouring out, besides, they penetrate inside erythrocytes. The liver and, especially, the
spleen actively destroy injured and bacteria-containing erythrocytes [33-36].
Diminished availability of oxygen at the cellular level determines general dysfunction of cells.
Tissue-related hypoxic injury results from hypoxemia and hypoperfusion and cytokine-mediated
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mitochondrial dysfunction termed cytopathic hypoxia [112-116]. The lack of oxygen transforms
cell metabolism from aerobic to anaerobic. As a result, Krebs cycle is suppressed and anaerobe
metabolism with lactic acid accumulation occurs. Elevated lactic acid is a marker for the
suboptimal supply of oxygen to the tissues and is associated with increased mortality in sepsis
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[117-127]. Lack of oxygen delivery to the tissues results in decreased cellular metabolism and
increase in cellular lactate production [117-121]. High levels of lactic acid are associated with
increased mortality [118-127]. This association is independent of organ dysfunction [118-122].
Lactate clearance is more useful parameter for guiding therapy (the initial lactate - subsequent
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7.Diagnostic problems
Sepsis diagnosis relies on nonspecific physiological criteria (including changes in temperature
and heart and respiration rates) and culture-based pathogen detection. This results in diagnostic
uncertainty, therapeutic delays, the mis- and overuse of antibiotics and many other problems that
increase mortality [128-131]. Blood cultures are used to identify the pathogens and are the gold
standard for the diagnosis of bacteremic patients. Blood cultures provide unambiguous etiology
of the infection and (following subculture) purified colonies for antimicrobial susceptibility
testing. However, getting the colonies takes twothree days and this approach is slow and leads
to delayed and inappropriate treatment [132-134]. Moreover, sepsis may be culture negative
[135-137] and culture false-positive [138-140]. The accurate and timely detection of sepsis
remains a challenge [141]. For early detection of sepsis different markers are used, for example,
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in an observational multicenter design with blood culture as the comparator [167]. Systems
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biology approaches such as transcriptomics, proteomics, and metabolomics have been tested as
sepsis biomarkers [168,169]. However, despite decades of research and attempts of sepsis early
diagnostics, improvements in the treatment of sepsis have been modest [170].
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Vital phase-contrast microscopy of the blood and microscopy of stained blood samples may be
informative for detection of sepsis. Revealing of living bacteria in erythrocytes shows that sepsis
is developing to more advanced stages. Bacteria may also be seen on the surface of erythrocyte
but as soon as blood is taken from a vessel erythrocytes lose triboelectric charge, and bacteria are
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released to plasma [32-35]. Out of the bloodstream (in vitro) bacteria are not triboelectrically
charged and can proliferate [33, 36]. The refractive index of some pathogens is close to the index
of erythrocyte inner media and so these bacteria may be optically invisible in erythrocytes [32].
Phase-contrast microscopy and differential interference-contrast microscopy are effective and
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simple methods for immediate revealing bacteremia and making predictions regarding its course.
Dark field microscopy is an additional microscopic technique, however, it has disadvantages
artifacts and image distortions. The microscopy of the blood plasma precipitate after plasma
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8.Treatment problems:
Sepsis is a systemic infection. Empiric antimicrobial therapy is the base of the treatment
[171,172]. Current guidelines recommend starting antibiotic therapy within one hour of
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identification of septic shock [173]. Every hour delay is associated with a 6% rise in mortality
[174-176]. Survival rates dropped when antimicrobial treatment was delayed to within the sixth
hour [131]. There are no prospective data that early broad-spectrum antibiotic therapy reduces
mortality in severe sepsis [177], but prompt initiation of antimicrobial therapy remains important
for suspected infections [179,179]. If the pathogen is resistant to antibiotic, early or late initiation
of antibiotic therapy cannot improve the outcome. Inappropriateness of empirical antibiotic
therapy can contribute to high level of mortality [180]. The crisis emerges of antibiotic resistance
for microbial pathogens [181-183]. Without new and effective antibiotics, the problem will
escalate. However, new antibiotics cannot increase the effectiveness of sepsis therapy if
pathogens proliferate inside erythrocytes. [34]. Antibiotics kill bacteria in blood plasma, but
insufficiently penetrate erythrocytes for killing bacteria there. Constant bacterial reservoirs in
erythrocytes decreases antibacterial and immune therapy effectiveness and may be one of the
factors that make sepsis therapy so problematic.
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9.Treatment perspectives
Although improvements in supportive care of patients with sepsis (more effective and less
damaging mechanical ventilation, improved fluid resuscitation, and broad-spectrum antibiotic
coverage) have improved survival rates, sepsis remains a condition with high mortality. Despite
many clinical trials, no FDA-approved drug is available for use in sepsis [184].
The biology of sepsis is complex and not specific to infection. More than 100 randomized
clinical trials have tested the hypothesis that modulating the septic response to infection can
improve survival. None of these have resulted in new treatments [185].
The treatment of sepsis should be based on the understanding of its pathogenesis. The
pathogenesis of sepsis is not fully understood. Bacteria from external or local sources enter
bloodstream causing bacteremia. Phagocytosis in the bloodstream is impossible and blood
humoral bactericidal factors and erythrocytes are the main antibacterial forces in the bloodstream.
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Both erythrocytes and bacteria are triboelectrically charged in the bloodstream. The charge of
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erythrocytes attracts the charge of bacteria and keeps bacteria on the surface of erythrocytes. The
interaction of the charges at the surface of erythrocytes stimulates the release of oxygen from
oxyhemoglobin. The oxygen is released from hemoglobin as a mixture of different allotropes of
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oxygen (monatomic oxygen O(3P), dioxygen, singlet oxygen, triatomic oxygen O3, etc.) that are
very reactive and kill bacteria by oxidation. This auspicious scenario is accompanied with no or
mild clinical signs and ends without complications. Bacteria can survive oxidation having thick
capsule, slime layer and producing catalase, SOD and GPX. If bacteria survive oxidation on the
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surface of erythrocyte, they may: 1. cause an intense release of oxygen from erythrocytes to the
plasma without penetrating erythrocytes; 2. cause the oxygen release and then penetrate
erythrocytes. If bacteria do not penetrate erythrocytes, immune complexes and antibiotics may
eliminate the infection. If bacteria are killed inside erythrocytes, bacteremia becomes self-limited
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and does not develop to sepsis. Released oxygen oxidizes components of plasma and causes
hypoxia and functional problems in organs and tissues. Sepsis starts when bacteria survive in
erythrocytes, becoming a constant source of bacterial proliferation and dissemination. Antibiotics
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and immune complexes cannot kill bacteria inside erythrocytes and the infection becomes
persistent and uncontrollable. Massive release of oxygen from erythrocytes causes disseminated
intravascular coagulation, oxidation of plasma components (hormones, proteins, peptides,
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cytokines, etc.), makes impossible oxygen delivery to cells, and leads to multiple organ failure.
The cornerstone of sepsis therapy should be: a. arterial blood clearing from pathogens; b.
prevention of premature release of oxygen from erythrocytes; c. prevention of bacterial reservoir
forming in erythrocytes. The following is promising:
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binding protein calprotectin (CP) reduces bacterial superoxide dismutase activity [190,191].
Bacterial MnSOD phosphorylation on serine and threonine residues decreases the bacteria
capacity to counteract ROS [192].
capsule production. As a result, bacterial virulence decreases and bacteria killing by oxidation
increases. Capsule inhibitory drugs may become an important addition to anti-sepsis therapies.
In the biofilm form, bacteria are more resistant to various antimicrobial treatments, can survive
harsh conditions and withstand the host's immune system [202, 203] Biofilm-associated
infections are very difficult to treat with conventional antibiotics. A potential antibiofilm drug
that can either facilitate the dispersion of preformed biofilms or inhibit the formation of new
biofilms is needed [204]. To date, many antibiofilm compounds have been identified from
diverse natural sources, for example, brominated furanones [205], ursine triterpenes [206],
corosolic acid and asiatic acid [207], ginseng [208] and 3-indolylacetonitrile [209].
Indole, which is generated by the degradation of tryptophan by tryptophanase [210] is an
intercellular signal molecule that can affect multiple aspects of some bacterial species [211]
inhibiting biofilm formation and motility [212]. N-acyl homoserine lactones, D-amino acids,
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monomeric trimethylsilane (TMS), ionic liquids, particularly, 1-alkylquinolinium bromide ionic
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liquids exhibit promising antimicrobial and antibiofilm properties [213-217].
Nitric oxide (NO) is a signal for biofilm dispersal, inducing the transition from the biofilm mode
of growth to the free swimming planktonic state [218].
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Unfortunately, till now no antibiofilm drug has been registered and used in clinical practice [219,
220].
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The idea of bacteria removal from the bloodstream was offered more than 25 years ago [221]. E.
coli bacteria were successfully removed from contaminated RBC/plasma by using a special
matrix of micro-encapsulated albumin activated charcoal (ACAC). The data indicated that the
bacteria adhered to the ACAC, but that the charcoal was not bactericidal.
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Another device for removing bacterial toxins from blood useful for treating sepsis was patented
10 years ago [222]. The device includes hollow fiber material for selective binding of the toxins
and removes bacterial lipopolysaccharides (LPS) and lipoteichoic acids (LTA) from blood or
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plasma in an extracorporeal perfusion system. Some years ago, for bacteria and endotoxin
removing from the blood magnetic nanoparticles (MNPs) modified with bis-Zn-DPA, a synthetic
ligand that binds to both Gram-positive and Gram-negative bacteria, was used [223].
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An external device that mimics the structure of a spleen and cleanses the blood in acute sepsis
has been tested recently[224]. Blood flowing from an infected individual is mixed with magnetic
nanobeads coated with an engineered human opsoninmannose-binding lectin (MBL)that
captures a broad range of pathogens and toxins without activating complement factors or
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coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed
blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-
negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing
through a biospleen unit. A mechanical devices has been developed to remove a variety of
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cytokines, lipopolysaccharide, or C5a from plasma [225]. It is unclear whether such devices
would be clinically efficacious for sepsis in humans.
A prototype in-line filtration/adsorption device has been developed using novel synthetic
pyrolysed carbon monoliths with controlled mesoporous domains of 250 nm [226]. Porosity was
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characterized by SEM and porosimetry. Removal of inflammatory cytokines TNF, IL-6, IL-1
and IL-8 was assessed by filtering cytokine spiked human plasma through the walls of the carbon
modules under pressure. The effect of carbon filtration on the plasma clotting response and total
plasma protein concentration was also assessed. Significant removal of the cytokines IL-6, IL-1
and IL-8 was observed
A cytokine adsorption device (CAD) filled with porous polymer beads which efficiently depletes
middle-molecular weight cytokines from a circulating solution has been also developed [227].
Continuous venovenous hemofiltration (CVVHF) combined with plasmapheresis (TPE) reduced
mortality in single- and double-organ failure as high as 28 % in septic patients with combined
extracorporeal detoxification [228].
Bacteria and erythrocytes are triboelctrically charged in the bloodstream. Presumably, dialysis
like device with electric trap for bacteria may attract and remove bacteria from the
bloodstream.
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(and also inside erythrocytes) versus the amount bound to cellular debris or otherwise inactivated
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by local condition [230]. Intraerythrocytic concentrations of antibiotics is higher for lipid-soluble
compounds, besides, plasma proteins binds antibiotics [231]. Sepsis treatment is impossible
without antibacterial drug penetration to erythrocyte. In sepsis the erythrocyte is a long-term
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bacterial reservoir. High concentration of antibacterial drugs in erythrocyte is indispensable for
infection elimination.
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Alternative use of these treatments in sepsis patients may give controversial results because their
positive potential may be carried out in case of adequate use only. Both hyperbaric oxygen
therapy [232-235] and ozone therapy [236, 237] were studied in experimental and clinical sepsis,
but there are no recommendations regarding adequate use of these therapies. The latter may
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improve or deteriorate the condition of sepsis patients depending upon the stage of sepsis,
infection resistance to oxidation, severity of hypoxia, etc. Ozone and hyperbaric oxygen
therapies, increasing the oxidative potential of erythrocytes in arterial blood, facilitate bacteria
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killing by oxidation, but in case of bacterial resistance to oxidation and premature release of
oxygen from erythrocytes, ozone and hyperbaric oxygen therapies may provoke disseminated
intravascular coagulation and intensify blood plasma oxidation.
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be performed.
9.7. Search for optimal blood transfusion triggers for sepsis patients
Approximately 40-50% of patients admitted to the ICU are transfused at least 1 RBC unit. RBC
transfusion in sepsis does not improve oxygen delivery and consumption, mixed venous oxygen
saturation or lactate levels [251, 252]. RBC transfusions in sepsis are not associated with an
improvement in tissue oxygenation in spite of a significant increase in hemoglobin levels [253].
The existing evidence supports the use of restrictive transfusion triggers in most patients [254].
Optimal transfusion triggers in sepsis patients are not known. RBC transfusions cause
complications, such as infection, acute lung injury (TRALI), circulatory overload (TACO),
immunomodulation (TRIM), multiorgan failure and increased mortality [255]. Performing RBC
transfusion in sepsis the following should be taken into account: 1. the blood should be as fresh
as possible. Bacteria easily penetrate old erythrocytes. The lack of oxygen in erythrocytes
facilitates bacterial penetration as well; 2. in-bag hemolysis increases free hemoglobin (protein
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and iron) in patients plasma stimulating bacterial growth and proliferation; 3. The more massive
is bacteremia, the less effective is blood transfusion; 4. Sepsis patients are sensitive to even
minimal number of bacteria in transfused blood. Before blood transfusion a sterility test is
necessary.
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following. After attraction and fixation of bacteria on the surface of erythrocyte direct physical
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contact of bacterial body and erythrocyte membrane occurs. Electric charge interaction causes the
release of bacterial toxins. High local concentration of toxins on the surface of erythrocyte
irritates the membrane of erythrocyte causing oxygen release from erythrocyte. If bacteria are
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resistant to oxidation they continue to stimulate oxygen release from erythrocytes. Released
oxygen oxidizes plasma components and causes disseminated intravascular coagulation.
Bacterial toxins injure erythrocyte membrane and form pores that provide bacteria penetration.
The inactivation of bacterial toxins may prevent oxygen release and the penetration of bacteria to
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erythrocytes. The following is promising: 1. toxin production inhibition by means of bacterial
protein inhibition; 2. toxin inactivation by binding with synthetic polymers, natural or synthetic
antibodies, different toxin-inactivating compounds; 3. toxin inactivation by modulation of target
cell membrane characteristics.
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9. 9. Biological weapon against sepsis causing bacteria
Predation and antagonism is persistent at all levels of life, found in all walks of life and possibly
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in all environments. Predation and antagonism between microorganisms has been known for a
long time [261]. Antibiotics are the best illustration of antagonism between fungi and bacteria.
Antagonism and predation against sepsis causing pathogens are very promising. The use of
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treating certain infections in humans [262-265]. Bacterial isolates from septicemia patients
spontaneously secrete phages active against other isolates of the same bacterial strain, but not to
the strain causing the disease [266]. Such phages were also detected in the initial blood cultures,
indicating that phages are circulating in the blood at the onset of sepsis. The fact that most of the
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septicemic bacterial isolates carry functional prophages suggests an active role of phages in
bacterial infections [266]. Prophages present in sepsis-causing bacterial clones play a role in
clonal selection during bacterial invasion. The use of phages is an attractive option to battle
antibiotic resistant bacteria in certain bacterial infections, but the role of phage ecology in
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9.9.3. Saccharomyces therapy
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Saccharomyces boulardii (SB) is a non-pathogenic, thermophilic yeast, used as a probiotic strain
in the prevention or the treatment of intestinal diseases, mainly diarrheas [277, 278]. SB directly
inhibits the growth of several pathogens (Candida albicans, E. coli, Shigella, Pseudomonas
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aeruginosa, Staphylococcus aureus, Entamoeba hystolitica), and cell invasion by Salmonella
typhimurium and Yersinia enterocolitica [279-281]. SB exerts several anti-microbial activities
that could be divided in two groups: direct anti-toxin effects and inhibition of growth and
invasion of pathogens. The anti-toxin action elicited by SB is mainly due to small peptides
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produced by the yeast. A 54kDa serine protease is able to inhibit enterotoxin and cyto-toxic
activities of C. difficile by degradation of toxin A and B [281].
SB produces a phosphatase able to dephosphorylate endotoxins (such as lipopolysaccharide of E.
coli 055B5) and inactivates its cytotoxic effects [282]. SB also has a positive effect on the
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maintenance of epithelial barrier integrity during bacterial infection [283]. SB affects the immune
response of host cells and stimulates the secretion of secretory immunoglobulin A [284,285]. SB
inhibits the growth of Candida albicans [286]. Probably, the antimicrobial and antifungal
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Bacteria cannot proliferate in big vessels (arteries, veins) because blood high velocity causes
triboelectric charging that inhibits bacterial transmembrane metabolism. In arterial blood bacteria
are attracted by electric charge of erythrocytes and killed by released oxygen. In capillaries
bacteria are killed by being squeezed between erythrocytes, besides, during oxygen/CO 2
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exchange between erythrocytes and the tissues, bacteria are killed by oxidation. In venules and
small veins, slow blood flow and deoxygenation are auspicious for the proliferation of bacteria.
Infection may grow in vessels with slow blood flow (systemic veins, skin venous plexuses).
Decreased blood velocity increases the risk of thrombosis. Blood viscosity in venules increases
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100% when blood flow reduces 60% [287]. Coagulation abnormalities in sepsis range from a
small decrease in platelet count and subclinical prolongation of global clotting times to fulminant
disseminated intravascular coagulation (DIC), characterized by simultaneous widespread
microvascular thrombosis and profuse bleeding from various sites [288]. Blood clots become a
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source of iron and protein for bacterial proliferation. The acceleration of blood flow velocity
increases turboelectric charging of bacteria and decreases the risk of thrombosis. Blood
circulation may be accelerated by different ways: muscular exercises and physical rehabilitation
[289,290], special physiotherapy [291], massage [292], etc. Unfortunately, these procedures give
short-term effect.
Conclusion
In bacteremia, two events are critical for the development of sepsis: infection resistance to
oxidation and intensive release of oxygen to arterial blood. The consequences of these two events
determine bacteremia progression to sepsis and its deterioration to septic shock.
Infection resistance to oxidation provides bacterial survival on the surface of erythrocytes,
penetration of pathogens to erythrocytes, forming infection reservoir inside erythrocytes,
destruction of erythrocytes and anemia, infection dissemination to all organs and tissues.
ACCEPTED MANUSCRIPT
12
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release of oxygen from oxyhemoglobin is very problematic. The most perspective approach to
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sepsis and septic shock is prevention of bacterial penetration to erythrocytes and premature
release of oxygen to arterial blood. It may be achieved by suppression of bacterial antioxidant
mechanisms and inactivation of bacterial endotoxins and exotoxins. Development of new
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antimicrobials is a temporary and less effective approach. Bloodstream bacteria removal by
technical devices, adequate replacement therapy and the use of biological weapon against
sepsis causing bacteria may be useful as addition to sepsis and septic shock combined therapy.
No funding US
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There is no conflict of interest
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REFERENCES
ED
1. Cohen J, Vincent J-L, Adhikari NKJ, Machado FR, Angus DC, Calandra T, Jaton K,
Giulieri S, Delaloye J, Opal S, Tracey K, van der Poll T, Pelfrene E. The Lancet
Infectious Diseases Commission: Sepsis: a roadmap for future research. Lancet Infect
PT
10. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide burden
of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med 2014;
2: 380386.
11. Walkey AJ, Wiener RS, Lindenauer PK. Utilization patterns and outcomes associated
with central venous catheter in septic shock: a population-based study. Crit Care Med.
2013;41(6):1450.
12. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe
sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-
2012. JAMA. 2014;311(13):1308.
13. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of sepsis.
The CUB-Rea network. Am J Respir Crit care Med. 2003; 168: 165-172.
14. Annane D, Bellissant E, Cavaillon JM. Septic shock: seminar. Lancet 2005;365:63-78
T
15. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes
IP
of infection in intensive care units. JAMA 2009;302:2323-2329.
16. Offord R. Causes and features of sepsis. Hospital Pharmacists. 2002; 9: 93-96.
17. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with
CR
septic shock. N Engl J Med 2012; 366:2055-2064.
18. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis
analyzed by causative microorganism and treatment effects of drotrecogin alfa
(activated). Clin Infect Dis 2003;37:50-58.
US
19. Balk RA. Severe sepsis and septic shock: definitions, epidemiology, and clinical
manifestations. Crit Care Clin 2000; 16: 179-192.
20. Horn KD. Evolving strategies in the treatment of sepsis and systemic inflammatory
response syndrome (SIRS).Q J Med. 1998; 91:265-277.
AN
21. Remick DG. Pathophysiology of Sepsis. Am J Pathol. 2007 May; 170(5): 14351444.
22. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune
responses to sepsis. Virulence. 2014 Jan 1;5(1):36-44.
M
23. Wiersinga WJ. Current insights in sepsis: from pathogenesis to new treatment targets.
Curr Opin Crit Care. 2011 Oct;17(5):480-486.
24. Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate
ED
26. Wu M, Gu J-T, Yi B, Tang Z-Z, Tao G-C. MicroRNA-23b regulates the expression of
inflammatory factors in vascular endothelial cells during sepsis. Exp Ther Med. 2015
Apr; 9(4): 11251132.
27. Lockhart PB, Brennan MT, Sasser HC, Fox PC, Paster BJ, Bahrani-Mougeot FK.
CE
Jun;33(6):401-407.
29. MacFarlane TW, Samaranayake LP. Clinical Oral Microbiology, London, Wright,
1989.223P
30. Hiffajee AD, Socransky SS, Dzink JL et al. Clinical, microbiological and immunological
features of subjects with destructive periodontal diseases. J Clin Periodontol.
1988;15:240-246.
31. Goodson JM. Tanner AC, Haffajec AD et al. Patterns of progression and regression of
advanced destructive periodontal disease. J Clin Periodont.1982;9:472-471.
32. Minasyan H. Erythrocyte and blood antibacterial defense. Eur J Microbiol Immunol.
2014;4(2):138143.
33. Minasyan H. Mechanisms and pathways for the clearance of bacteria from blood
circulation in health and disease. Pathophysiology, 2016;23:61-66.
ACCEPTED MANUSCRIPT
14
34. Minasyan H. Erythrocyte: Bacteria Killer and Bacteria Pray. International Journal of
Immunology. Special Issue: Antibacterial Cellular and Humoral Immunity. 2014;2(5-
1):1-7.
35. Minasyan H. Erythrocyte and Leukocyte: Two Partners in Bacteria Killing. International
Reviews of Immunology. 2014;33 (6):490497.
36. Minasyan H, Urumyan SA, Mkhitaryan DS. Erythrocytes bactericidal role in human
immunity. The New Armenian Medical Journal, 2014;8(2):18-32.
37. Sriskandan S, Cohen J. Gram-positive sepsis. Mechanisms and differences from gram-
negative sepsis. Dis Clin North Am. 1999 Jun;13(2):397-412.
38. Morgan MP, Szakmany T, Power SG, Olaniyi P, Hall JE, Rowan K, Eberl M. Sepsis
Patients with First and Second-Hit Infections Show Different Outcomes Depending on
T
the Causative Organism. Front Microbiol. 2016;7:207. Epub 2016 Feb 26.
39. Hogg, S. (2005). Essential Microbiology (1st ed.). Wiley. pp. 99100. ISBN 0-471-
IP
49754-1.
40. Rock JD, Moir JW. Microaerobic denitrification in Neisseria meningitidis. Biochem Soc
CR
Trans. 2005 Feb; 33(Pt 1):134-136.
41. Rock JD, Mahnane MR, Anjum MF, Shaw JG, Read RC, Moir JW. The pathogen
Neisseria meningitidis requires oxygen, but supplements growth by denitrification.
Nitrite, nitric oxide and oxygen control respiratory flux at genetic and metabolic levels.
US
Mol Microbiol. 2005 Nov;58(3):800-809.
42. Miller RA, Britigan BE. Role of oxidants in microbial pathophysiology. Clin Microbiol
Rev. 1997;10:118.
43. Haas A, Goebel W. Microbial strategies to prevent oxygen-dependent killing by
AN
phagocytes. Free Radic. Res. Commun. 1992;16:137-157.
44. Lee W L, Harrison RE, Grinstein S. Phagocytosis by neutrophils, Microbes Infect.
2003;5 (14):1299-1306.
45. Roos D. Winterbourn CC. Immunology. Lethal weapons, Science. 2002;296
M
(5568):669-671.
46. Roos D, van Bruggen R, Meischl C. Oxidative killing of microbes by neutrophils,
Microbes Infect. 2003;5 (14):1307-15.
ED
2004;303 (5663):1532-1535.
49. Thomas MP, Whangbo J, McCrossan G, et al. Leukocyte protease binding to nucleic
acids promotes nuclear localization and cleavage of nucleic acid binding proteins. Journal
CE
T
Grenfell AM, Hicks JJ. Oxidation by reactive oxygen species (ROS) alters the structure
of human insulin and decreases the insulin-dependent D-glucose-C14 utilization by
IP
human adipose tissue. Front Biosci. 2005 Sep 1;10:3127-3131.
63. Taylor JH, Beilman GJ. Hyperglycemia in the intensive care unit: no longer just a marker
of illness severity. Surg Infect (Larchmt). 2005;6:233245.
CR
64. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van
Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N
Engl J Med. 2006;354:449461.
65. Leonidou L, Michalaki M, Leonardou A, Polyzogopoulou E, Fouka K, Gerolymos M,
US
Leonardos P, Psirogiannis A, Kyriazopoulou V, Gogos CA. Stress-induced
hyperglycemia in patients with severe sepsis: a compromising factor for survival. Am J
Med Sci. 2008 Dec; 336(6):467-471.
AN
66. Inzucchi SE. Management of hyperglycemia in the hospital setting. The New England
Journal of Medicine. 2006;355(18):19031911.
67. Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency. Crit Care Clin.
2001;17:25-41.
M
68. Annane D, Sbille V, Troch G, Raphal JC, Gajdos P, Bellissant E. A 3-level prognostic
classification in septic shock based on cortisol levels and cortisol response to
corticotropin. JAMA. 2000;283:1038-1045.
ED
69. Koo DJ, Jackman D, Chaudry IH, Wang P. Adrenal insufficiency during the late stage of
polymicrobial sepsis. Crit Care Med 2001;29:618-622
70. Schroeder S, Wichers M, Klingmller D, et al. The hypothalamic-pituitary-adrenal axis
of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit
PT
72. Lodha R, Vivekanandhan S, Sarthi M, Arun S, Kabra SK. Thyroid function in children
with sepsis and septic shock. Acta Paediatr. 2007 Mar;96(3):406-409.
73. Burman KDWartofsky L Thyroid function in the intensive care unit setting. Crit Care
AC
Clin2001;1743-17 57
74. Ho H C, Chapital AD, Yu M. Hypothyroidism and Adrenal Insufficiency in Sepsis and
Hemorrhagic Shock. Arch Surg. 2004;139(11):1199-1203.
75. Leonard JL, Visser TJ. Biochemistry of deiodination. In: Thyroid Hormone Metabolism
(Hennemann, G., ed.), Marcel Dekker, New York, NY.1986, pp.189-229.
76. McNabb FMA. Thyroid Hormones. Prentice Hall, En-glewood Cliffs, NJ, 1992.
77. Rosei MA, Coccia R, Blarzino C, Foppoli C, Mosca L. The oxidation of oxytocin and
vasopressin by peroxidase/H2O2 system. Amino Acids, 1995;8:385-391
78. Singh Ranger G. Antidiuretic hormone replacement therapy to prevent or ameliorate
vasodilatory shock. Med Hypotheses. 2002 Sep;59(3):337-340.
79. Baldasso E, Ramos Garcia PC, Piva JP, Einloft PR. Hemodynamic and metabolic
effects of vasopressin infusion in children with shock. J Pediatr (Rio J). 2007
Nov;83(5 Suppl):137-145.
80. Holmes CL, Patel BM, Russell JA, Walley KR.Physiology of vasopressin relevant to
management of septic shock. Chest. 2001 Sep;120(3):989-1002.
ACCEPTED MANUSCRIPT
16
T
Hirayama K. Identification and characterization of oxidized human serum albumin. A
IP
slight structural change impairs its ligand-binding and antioxidant functions.FEBS J.
2006 Jul; 273(14):3346-3357.
88. Yamada N, Nakayama A, Kubota K, Kawakami A, Suzuki E. Rinsho Byori .Structure
CR
and function changes of oxidized human serum albumin: physiological significance of
the biomarker and importance of sampling conditions for accurate measurement. 2008
May; 56(5):409-415.
89. Anraku M, Chuang VT, Maruyama T, Otagiri M. Redox properties of serum albumin.
US
Biochim Biophys Acta. 2013 Dec;1830(12):5465-5472. Epub 2013 May 3.
90. Lee SH, Jo YH, Kim K, Lee JH, Park HM, Rhee JE, Kim DH. Prognostic Importance
of Hypoalbuminemia in Patients with Severe Sepsis and Septic Shock. J Korean Soc
Emerg Med. 2013 Oct;24(5):599-606.
AN
91. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al; Surviving
Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving
Sepsis Campaign: international guidelines for management of severe sepsis and septic
M
from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006;333:1044.
94. Dubois MJ, Orellana-Jimenez C, Melot C, De Backer D, Berre J, Leeman M, et al.
Albumin administration improves organ function in critically ill hypoalbuminemic
patients: A prospective, randomized, controlled, pilot study. Crit Care
CE
Med.2006;34:2536-2540.
95. Bozic B, Cucnik S, Kveder T, Rozman B. Autoimmun Rev. 2006 Nov;6(1):28-32. Epub
2006 Jan 27.
96. Amano M, Kobayashi N, Yabuta M, Uchiyama S, Fukui K. Detection of histidine
AC
T
severe sepsis and septic shock. Critical Care Clinics. 2000;16( 2): 337352.
IP
106. Johnson D, Mayers I. Multiple organ dysfunction syndrome: a narrative review.
Canadian Journal of Anesthesia.2001; 48(50: 502-509.
107. Fry D E. Sepsis, Systemic Inflammatory Response, and Multiple Organ Dysfunction:
CR
The Mystery Continues. The American Surgeon, 2012;78( 1): 1-8.
108. Piagnerelli M, Boudjeltia KZ, Gulbis B. Vanhaeverbeek M, Vincent JS Anemia in sepsis:
the importance of red blood cell membrane changes. Transfusion Alternatives in
Transfusion Medicine, 2007; 9(3):143149.
US
109. van Beest PA, Hofstra JJ, Schultz MJ, Boerma EC, Spronk PE, Kuiper MA. The
incidence of low venous oxygen saturation on admission to the intensive care unit: a
multi-center observational study in The Netherlands. Crit Care. 2008;12(2):33.
110. Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in critical illness: insights into
AN
etiology, consequences, and management. Am J Respir Crit Care Med.
2012;185(10):1049-1057.
111. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon
M
115. Loiacono LA, Shapiro DS. Detection of hypoxia at the cellular level. Crit Care Clin. 2010
Apr;26(2):409-421.
116. Fink MP. Cytopathic Hypoxia : Mitochondrial Dysfunction as Mechanism Contributing
to Organ Dysfunction in Sepsis. Critical Care Clinics. 2001;17(1):219237.
CE
117. Arnold RC, Shapiro NI, Jones AE, et al; Emergency Medicine Shock Research Network
(EMShockNet) Investigators. Multicenter study of early lactate clearance as a
determinant of survival in patients with presumed sepsis. Shock. 2009;32(1):3539.
118. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with
AC
mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009;
37(5):16701677.
119. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with
improved outcome in severe sepsis and septic shock. Crit Care Med 2004;32(8):1637
1642.
120. Nguyen HB, Loomba M, Yang JJ, et al. Early lactate clearance is associated with
biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in
severe sepsis and septic shock. J Inflamm (Lond). 2010;7:6.
121. Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed
paradigm. OA Critical Care 2013 Mar 01;1(1):3.
122. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM. Surviving Sepsis
Campaign: International Guielines for Management of Severe Sepsis and Septic Shock:
2012. Crit Care Med. 2013 Feb;41(2):580-637.
ACCEPTED MANUSCRIPT
18
123. Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care. 2006
Aug;12(4):315-321.
124. Regnier MA, Raux M, Le MY, Asencio Y, Gaillard J, Devilliers C. Prognostic
significance of blood lactate and lactate clearance in trauma patients. Anesthesiology.
2012 Dec;117(6):1276-1288.
125. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE. Serum lactate
as a predictor of mortality in emergency department patients with infection. Ann Emerg
Med. 2005 May;45(5):524-528.
126. Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C, Milcarek B. Serum lactate
as a predictor of mortality in patients with infection. Intensive Care Med. 2007
Jun;33(6):970-977.
127. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettila V. Hemodynamic
T
variables related to outcome in septic shock. Intensive Care Med 2005 Aug;31(8):1066-
IP
1071.
128. Claus RA, Otto GP, Deigner HP, Bauer M. Approaching clinical reality: markers for
monitoring systemic inflammation and sepsis.Curr Mol Med. 2010 Mar; 10(2):227-235.
CR
129. Bauer M, Reinhart K. Molecular diagnostics of sepsis--where are we today? Int J Med
Microbiol. 2010 Aug; 300(6):411-413. Epub 2010 May 26.
130. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed
antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect
US
Dis. 2003 Jun 1; 36(11):1418-1423.
131. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D,
Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before
initiation of effective antimicrobial therapy is the critical determinant of survival in
AN
human septic shock. Crit Care Med. 2006 Jun; 34(6):1589-1596.
132. Ho KM, Robinson JO. Risk factors and outcomes of methicillin-resistant Staphylococcus
aureus bacteraemia in critically ill patients: a case control study. Anaesth Intensive Care.
M
135. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United
States from 1979 through 2000. N Engl J Med. 2003, 348:1546-1554.
136. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis.
BMJ 2007, 335:879-883.
CE
137. Cantey JB., Snchez PJ. Prolonged Antibiotic Therapy for Culture-Negative Sepsis in
Preterm Infants: Its Time to Stop! J Pediat 2011;159 (5):707708
138. Raja NS, Parratt D, Meyers M. Blood culture contamination in a district general hospital
in the UK: a 1-year study. Healthcare Infection. 2009;14(3):95100
AC
143. Ho KM, Lee KY, Dobb GJ, Webb SA. C-reactive protein concentration as a predictor of
in-hospital mortality after ICU discharge: a prospective cohort study. Intensive Care
Med. 2008 Mar; 34(3):481-487.
144. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation.
N Engl J Med. 1999 Feb 11; 340(6):448-454.
145. Sexton PM, Christopoulos G, Christopoulos A, Nylen ES, Snider RH Jr, Becker KL.
Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator
implications in sepsis. Crit Care Med. 2008 May; 36(5):1637-1640.
146. Limper M, de Kruif MD, Duits AJ, Brandjes DP, van Gorp EC. The diagnostic role of
procalcitonin and other biomarkers in discriminating infectious from non-infectious
fever. J Infect. 2010 Jun; 60(6):409-416.
147. Clec'h C, Fosse JP, Karoubi P, Vincent F, Chouahi I, Hamza L, Cupa M, Cohen Y.
T
Differential diagnostic value of procalcitonin in surgical and medical patients with septic
IP
shock. Crit Care Med. 2006 Jan; 34(1):102-107.
148. de Kruif MD, Limper M, Sierhuis K, Wagenaar JF, Spek CA, Garlanda C, Cotena A,
Mantovani A, ten Cate H, Reitsma PH, van Gorp EC. TX3 predicts severe disease in
CR
febrile patients at the emergency department. J Infect. 2010 Feb; 60(2):122-127.
149. Bottazzi B, Garlanda C, Cotena A, Moalli F, Jaillon S, Deban L, Mantovani A. The long
pentraxin PTX3 as a prototypic humoral pattern recognition receptor: interplay with
cellular innate immunity. Immunol Rev. 2009 Jan; 227(1):9-18.
US
150. Tsalik EL, Jaggers LB, Glickman SW, Langley RJ, van Velkinburgh JC, Park LP, Fowler
VG, Cairns CB, Kingsmore SF, Woods CW Discriminative value of inflammatory
biomarkers for suspected sepsis. J Emerg Med. 2012 Jul; 43(1):97-106.
151. Andaluz-Ojeda D, Bobillo F, Iglesias V, Almansa R, Rico L, Ganda F, Resino S,
AN
Tamayo E, de Lejarazu RO, Bermejo-Martin JF. A combined score of pro- and anti-
inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine. 2012
Mar; 57(3):332-336.
M
MT. Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis.
Shock. 2004 Oct; 22(4):309-313.
154. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J
Intern Med. 2004 Mar; 255(3):320-331.
PT
and mortality in a surgical intensive care unit..Anesth Analg. 2007 Sep; 105(3):715-723.
157. Dhainaut JF, Shorr AF, Macias WL, Kollef MJ, Levi M, Reinhart K, Nelson DR.
Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with
mortality and organ failure. Crit Care Med. 2005 Feb; 33(2):341-348.
AC
diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012 Jul
1;186(1):65-71.
164. Calandra T, Cohen J, International Sepsis Forum Definition of Infection in the ICU
Consensus Conference. The international sepsis forum consensus conference on
definitions of infection in the intensive care unit. Crit Care Med. 2005 Jul; 33(7):1538-
1548.
165. Socan M, Marinic-Fiser N, Kese D. Comparison of serologic tests with urinary antigen
detection for diagnosis of legionnaires' disease in patients with community-acquired
pneumonia. Clin Microbiol Infect. 1999 Apr; 5(4):201-204.
166. Peters RP, van Agtmael MA, Danner SA, Savelkoul PH, Vandenbroucke-Grauls CM.
New developments in the diagnosis of bloodstream infections. Lancet Infect Dis. 2004
Dec; 4(12):751-760.
T
167. Tissari P, Zumla A, Tarkka E, Mero S, Savolainen L, Vaara M, Aittakorpi A, Laakso S,
IP
Lindfors M, Piiparinen H, Mki M, Carder C, Huggett J, Gant V. Accurate and rapid
identification of bacterial species from positive blood cultures with a DNA-based
microarray platform: an observational study. Lancet. 2010 Jan 16; 375(9710):224-230.
CR
168. Hartlova A, Krocova Z, Cerveny L, Stulik J. A proteomic view of the host-pathogen
interaction: The host perspective.Proteomics. 2011 Aug; 11(15):3212-3220.
169. Wong HR. Genetics and genomics in pediatric septic shock. Crit Care Med. 2012 May;
40(5):1618-1626.
US
170. Franks Z, Carlisle M, and Rondina MT. Current challenges in understanding immune
cell functions during septic syndromes. BMC Immunol. 2015; 16: 11.
171. Burgess DS, Abate JB. Antimicrobial regimen selection. In: Dipiro JT, Talbert RL, Yee
GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy a pathophysiologic
AN
approach. 6th ed. New York: McGraw-Hill; 2005. pp. 19201921.
172. Opal SM. The Evolution of the Understanding of Sepsis, Infection, and the Host
Response: A Brief History Crit Care Clin 2009;25(4):637-663.
M
173. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med.
2008;36(1):296-327.
ED
174. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al. Surviving sepsis
campaign: international guidelines for management of severe sepsis and septic shock:
2012. Crit Care Med 2013;41: 580-637.
175. Soong J, Soni N. Sepsis: recognition and treatment. Clin Med 2012;12: 276-280.
PT
176. Reade MC, Angus DC. Epidemiology of sepsis and Non-infectious SIRS. In: Cavaillon
JM, editor. Sepsis and non-infection systemic inflamation, from biology to critical
care. Weinheim: Wiley-VCH Verlag GMbH and Co. KGaA; 2009. pp. 1327.
177. Siddiqui S, Razzak J. Early versus late pre-intensive care unit admission broad spectrum
CE
antibiotics for severe sepsis in adults. Cochrane Database Syst Rev. 2010;(10):CD007081
178. Brook I. The role of anaerobic bacteria in bacteremia. Anaerobe. 2010;16:183-189.
179. Textoris J, Wiramus S, Martin C, Leone M. Overview of antimicrobial therapy in
intensive care units. Expert Rev Anti Infect Ther. 2011;9:97-109.
AC
185. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med 2014; 20(4):195
203.
186. Phan TN, Kirsch AM, Marquis RE. Selective sensitization of bacteria to peroxide
damage associated with fluoride inhibition of catalase and pseudocatalase. Oral
Microbiol Immunol. 2001 Feb;16(1):28-33.
187. Tamanai-Shacoori Z.; Shacoori V. Jolivet-Gougeon A. Vo Van J M, Repre M,
Donnio PY, Bonnaure-Mallet M . The antibacterial activity of tramadol against bacteria
associated with infectious complications after local or regional anesthesia. Anesth Analg.
2007;105: 524-527.
188. Al-kuraishy H.M. Possible antibacterial possessions of tramadol hydrochloride for
urinary tract infection: In vitro study. Int. Pharmaceut. Sciencia. 2012;2:97-102 .
189. Minai-Tehrani D, Ashrafi IS, Mohammadi MK, Damavandifar ZS., Zonouz ER,
T
Pirshahed TE. Comparing Inhibitory Effect of Tramadol on Catalase of Pseudomonas
IP
aeruginosa and Mouse Liver. Current Enzyme Inhibition. 2014;10:54-58.
190. Damo S, Chazin W J, Skaar EP, Kehl-Fie TE . Inhibition of bacterial superoxide defense.
A new front in the struggle between host and pathogen. Virulence. 2012 May 1; 3(3):
CR
325328. doi: 10.4161/viru.19635 PMCID: PMC3442845.
191. Kehl-Fie TE, Chitayat S, Hood MI, Damo S, Restrepo N, Garcia C, et al. Nutrient metal
sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil
killing of Staphylococcus aureus Cell Host Microbe. 2011;10:158. 64 doi:
US
10.1016/j.chom.2011.07.004.
192. Archambaud C, Nahori MA, Pizarro-Cerda J, Cossart P, Dussurget O. Control of Listeria
superoxide dismutase by phosphorylation. J Biol Chem. 2006 Oct 20;281(42):31812-
AN
31822.
193. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, et al. Bad bugs, no drugs:
no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect
Dis. 2009;48:112.
M
194. Hyams C, Camberlein E, Cohen JM, Bax K, Brown JS. The Streptococcus
pneumoniae capsule inhibits complement activity and neutrophil phagocytosis by
multiple mechanisms. Infect Immun. 201078: 704715.
ED
2004 December;72(12):7107-7114.
198. Dinkla K, Sastalla I, Godehardt AW, Janze N, Chhatwal GS, Rohde M, Medina E.
Upregulation of capsule enables Streptococcus pyogenes to evade immune recognition by
AC
203. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant
microorganisms. Clin. Microbiol. Rev. 2002;15(2):167193.
204. Rabin N, Zheng Y, Opoku-Temeng C, Du Y, Bonsu E, O Sintim Herman.. Agents that
inhibit bacterial biofilm formation. Future Medicinal Chemistry. 2015; 7(5):647-671.
205. Hentzer M, Riedel K, Rasmussen TB Inhibition of quorum sensing in Pseudomonas
aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology.
2002;148(1): 87102.
206. Hu J-F, Garo E, Goering MG Bacterial biofilm inhibitors from Diospyros dendo. J. Nat.
Prod. 2006;69(1): 118120.
207. Garo E, Eldridge GR, Goering MG Asiatic acid and corosolic acid enhance the
susceptibility of Pseudomonas aeruginosa biofilms to tobramycin. Antimicrob. Agents
Chemother. 2007;51(5):18131817.
T
208. Wu H, Lee B, Yang L Effects of ginseng on Pseudomonas aeruginosa motility and
IP
biofilm formation. FEMS Immunol. Med. Microbiol. 2011;62(1):4956.
209. Lee JH, Cho MH, Lee J. 3-indolylacetonitrile decreases Escherichia coli O157:H7
biofilm formation and Pseudomonas aeruginosa virulence. Environ. Microbiol.
CR
2011;13(1):6273.
210. Martino PD, Fursy R, Bret L, Sundararaju B, Phillips RS. Indole can act as an
extracellular signal to regulate biofilm formation of Escherichia coli and other indole-
producing bacteria. Can. J. Microbiol. 2003;49(7):443449.
US
211. Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS
Microbiol Rev. 2010;34(4):426444
212. Bansal T, Englert D, Lee J, Hegde M, Wood TK, Jayaraman A. Differential effects of
epinephrine, norepinephrine, and indole on Escherichia coli O157:H7 chemotaxis,
AN
colonization, and gene expression. Infect. Immun. 2007;75(9):45974607.
213. Geske GD, Wezeman RJ, Siegel AP, Blackwell HE. Small molecule inhibitors of
bacterial quorum sensing and biofilm formation. J Am Chem Soc. 2005;127(37):12762
M
12763.
214. de la Fuente-Nez C, Korolik V, Bains M Inhibition of bacterial biofilm formation and
swarming motility by a small synthetic cationic peptide. Antimicrob Agents Chemother.
ED
2012;56(5), 26962704.
215. Kolodkin-Gal I, Romero D, Cao S, Clardy J, Kolter R, Losick R. D-amino acids trigger
biofilm disassembly. Science. 2010;328(5978):627629.
216. Ma Y, Chen M, Jones JE, Ritts AC, Yu Q, Sun H. Inhibition of Staphylococcus
PT
218. Barraud N, Hassett DJ, Hwang SH, Rice SA, Kjelleberg S, Webb JS. Involvement of
nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J Bacteriol
2006;188(21):73447353.
219. Garrison AT, Bai F, Abouelhassan Y, Paciaroni NG, Jin S, Huigens III RW.
AC
224. Kang JH, Super MI, Yung CW, Cooper RM, Domansky K, Graveline AR. An
extracorporeal blood-cleansing device for sepsis therapy. Nature Medicine. 2014;20:1211
1216. doi:10.1038/nm.3640
225. Marshall, J.C. Sepsis: rethinking the approach to clinical research. J Leukoc Biol. 2008;
83: 471482
226. Sandeman, S.R., Howell, C.A., Mikhalovsky, S.V., Phillips, G.J., Lloyd, A.W., Davies,
J.G., Tennison, S.R., Rawlinson, A.P., and Kozynchenko, O.P. Inflammatory cytokine
removal by an activated carbon device in a flowing system. Biomaterials. 2008; 29:
16381644
227. DiLeo MV, Fisher JD, Burton BM, Federspiel WJ. Selective improvement of tumor
necrosis factor capture in a cytokine hemoadsorption device using immobilized anti-
T
tumor necrosis factor. J Biomed Mater Res B Appl Biomater. 2011; 96: 127133.
228. Schmidt J, Mann S, Mohr VD, Lampert R, Firla U, Zirngibl H. Plasmapheresis combined
IP
with continuous venovenous hemofiltration in surgical patients with sepsis. Intensive
Care Med. 2000;26: 532. doi:10.1007/s001340051200
CR
229. Opal SM. The evolution of the understanding of sepsis, infection, and the host response:
a brief history. Crit Care Nurs Clin North Am. 2011 Mar;23(1):1-27. doi:
10.1016/j.ccell.2010.12.001.
US
230. Schentag JJ, Gengo FM. Principles of Antibiotic Tissue Penetration and Guidelines for
Pharmacokinetic Analysis. Med Clin North Am. 1982;66(1):39-49.
231. Kornguth ML, Kunin CM. Uptake of Antibiotics by Human Erythrocytes. J Infect Dis.
1976;133(2):175-184. doi: 10.1093/infdis/133.2.175
AN
232. Ferr F, Silva S, Ruiz J, Mari A, Mathe O, Sanchez-Verlaan P, Riu-Poulenc
B, Fourcade O, Gnestal M. Microcirculatory effect of hyperbaric oxygen therapy in
septic patients. Crit Care. 2011;15(Suppl 1):284.
M
233. Buras JA, Holt D, Orlow D, Belikoff B, Pavlides S, Reenstra WR. Hyperbaric oxygen
protects from sepsis mortality via an interleukin-10-dependent mechanism. Crit Care
Med. 2006 Oct;34(10):2624-2629.
234. Oter S, Edremitlioglu M, Korkmaz A. et al. Effects of hyperbaric oxygen treatment on
ED
liver functions, oxidative status and histology in septic rats. Intensive Care
Med. 2005;31:1262-1268.
235. Imperatore F, Cuzzocrea S, Luongo C. et al. Hyperbaric oxygen therapy prevents
PT
237. Madej P, Plewka A, Madej JA. et al. Ozonotherapy in an induced septic shock. I. Effect
of ozonotherapy on rat organs in evaluation of free radical reactions and selected
enzymatic systems. Inflammation. 2007;30:52-58
238. Annane D. Replacement therapy with hydrocortisone in catecholamine-dependent septic
AC
243. Russell JA, Vasopressin in vasodilatory and septic shock, Curr Opin Crit Care 13 (2007),
383391.
244. Vanhorebeek I, Langouche L, Van den Berghe G. Tight blood glucose control with
insulin in the ICU: facts and controversies, Chest 2007;132: 268278
245. Russell JA, Walley KR, Singer J. et al., Vasopressin versus norepinephrine infusion in
patients with septic shock, New Engl J Med 2008;358:877887.
246. Angelousi A, Karageoropoulos D, Kapaskelis A, Falagas M. Association between thyroid
function tests at baseline and the outcome of patients with sepsis or septic shock: a
systematic review. European Journal of Endocrinology. 2011;164:147- 155.
247. Takala J, Ruokenen E, Webster N, Nielsen M, Zandstra D, Vundelinckx G, et al.
Increased mortality associated with growth hormone treatment in critically ill adults. N
Engl J Med. 1999;341:785-792
T
248. Yi C, Cao Y, Mao SH, Liu H, Ji LL, Xu SY, et al. Recombinant human growth hormone
IP
improves survival and protects against acute lung injury in murine Staphylococcus aureus
sepsis. Inflamm Res 2009; 58(12): 855862.
249. Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on
CR
murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology 2009;
150(8): 3877-3884.
250. Kanda N, Tsuchida T, Tamaki K. Testosterone inhibits immunoglobulin production by
human peripheral blood mononuclear cells. Clin Exp Immunol 1996; 106(2): 410-415.
US
251. Zimmerman JL. Use of blood products in sepsis: An evidence-based review. Crit Care
Med 2004;32: S542-S547.
252. Fernandes CJ Jr, Akamine N, De Marco FV, De Souza JA, Lagudis S, et al. RBC
transfusion does not increase oxygen consumption in critically ill septic patients. Crit
AN
Care 2001;5: 362-367.
253. Mazza BF, Machado FR, Mazza DD, Hassmann V. Evaluation of blood transfusion
effects on mixed venous oxygen saturation and lactate levels in patients with SIRS/sepsis.
M
255. Carson JL, Carless PA, Hebert PC (2012) Transfusion thresholds and other strategies for
guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 4: CD002042.
256. Holzheimer RG. Induced endotoxin release and clinical sepsis: a review. J
Chemother. 2001 Nov;13 Spec No 1(1):159-172.
PT
257. Grandel U, Grimminger F. Endothelial responses to bacterial toxins in sepsis. Crit Rev
Immunol. 2003;23(4):267-299.
258. LaRocca TJ, Stivison EA, Hod EA, Spitalnik SL, Cowan PJ, Randis TM, Ratner AJ.
Human-specific bacterial pore-forming toxins induce programmed necrosis in
CE
267. Kadouri, D. E., K. To, R. M. Shanks, Y. Doi.Predatory bacteria: a potential ally against
multidrug-resistant Gram-negative pathogens. PLoS One. 2013;8:e63397.
268. Harini K, Ajila V, Hegde S. Bdellovibrio bacteriovorus: A future antimicrobial agent?
Journal of Indian Society of Periodontology. 2013;17(6):823-825. doi:10.4103/0972-
124X.124534.
269. Dwidar M, Monnappa AK, Mitchell RJ The dual probiotic and antibiotic nature of
Bdellovibrio bacteriovorus. BMB Rep. 2012 Feb; 45(2):71-78.
270. Monnappa AK, Dwidar M, Seo JK, Hur JH, Mitchell RJ. Bdellovibrio bacteriovorus
inhibits Staphylococcus aureus biofilm formation and invasion into human epithelial cells.
Sci Rep. 2014 Jan 22;4:3811. doi: 10.1038/srep03811.
271. Iebba V, Totino V, Santangelo F, Gagliardi A, Ciotoli L, Virga A, Ambrosi C, Pompili M,
De Biase RV, Selan L, et al. Bdellovibrio bacteriovorus directly attacks Pseudomonas
T
aeruginosa and Staphylococcus aureus Cystic fibrosis isolates. Front Microbiol. 2014;
IP
5:280. Epub 2014 Jun 5.
272. Stolp H, Starr MP. Bdellovibrio bacteriovorus gen.etsp.n., a predatory, ectoparasitic, and
bacteriolytic microorganism. Antonie Van Leeuwenhoek. 1963;29:217248. [PubMed]
CR
273. Kadouri D, OToole GA. Susceptibility of biofilms to Bdellovibrio bacteriovorus attack.
Appl Environ Microbiol. 2005;71:40444051.
274. Sockett, R. E. Predatory lifestyle of Bdellovibrio bacteriovorus. Annu. Rev. Microbiol.
2009;63:523-539.
US
275. Wolfe AJ. Sighting the Alien Within: a New Look at Bdellovibrio. J. Bacteriol. December
2010 vol. 192 no. 24: 6327-6328.
276. Dwidar M, Monnappa AK, Mitchell RJ. The dual probiotic and antibiotic nature of
Bdellovibrio bacteriovorus. BMB Rep. 2012;45:7178.
AN
277. McFarland LV, Surawicz CM, Greenberg RNet al. A randomized placebo-controlled trial
of Saccharomyces boulardi in combination with standard antibiotic for Clostridium
difficile disease. JAMA-J Am Med Assoc. 1994;271:19131918.
M
279. Mumy KL, Chen X, Kelly CP, McCormick BA. Saccharomyces boulardii interferes with
Shigella pathogenesis by post-invasion signaling events. Am J Physiol Gastrointest Liver
Physiol. 2008;294: G599-609
280.Zbinden R, Bonczi E, Altwegg M. Inhibition of Saccharomyces boulardii on cell invasion
PT
produces in rat small intestine a novel protein phosphatase that inhibits Escherichia coli
endotoxin by dephosphorylation. Pediatr Res. 2006;60:24-29.
283. Czerucka D, Dahan S, Mograbi B, Rossi B & Rampal P. Saccharomyces boulardiipreserve
the barrier function andmodulates the signal transduction pathway induced
inenteropathogenic Escherichia coli-infected T84 cells.InfectImmun. 2000;68: 59986004.
284. Buts J & de Keyser N. Effect of Saccharomyces boulardii on intestinal mucosa. Digest Dis
Sci. 2006;51: 14851492.
285. Swidsinski A, Loening-Baucke V, Verstraelen H, Osowska S, Doerffel Y. Biostructure of
fecal microbiota in healthy subjects and patients with chronic idiopathic diarrhea.
Gastroenterology. 2008;135:568579.
286. Jawhara S, Poulain D. Saccharomyces boulardiidecreasesinflammation and intestinal
colonization byCandida albicansin a mouse model of chemically-induced colitis.Med
Myco.l 2007;45:691700.
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287. Levi M, Shultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost. 2013
Jul;39(5)559-566.
288. House SD, Johnson PC. Diameter and blood flow of skeletal muscle venules during local
flow regulation.Am J Physiol. 1986 May;250(5 Pt 2):H828-37.
289. Skinner EH. Early physical rehabilitation may improve physical quality of life domains in
patients admitted to ICU with sepsis syndromes [synopsis] J Physyother 2015
Jul;61(3):158.
290. Paratz JD, Kajambu G. Early exercise and attenuation of myopathy in the patient with
sepsis in ICU. Phys Ther Rev 2011 Feb;16(1):58-65.
291. Sossdorf M, Otto GP, Menge K, Claus RA, Lsche W, Kabisch B, Kohl M, Smolenski
UC, Schlattmann P, Reinhart K, Winning J. Potential effect of physiotherapeutic treatment
on mortality rate in patients with severe sepsis and septic shock: a retrospective cohort
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analysis. J Crit Care. 2013. Dec;28(6):954-958.
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292. Mendes EW, Procinov RS. Massage therapy reduces hospital stay and occurrence of late-
onset sepsis in very preterm neonates. J Perinatol. 2008 Dec;28(12):815-820.
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Table 1
THE DYNAMICS OF SEPSIS AND SEPTIC SHOCK INCIDENCE AND
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- Global estimates of sepsis (cases a year)
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- US Census included 308,745,538 individuals
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- 28 day mortality
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Table 2
THE COMMON FEATURES OF SEPSIS CAUSING BACTERIA.
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A aerobic bacteria
FAN facultative anaerobic bacteria
MA micro aerobic bacteria
OANA obligate anaerobic bacteria
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Highlights
Bacteria in the bloodstream are killed by oxygen released from
erythrocytes.
Sepsis development depends upon bacterial resistance to oxidation .
Released oxygen oxidizes plasma components and destroys humoral
regulation.
Oxygen release in arterial blood causes hypoxia in the tissues.
The severity of sepsis correlates with the amount of released oxygen.
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