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Septic encephalopathy is a devastating symptom of severe sepsis. Many studies have been performed to uncover the pathophysiological mechanisms of septic encephalopathy; however, novel technical approaches are still required to overcome this complex symptom. Because patients are suffering from severe cognitive impairment, coma, or delirium, which burden not only patients but also caregivers, overcoming septic encephalopathy is still a major social problem worldwide, especially in the intensive care. Septic encephalopathy seems to be caused by cytokine invasion and/or oxidative stress into the brain, and this pathological state leads to imbalance of neurotransmitters. In addition to this pathophysiology, septic encephalopathy causes complicated symptoms (e.g., ischemic stroke, edema, and aberrant sensory function). For these pathophysiological mechanisms, electrophysiology using animal models, positron emission tomography (PET), computed tomography, and magnetic resonance imaging for septic patients has provided important clues. However, the research for septic encephalopathy is currently confronted with the difficulty of complex symptoms. To overcome this situation, in this chapter, we introduce our novel methods for in vivo imaging of septic encephalopathy using near infrared (NIR) nanoparticles, quantum dots. In addition to our recent progress, we propose a strategy for the future approach to in vivo imaging of septic encephalopathy.
Laboratory for Nano‐Bio Probes, Quantitative Biology Center, Riken, Japan
Yuki Murakami
Laboratory of Developmental Neurobiology, Graduate School of Brain Science, Doshisha University, Japan
Naoya Matsumoto
Department of Acute and Critical Care Center, Osaka University Hospital, Japan
Hisatake Matsumoto
Department of Acute and Critical Care Center, Osaka University Hospital, Japan
Satoko Mitani
Department of Nursing, School of Health Sciences, Gifu University of Medical Sciences, Gifu, Japan
Kentaro Shimizu
Department of Acute and Critical Care Center, Osaka University Hospital, Japan
Hiroshi Ogura
Department of Acute and Critical Care Center, Osaka University Hospital, Japan
Takeshi Shimazu
Department of Acute and Critical Care Center, Osaka University Hospital, Japan
Takashi Jin
Laboratory for Nano‐Bio Probes, Quantitative Biology Center, Riken, Japan
*Address all correspondence to: yukio.imamura@riken.jp
1. Introduction
Although the pathophysiological mechanism of septic encephalopathy (SE) still includes some mystery, recent progress of challenging research using animal models of sepsis has gradually uncovered the molecular pathogenesis of SE. For instance, recent pathophysiological findings for SE include synaptic deficiency by interleukin‐1 beta [1] and acetylcholine [2] and brain ischemia or edema with disseminated intravascular coagulation (DIC) [3]. These phenomena are dynamically altered in a time‐dependent manner based on the content of symptoms. Functional magnetic resonance imaging (fMRI) for patients of SE can describe the status of symptoms; however, it is difficult to track these time‐dependent changes in the septic brain because of the low time resolution of its measurement. To overcome this technical difficulty, we are working to develop noninvasive near infrared (NIR) imaging as a novel method to analyze the pathological state of SE.
In this chapter, we introduce current understanding of pathophysiology, the imaging technology, and the application of novel imaging technology to visualize the pathophysiological mechanism of SE. The contents are described as follows: (1) etiology of SE, (2) molecular mechanisms of pathogenesis, (3) NIR in vivo imaging, and (4) application to SE. In particular, we focus on DIC and our approach firstly demonstrates the novel application of NIR in vivo imaging to DIC. We expect that this review will be helpful to readers such as basic biomedical students, and scientists who are interested in the future preclinical and clinical application to SE.
Septic encephalopathy (SE) is a symptom with brain dysfunction caused by sepsis. Up to 70% of severe septic patients encountered developed SE [4]. Patients with SE are often suffering from various neurological symptoms. Many research reports and reviews have discussed cognitive impairment [5, 6], delirium [7], coma [8–11], and recently seizure and aberrant sensory function [12–16]. In addition, complication symptoms such as ischemic stroke, edema, etc. occurred [17–19]. However, not all of pathophysiological mechanisms for SE have been clarified in Ref. [20], and a better understanding of SE is still an important social problem worldwide [21].
2.1. Etiology
The SE is often found in acute liver failure and cirrhosis patients and triggered by the various chemical mediators followed by systemic inflammatory response syndromes, whole‐body inflammation [22–24]. SE is different from the brain “encephalitis” which occurs due to pathogens (e.g., bacteria, virus, etc.) direct invasion into the brain. Rather than the direct invasion, SE is caused indirectly by excessive inflammatory response (e.g., cytokine storm). Thus, SE is a symptom. Clinical studies for SE reported that patients with SE often suffered from hypotension [25], imbalance of amino acids in plasma [26], and neuronal injury with edema [27, 28]. Several lines of evidences suggest that a rodent model of SE showed aberrant behavior: altered sensory function [29, 30], increased anxiety [31, 32], and cognitive impairment [33]. These results are similar to the symptoms of brain dysfunction in SE patients [34]. Thus, neurological impairment leads to various symptoms in SE.
To understand the molecular mechanisms, pathophysiological factors (e.g., imbalance of chemical substances, cellular environment, and molecules) are discussed. Overall pathogenesis for SE is summarized in Figure 1 . When SE is occurred, various chemical substances (e.g., neurotransmitter, modulator, etc.) were involved as reviewed elsewhere in Refs. [35, 36]. These chemical substances were mainly important for maintaining homeostasis in the normal condition. After the SE occurred, the imbalanced rate of substances (e.g., amino acids) [37–41] abrogated brain metabolic function (e.g., tryptophan metabolism) [42–44], microglial activation in the brain followed by detachment of pericyte from microvascular basal lamina [45, 46].
Figure 1.
Overview of pathogenesis for septic encephalopathy (SE). Severe sepsis often results in septic encephalopathy, mainly followed by oxidative stress and cytokine storm. Accompanying BBB impairment and DIC, invaded inflammatory mediators cause aberrant neuronal function. PAMPs: pathogen‐associated molecular pattern; DAMPs: damage‐associated molecular patterns; BBB: blood brain barrier; IL: interleukin; TNF: tumor necrosis factor.
Normally, the brain is protected with a barrier called blood brain barrier (BBB). The barrier consists of brain endothelial cells, and these cells are tightly attached with tight junction. The barrier is selectively permeable to transport of amino acid, gas, and lipid‐soluble chemicals which are important for neuronal function. Therefore, the inflammatory molecules cannot affect brain function in the normal condition because the brain is protected with blood brain barrier, and foreign substances are impeded by this barrier.
In the septic condition, occurrence of systemic inflammatory response syndromes is followed by sepsis, the syndromes lead to destruction of this blood brain barrier [47, 48], and harmful chemical substances disrupt normal brain function. Then, the chemical substances cause the aberrant neuronal transmission and plasticity [1, 30]. The components of tight junctions are claudin, occludin, zona occludin, etc. [49]. This tight junction serves as if an adhesive of cells and underpins the blood brain barriers. Using a mouse model of sepsis, we clearly demonstrated that the occludin protein was destroyed 20 h after induction of sepsis and led to a permeabilization of cytokine [1, 30]. Other groups reported that tumor necrosis factor (TNF)‐alpha and calcium‐binding proteins were increased in the SE [50].
3.2. Blood brain barrier (BBB) impairment
Why was the tight junction disrupted? Overall mechanisms are still unclear, a hypothesis is, however, addressed. Neuroinflammation (e.g., microglia/macrophage activation, nitrogen oxide gas production) resulted in the mitochondria dysfunction with reactive oxygen synthesis (ROS) [51–55] and dysfunction of cerebrovascular endothelial cells [56]. The process is impeded by ROS inhibitors [57] or mitochondria‐targeted peptides [55].
Another hypothesis is as follows. Septic patients sometimes showed a rapid vasoconstriction of blood vessels, and this mechanical alteration may cause the damage to the microvasculature structure [58, 59]. Endothelin and its receptor which constrict blood vessels might be involved in that process [60, 61]. Phosphoinositide 3‐kinase cascade activated microglial cell and matrix metalloproteinase (i.e., marker of inflammation) and aggravated BBB impairment [62]. Consequently, the BBB disruption finally leads to the invasion of inflammatory mediators into the brain of SE [63].
3.3. Effect of cytokine storm on brain function
In any case, the dysfunction of blood brain barrier after sepsis increases the permeability of inflammatory molecules as described below and finally causes the brain malfunction.
For example, there are widely discussed cytokines such as interleukins (interleukin‐1, ‐6, ‐10) [37, 64], tumor necrosis factor (TNF)‐alpha [65, 66], complement C5a [67], and cascade [68]. Epigenetic modulation (e.g., histone acetylation) participates in the trigger of aberrant glutamate receptor subunits [29, 69] and causes memory deficit [70]. In addition, disseminated blood coagulation [71, 72] and oxidative stress [73–75] aggravated brain dysfunction of SE. MicroRNA (i.e., noncoding small RNA) involved in RNA silencing and posttranscriptional modification [76]. Besides nitric oxide (NO), lipid peroxidase, S100B protein [77], and the prion protein [78] may participate in SE.
3.4. Imbalance of synaptic transmissions on neurons
As a morphological study revealed that the neuronal spine was destabilized in a mouse model [79], neuronal environment may possibly be altered in SE. Actually, for other potent factors related to neurotransmission, norepinephrine [80], adrenergic system [81, 82], serotonergic system [83], acetylcholine [84–86], gamma‐aminobutyric receptor A [87], N‐methyl‐D‐aspartate receptor 2B [29], and brain neurovascular dysfunction [88] were involved in the pathogenesis of SE. In summary, sepsis leads to the aberrant conditions in the neuronal and/or glial environments and may result in the devastating symptoms in the pathogenesis of SE.
4. Brain activity measurements: from electrophysiology to imaging
4.1. Electrophysiology
Neurophysiological studies have uncovered the neuronal dysfunction in SE. Neurophysiologists have developed various experimental techniques to study neuronal cell activity. Neuronal activities recordings can be classified as follows: (1) single neuronal activity and (2) multiple neuronal activity. To record the single neuronal activity, there are techniques such as patch clamp recording and intracellular recording.
On the other hand, to record multiple neuronal activity, there are several established techniques. For example, there are field excitatory postsynaptic potentials (in vitro), local field potential (in vivo), and optical recording with voltage sensitive dye (in vitro and in vivo). For example, Kafa et al. reported reduced neuronal population activities in a rat model of SE [89], and Wang et al. also showed suppression of local field potentials during sensory stimulation in SE [30]. These findings are clearly similar to the clinical state of sensory dysfunction in septic patients [90]. It is useful to uncover the pathophysiological mechanism. These techniques are very powerful for studying the single neuron or several neurons in the local region of the brain. However, symptoms of SE are versatile with complicated diseases (e.g., stroke, edema, myopathy, etc.) [35, 91, 92]. Integrative analysis with multiple viewpoints is still required [93].
4.2. Brain imaging
Noninvasive measurement was sought to determine the pathological state and followed by prognosis of SE [94]. Several research reports suggest that electroencephalogram (EEG) that placed to the surface of head was useful to study brain dysfunction by various encephalitis and encephalopathy [95, 96]. In SE, for example, the EEG recordings revealed decreased amplitudes of EEG signals [97]. Using a rat model, EEG signals were attenuated [83]. In addition, child patient with coma showed 6‐Hz burst firing pattern in SE [98]. Hence, EEG abnormality was found in the SE [99].
Why have these altered activity patterns due to brain dysfunction occurred? Functional magnetic resonance imaging (fMRI) has been used to capture the pathological state of brain cortex in SE [100]. Clinically, patients of SE showed cerebral infarction with multiple ischemic stroke and white matter lesions [13, 101]. Additionally, cerebral edema was reported [102]. Recently, brain atrophy within the regions including amygdala, hippocampus, basal ganglia, brainstem, thalamic, and cerebellar neurons was also shown in Ref. [103, 104]. Hence, complicated symptoms, if they represent irreversible morphological alteration, have been found with fMRI. In addition to fMRI, positron emission tomography (PET) using 18 F‐FDG was applied [105]; however, the application was limited. Conversely, reversible and time‐dependent altered symptoms (e.g., neuronal transmission) cannot be determined with fMRI imaging (and PET) [106]. Because fMRI takes 10–30 min or more to capture a brain image with the high spatial resolution, it only determines the stable state of the pathology for SE. To overcome this weak point, we are currently focused on the noninvasive NIR imaging.
NIR imaging is a powerful tool for noninvasive in vivo imaging. Conventionally, visible light (400–700 nm) has been used for molecular fluorescent imaging in cellular dynamics [107, 108]. However, visible light is difficult to apply to deep‐tissue imaging because of the robust light absorption and scattering by intrinsic chromophores (hemoglobin, melanin, flavin, etc.) and organelles (mitochondria and cytoskeleton). Autofluorescence from tissues (heart, skin, and brain) which is excited by NIR light (700–1400 nm) is much lower than that by excited visible light [109]. In addition, NIR light permeates tissues more than visible light (400–700 nm) ( Figure 2 ). Therefore, the NIR light, especially 2nd optical window (1000–1400 nm), is currently expected to be applicable to noninvasive deep tissue imaging.
Figure 2.
(a) Autofluorescence spectra of the dorsal side of a mouse body. The autofluorescence spectra were taken by excitation of 482, 670, and 785 nm. The dotted and solid arrows show the wavelength rage of 1st NIR optical window (I) and 2nd NIR optical window (II), respectively. (b) Absorption spectra of tissue slices of mouse skin, brain, and heart. Slice thickness of the skin, brain, and heart is 120, 100, and 200 μm, respectively. (Citation from Ref. [110]).
To label the target tissue, fluorescent probes are necessary. Compared to the visible light probes, NIR fluorescence probes are limited. For example, single‐walled carbon nanotubes (SWNTs), Ag2S quantum dots, PbS quantum dots, and rare‐earth‐doped nanocomposites are developed for 2nd optical windows for in vivo imaging (reviewed in Ref. [110]). We previously compared these fluorescence probes in the same condition and found that PbS quantum dots were much brighter than other probes ( Figure 3 ).
Figure 3.
(a) Fluorescence spectra of nanomaterials that emit in the 2nd NIR window: SWNT, Ag2S QD, and PbS QD. (b) Bright field and fluorescence images (>1000 nm) of SWNT, Ag2S QD, and PbS QD. To compare the fluorescence brightness, absorbance at the excitation wavelength (720 nm) was adjusted to be the same value of 0.5 for SWNT, Ag2S QD, and PbS QD. (Citation from Ref. [110]).
5.2. In vivo imaging
We applied PbS quantum dots (maximum fluorescence intensity: 1100 nm) from mouse tail vein and successfully recorded blood flow in the mouse head in a noninvasive manner [71] ( Figure 4 ). The head of an anesthetized mouse was fixed on a stage of a microscope, and fluorescence was recorded through skin and skull ( Figure 4a ). The fluorescent intensity was recorded with InGaAs camera which is sensitive from 900–1600 nm. Soon after injection, brain blood vessels were visible on a mouse head ( Figure 4b , right), and the picture was entirely similar to the image of blood vessels after scalp removal ( Figure 4c , upper) and isolated brain ( Figure 4c , lower). These findings suggest that the NIR in vivo imaging can visualize the brain blood flow non‐invasively. If we would like to apply this method to the pathophysiology of SE, what is the target?
Figure 4.
(a) Experimental setup for NIR fluorescence imaging of cerebral blood vessels. An anesthetized mouse was administered QD1100 in a caudal vein. An optical laser (785 nm wavelength) was used as an excitation light source, and NIR fluorescence was detected with an InGaAs camera; (b) imaging of a mouse head. Bright field image (left), NIR fluorescence image without QD administration (middle), and the NIR fluorescence image with QD administration (right). Scale bar: 1 mm; (c) NIR fluorescence images of cerebral blood vessels. Upper: fluorescence image after scalp removed, lower: fluorescence image after isolation. Scale bars: 1 mm. (Citation from Ref. [71]).
Brain blood vessels are aggravated in SE. Previous reports addressed that, using an animal model, cerebral microcirculation was reported to be impaired [111]. Disseminated intravascular coagulation (DIC) is an important pathological state of sepsis and worsening of DIC increases multiple organ dysfunction. Anticoagulant therapy was performed, however, its effect was limited. Repetitive administration of anticoagulant drug increases the rate of side effects such as thrombocytopenia [112] and bleeding [113]. To find the pathological state of DIC, we examined whether NIR in vivo imaging detect DIC in the septic brain as described in the next section.
6. Application of NIR in vivo imaging to pathological analyses for septic encephalopathy
Next, we applied the NIR in vivo imaging to SE brain. To examine this, we studied whether DIC can be recorded with NIR imaging. Figure 5 demonstrated lipopolysaccharide (LPS)‐induced DIC. Eighteen hours after LPS, clots (arrowheads) can be recorded noninvasively ( Figure 5b , middle). In the isolated brain, the number of clots remarkably increased in the SE brain ( Figure 6 ). Conversely, the increased clots were similar to the control level in the presence of heparin (i.e., inhibitor of clots formation), suggesting that the NIR imaging can record DIC in SE brain.
Figure 5.
(a) Time course of experimental procedure for lipopolysaccharide (LPS) and heparin administration; (b) NIR fluorescence images (>1000 nm) of cerebral blood vessels before and after administration of LPS (LPS (−) and LPS (+)), and the image following additional administration of heparin (LPS + heparin) with scalp removed. Lower panel shows the magnification of the images shown by red rectangles. Arrowheads show clots. Scale bars: 1 mm; (c) statistical analyses of the clots in the cerebral vessels. *:p < 0.05, number of mice: LPS (−):n = 5, LPS (+):n = 5, LPS + heparin:n = 3; (d) immunofluorescence staining of LPS‐treated cerebral blood vessels, where antifibrinogen antibody (Alexa Fluor 488) was used for staining of fibrinogen. Fibrinogen helps the formation of blood clots. Scale bar: 10 μm; (e) ELISA assays for thrombin–antithrombin complex (TAT) in blood plasma. *:p < 0.05, number of mice: LPS (−):n = 5, LPS (+):n = 5, LPS + heparin:n = 3. (Citation from Ref. [71]).
Figure 6.
(a) Upper panel: NIR fluorescence images (>1000 nm) of cerebral blood vessels of isolated mouse brains. Left: LPS (−), Middle: LPS (+), Right: LPS + heparin. Red circles: clots. Blue squares: region of interests for the magnified views of lower panels. Scale bars: 1 mm. Lower panel: magnified NIR fluorescence image of cerebral blood vessels at the bregma. Red arrows: clots. Scale bars: 100 μm; (b) Number of clots for each mouse. *:p < 0.05, number of mice: LPS (−):n = 5, LPS (+):n = 5, LPS + heparin:n = 4. (Citation from Ref. [71]).
What is the importance of these findings? In blood vessels of the brain, tissue factor activation including thrombin and fibrinogen which enhanced blood clot formation was occurred [114, 115], and this pathology finally led to multiple organ (e.g., lung, liver, kidney, and brain, etc.) dysfunction [116]. However, it has been difficult to visualize the pathological state of DIC because of a lack of an effective biomarker [117]. Our present findings developed a novel approach to analyze the pathological state of brain blood vessels in SE.
In this chapter, we introduce the application of NIR in vivo imaging to SE. Currently, imaging technology is confronted with a turning point. Although there are several noninvasive imaging technologies (PET, MRI, etc.), NIR noninvasive imaging can possibly record the faster time‐dependent changes of pathological state in SE, though further developments of the imaging algorithm are required. In addition, the NIR imaging can label the distinct proteins by several specific antibodies and perform the multiple molecular in vivo imaging. Therefore, using the biomarker for SE, we may be able to visualize the novel pathophysiological mechanisms of SE.
Finally, in addition to our challenges, other candidate biomarkers which employ correlation to the pathological state of SE are recently addressed: S100β (i.e., astrocyte‐secreting protein) [77, 118–120], free radicals [121, 122], ascorbate [123–125], and various neuropeptides [126]. In addition, adult neurogenesis was induced in a rat model of SE and the neurogenesis marker (e.g., 5‐bromo‐2′‐deoxyuridine) might be useful [127]. In conclusion, these multidisciplinary approaches may overcome the pathophysiology and lead to innovative therapeutics for SE.
We thank Sumire Hino for secretary assistance, Dr. Jun Imamura for preparing Figure 1 , Dr. Akitoshi Seiyama for critical reading of manuscript, and Kylius Wilkins for English corrections. This work is supported by Grant‐in‐Aid for Scientific Research of YI (24592734).
References
1.Imamura, Y., H. Wang, N. Matsumoto, T. Muroya, J. Shimazaki, H. Ogura,et al., Interleukin‐1beta causes long‐term potentiation deficiency in a mouse model of septic encephalopathy. Neuroscience. 2011;187: 63‐69.
2.Rada, P., G.P. Mark, M.P. Vitek, R.M. Mangano, A.J. Blume, B. Beer,et al., Interleukin‐1 beta decreases acetylcholine measured by microdialysis in the hippocampus of freely moving rats. Brain Res. 1991;550(2): 287‐290.
3.Polito, A., F. Eischwald, A.L. Maho, A. Polito, E. Azabou, D. Annane,et al., Pattern of brain injury in the acute setting of human septic shock. Crit Care. 2013;17(5): R204, DOI: 10.1186/cc12899.
5.Streck, E.L., C.M. Comim, T. Barichello, and J. Quevedo, The septic brain. Neurochem Res. 2008;33: 2171‐2177.
6.Widmann, C.N. and M.T. Heneka, Long‐term cerebral consequences of sepsis. Lancet Neurol. 2014;13(6): 630‐636, DOI: 10.1016/s1474‐4422(14)70017‐1.
7.Tsuruta, R. and Y. Oda, A clinical perspective of sepsis‐associated delirium. J Intensive Care. 2016;4: 18, DOI: 10.1186/s40560‐016‐0145‐4.
8.Comim, C.M., L.C. Constantino, T. Barichello, E.L. Streck, J. Quevedo, and F. Dal‐Pizzol, Cognitive impairment in the septic brain. Curr Neurovasc Res. 2009;6: 194‐203.
9.Luitse, M.J., C.J. van Asch, and C.J. Klijn, Deep coma and diffuse white matter abnormalities caused by sepsis‐associated encephalopathy. Lancet. 2013;381(9884): 2222, DOI: 10.1016/s0140‐6736(13)60682‐0.
10.Papadopoulos, M.C., D.C. Davies, R.F. Moss, D. Tighe, and E.D. Bennett, Pathophysiology of septic encephalopathy: a review. Crit Care Med. 2000;28: 3019‐3024.
11.Piva, S., V.A. McCreadie, and N. Latronico, Neuroinflammation in sepsis: sepsis associated delirium. Cardiovasc Hematol Disord Drug Targets. 2015;15(1): 10‐18.
12.Berisavac, II, V.V. Padjen, M.D. Ercegovac, G. Beslac‐Bumbasirevic Lj, P. Stanarcevic, M.S. Stefanovic‐Budimkic,et al., Focal epileptic seizures, electroencephalography and outcome of sepsis associated encephalopathy‐A pilot study. Clin Neurol Neurosurg. 2016;148: 60‐66, DOI: 10.1016/j.clineuro.2016.06.013.
13.Siami, S., D. Annane, and T. Sharshar, The encephalopathy in sepsis. Crit Care Clin. 2008;24(1): 67‐82, viii, DOI: 10.1016/j.ccc.2007.10.001.
14.Yamaguchi, H., T. Tanaka, A. Maruyama, and H. Nagase, Septic encephalopathy characterized by acute encephalopathy with biphasic seizures and late reduced diffusion and early nonconvulsive status epilepticus. Case Rep Neurol Med. 2016;2016: Article ID 7528238, DOI: 10.1155/2016/7528238.
15.Young, G.B., C.F. Bolton, T.W. Austin, Y.M. Archibald, J. Gonder, and G.A. Wells, The encephalopathy associated with septic illness. Clin Invest Med. 1990;13: 297‐304.
17.Kafa, I.M., I. Ari, and M.A. Kurt, The peri‐microvascular edema in hippocampal CA1 area in a rat model of sepsis. Neuropathology. 2007;27: 213‐220.
18.Kondo, A., C. Sugiura, Y. Fujii, T. Inoue, Y. Maegaki, and K. Ohno, Fulminant sepsis‐associated encephalopathy in two children: serial neuroimaging findings and clinical course. Neuropediatrics. 2009;40(4): 157‐161, DOI: 10.1055/s‐0029‐1243626.
19.Sari, A., S. Yamashita, S. Ohosita, H. Ogasahara, K. Yamada, A. Yonei,et al., Cerebrovascular reactivity to CO2 in patients with hepatic or septic encephalopathy. Resuscitation. 1990;19(2): 125‐134.
20.Sweis, R., J. Ortiz, and J. Biller, Neurology of Sepsis. Curr Neurol Neurosci Rep. 2016;16(3): 21, DOI: 10.1007/s11910‐016‐0623‐z.
21.Lamar, C.D., R.A. Hurley, and K.H. Taber, Sepsis‐associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatr Clin Neurosci. 2011;23(3): 237‐241, DOI: 10.1176/appi.neuropsych.23.3.23710.1176/jnp.23.3.jnp237.
22.Gustot, T., F. Durand, D. Lebrec, J.L. Vincent, and R. Moreau, Severe sepsis in cirrhosis. Hepatology. 2009;50: 2022‐2033.
23.Rolando, N., J. Wade, M. Davalos, J. Wendon, J. Philpott‐Howard, and R. Williams, The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32(4 Pt 1): 734‐739, DOI: 10.1053/jhep.2000.17687.
24.Tsai, M.H., Y.S. Peng, Y.C. Chen, N.J. Liu, Y.P. Ho, J.T. Fang,et al., Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006;43(4): 673‐681, DOI: 10.1002/hep.21101.
25.Wijdicks, E.F. and M. Stevens, The role of hypotension in septic encephalopathy following surgical procedures. Arch Neurol. 1992;49(6): 653‐656.
26.Berg, R.M., S. Taudorf, D.M. Bailey, C. Lundby, F.S. Larsen, B.K. Pedersen,et al., Effects of lipopolysaccharide infusion on arterial levels and transcerebral exchange kinetics of glutamate and glycine in healthy humans. Apmis. 2012;120(9): 761‐766, DOI: 10.1111/j.1600‐0463.2012.02904.x.
27.Ari, I., I.M. Kafa, and M.A. Kurt, Perimicrovascular edema in the frontal cortex in a rat model of intraperitoneal sepsis. Exp Neurol. 2006;198: 242‐249.
28.Papadopoulos, M.C., F.J. Lamb, R.F. Moss, D.C. Davies, D. Tighe, and E.D. Bennett, Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci. (Lond). 1999;96: 461‐466.
29.Imamura, Y., N. Yoshikawa, Y. Murkami, S. Mitani, N. Matsumoto, H. Matsumoto,et al., Effect of histone acetylation on N‐methyl‐D‐aspartate 2B receptor subunits and interleukin‐1 receptors in association with nociception‐related somatosensory cortex dysfunction in a mouse model of sepsis. Shock. 2016;45(6): 660‐667, DOI: 10.1097/SHK.0000000000000547.
30.Wang, H., Y. Imamura, N. Matsumoto, N. Yoshikawa, J. Nakagawa, K. Yamakawa,et al., Matrix metalloproteinase‐9 triggers the gap junction impairment and somatosensory neuronal dysfunction in septic encephalopathy. Biochem Pharmacol: Open Access. 2013;02(01): 7, DOI: 10.4172/2167‐0501.1000108.
31.Anderson, S.T., S. Commins, P.N. Moynagh, and A.N. Coogan, Lipopolysaccharide‐induced sepsis induces long‐lasting affective changes in the mouse.Brain Behav Immun. 2015;43: 98‐109, DOI: 10.1016/j.bbi.2014.07.007.
32.Calsavara, A.C., D.H. Rodrigues, A.S. Miranda, P.A. Costa, C.X. Lima, M.C. Vilela,et al., Late anxiety‐like behavior and neuroinflammation in mice subjected to sublethal polymicrobial sepsis. Neurotox Res. 2013;24(2): 103‐108, DOI: 10.1007/s12640‐012‐9364‐1.
33.Michels, M., A.S. Vieira, F. Vuolo, H.G. Zapelini, B. Mendonca, F. Mina,et al., The role of microglia activation in the development of sepsis‐induced long‐term cognitive impairment. Brain Behav Immun. 2015;43: 54‐59, DOI: 10.1016/j.bbi.2014.07.002.
34.Gupta, R., S. Saigal, R. Joshi, P. Tagore, N. Rai, and K. Prasad, Unrecognized catatonia as a cause for delayed weaning in Intensive Care Unit. Indian J Crit Care Med. 2015;19(11): 693‐694, DOI: 10.4103/0972‐5229.169360.
35.Imamura, Y., S. Hori, N. Matsumoto, K. Yamakawa, J. Nakagawa, J. Shimazaki,et al., Septic encephalopathy. Encephalitis, Encephalomyelitis and Encephalopathies. Vol. 8. 2013: Nova Science Publisher. 163-176.
36.Imamura, Y., H. Wang, N. Matsumoto, H. Ogura, T. Shimazu, T. Jin,et al., Neurochemistry in the pathophysiology of septic encephalopathy. Neuroscience‐Dealing with Frontiers ed. Neurochemistry, ed. M. Contreras. 2012, Croatias: In‐tech Open Access Publisher.
37.Basler, T., A. Meier‐Hellmann, D. Bredle, and K. Reinhart, Amino acid imbalance early in septic encephalopathy. Intensive Care Med. 2002;28: 293‐298.
38.Berg, R.M., S. Taudorf, D.M. Bailey, C. Lundby, F.S. Larsen, B.K. Pedersen,et al., Cerebral net exchange of large neutral amino acids after lipopolysaccharide infusion in healthy humans. Crit Care. 2010;14(1): R16, DOI: 10.1186/cc8873.
39.Freund, H., S. Atamian, J. Holroyde, and J.E. Fischer, Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg. 1979;190: 571‐576.
40.Nakamura, T., Y. Kawagoe, T. Matsuda, I. Ebihara, and H. Koide, Effects of polymyxin B‐immobilized fiber hemoperfusion on amino acid imbalance in septic encephalopathy. Blood Purif. 2003;21: 282‐286.
41.Takezawa, J., N. Taenaka, M.K. Nishijima, T. Hirata, T. Okada, Y. Shimada,et al., Amino acids and thiobarbituric acid reactive substances in cerebrospinal fluid and plasma of patients with septic encephalopathy. Crit Care Med. 1983;11(11): 876‐879.
42.Freund, H.R., M. Muggia‐Sullam, R. LaFrance, J. Holroyde, and J.E. Fischer, Regional brain amino acid and neurotransmitter derangements during abdominal sepsis and septic encephalopathy in the rat. The effect of amino acid infusions. Arch Surg. 1986;121: 209‐216.
43.Gao, R., M.Q. Kan, S.G. Wang, R.H. Yang, and S.G. Zhang, Disrupted tryptophan metabolism induced cognitive impairment in a mouse model of sepsis‐associated encephalopathy. Inflammation. 2016;39(2): 550‐560, DOI: 10.1007/s10753‐015‐0279‐x.
44.Sprung, C.L., F.B. Cerra, H.R. Freund, R.M. Schein, F.N. Konstantinides, E.H. Marcial,et al., Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med. 1991;19: 753‐757.
45.Nishioku, T., S. Dohgu, F. Takata, T. Eto, N. Ishikawa, K.B. Kodama,et al., Detachment of brain pericytes from the basal lamina is involved in disruption of the blood‐brain barrier caused by lipopolysaccharide‐induced sepsis in mice. Cell Mol Neurobiol. 2009;29: 309‐316.
46.Pytel, P. and J.J. Alexander, Pathogenesis of septic encephalopathy. Curr Opin Neurol. 2009;22: 283‐287.
47.Ballabh, P., A. Braun, and M. Nedergaard, The blood‐brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16: 1‐13.
48.Varatharaj, A. and I. Galea, The blood‐brain barrier in systemic inflammation. Brain Behav Immun. 2016;60: 1-12. DOI: 10.1016/j.bbi.2016.03.010.
49.Nico, B. and D. Ribatti, Morphofunctional aspects of the blood‐brain barrier. Curr Drug Metab. 2012;13: 50‐60.
50.Zhang, L.N., X.H. Wang, L. Wu, L. Huang, C.G. Zhao, Q.Y. Peng,et al., Diagnostic and predictive levels of calcium‐binding protein A8 and tumor necrosis factor receptor‐associated factor 6 in sepsis‐associated encephalopathy: a prospective observational study. Chin Med J (Engl). 2016;129(14): 1674‐1681, DOI: 10.4103/0366‐6999.185860.
51.Berg, R.M., K. Moller, and D.M. Bailey, Neuro‐oxidative‐nitrosative stress in sepsis. J Cereb Blood Flow Metab. 2011;31(7): 1532‐1544, DOI: 10.1038/jcbfm.2011.48.
52.Bozza, F.A., J.C. D’Avila, C. Ritter, R. Sonneville, T. Sharshar, and F. Dal‐Pizzol, Bioenergetics, mitochondrial dysfunction, and oxidative stress in the pathophysiology of septic encephalopathy. Shock. 2013;39(Suppl 1): 10‐16, DOI: 10.1097/SHK.0b013e31828fade1.
53.Hara, N., M. Chijiiwa, M. Yara, Y. Ishida, Y. Ogiwara, M. Inazu,et al., Metabolomic analyses of brain tissue in sepsis induced by cecal ligation reveal specific redox alterations‐‐protective effects of the oxygen radical scavenger edaravone. Shock. 2015;44(6): 578‐584, DOI: 10.1097/shk.0000000000000465.
54.Michels, M., L.G. Danielski, F. Dal‐Pizzol, and F. Petronilho, Neuroinflammation: microglial activation during sepsis. Curr Neurovasc Res. 2014;11(3): 262‐270.
55.Wu, J., M. Zhang, S. Hao, M. Jia, M. Ji, L. Qiu,et al., Mitochondria‐targeted peptide reverses mitochondrial dysfunction and cognitive deficits in sepsis‐associated encephalopathy. Mol Neurobiol. 2015;52(1): 783‐791, DOI: 10.1007/s12035‐014‐8918‐z.
56.Handa, O., J. Stephen, and G. Cepinskas, Role of endothelial nitric oxide synthase‐derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. Am J Physiol Heart Circ Physiol. 2008;295(4): H1712‐H1719, DOI: 10.1152/ajpheart.00476.2008.
57.Zhou, T., L. Zhao, R. Zhan, Q. He, Y. Tong, X. Tian,et al., Blood‐brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone. Biochem Biophys Res Commun. 2014;453(3): 419‐424, DOI: 10.1016/j.bbrc.2014.09.093.
58.Pierrakos, C., A. Antoine, D. Velissaris, I. Michaux, P. Bulpa, P. Evrard,et al., Transcranial doppler assessment of cerebral perfusion in critically ill septic patients: a pilot study. Ann Intensive Care. 2013;3: 28, DOI: 10.1186/2110‐5820‐3‐28.
59.Szatmari, S., T. Vegh, A. Csomos, J. Hallay, I. Takacs, C. Molnar,et al., Impaired cerebrovascular reactivity in sepsis‐associated encephalopathy studied by acetazolamide test. Crit Care. 2010;14: R50.
60.Naito, Y., K. Yoshioka, K. Tanaka, K. Tatsumi, S. Kimura, and Y. Kasuya, Endothelin B receptor‐mediated encephalopathic events in mouse sepsis model. Life Sci. 2014;118(2): 340‐346, DOI: 10.1016/j.lfs.2014.03.012.
61.Shimojo, N., S. Jesmin, S. Zaedi, S. Maeda, S. Gando, I. Yamaguchi,et al., Alterations of gene expressions of preproET‐1 and ET receptors in brains of endotoxemic Sprague‐Dawley rats. Exp Biol Med. (Maywood). 2006;231: 1058‐1063.
62.Frister, A., C. Schmidt, N. Schneble, M. Brodhun, F.A. Gonnert, M. Bauer,et al., Phosphoinositide 3‐kinase gamma affects LPS‐induced disturbance of blood‐brain barrier via lipid kinase‐independent control of cAMP in microglial cells. Neuromolecular Med. 2014;16(4): 704‐713, DOI: 10.1007/s12017‐014‐8320‐z.
63.Pierrakos, C., R. Attou, L. Decorte, A. Kolyviras, S. Malinverni, P. Gottignies,et al., Transcranial Doppler to assess sepsis‐associated encephalopathy in critically ill patients. BMC Anesthesiol. 2014;14: 45, DOI: 10.1186/1471‐2253‐14‐45.
64.Ji, M.H., L.L. Qiu, H. Tang, L.S. Ju, X.R. Sun, H. Zhang,et al., Sepsis‐induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflammat. 2015;12: 182, DOI: 10.1186/s12974‐015‐0401‐x.
65.Alexander, J.J., A. Jacob, P. Cunningham, L. Hensley, and R.J. Quigg, TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor‐1. Neurochem Int. 2008;52: 447‐456.
66.Erbas, O. and D. Taskiran, Sepsis‐induced changes in behavioral stereotypy in rats; involvement of tumor necrosis factor‐alpha, oxidative stress, and dopamine turnover. J Surg Res. 2014;186(1): 262‐268, DOI: 10.1016/j.jss.2013.08.001.
67.Flierl, M.A., P.F. Stahel, D. Rittirsch, M. Huber‐Lang, A.D. Niederbichler, L.M. Hoesel,et al., Inhibition of complement C5a prevents breakdown of the blood‐brain barrier and pituitary dysfunction in experimental sepsis. Crit Care. 2009;13: R12.
68.Jacob, A., L.K. Hensley, B.D. Safratowich, R.J. Quigg, and J.J. Alexander, The role of the complement cascade in endotoxin‐induced septic encephalopathy. Lab Invest. 2007;87: 1186‐1194.
69.Sui, D.M., Q. Xie, W.J. Yi, S. Gupta, X.Y. Yu, J.B. Li,et al., Resveratrol protects against sepsis‐associated encephalopathy and inhibits the NLRP3/IL‐1beta axis in microglia. Mediators Inflamm. 2016;2016: 1045657 Article ID 1045657, DOI: 10.1155/2016/1045657.
70.Fang, J., Y. Lian, K. Xie, S. Cai, and P. Wen, Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis‐associated encephalopathy. Neurol Sci. 2014;35(2): 283‐288, DOI: 10.1007/s10072‐013‐1508‐4.
71.Imamura, Y., S. Yamada, S. Tsuboi, Y. Nakane, Y. Tsukasaki, A. Komatsuzaki,et al., Near‐infrared emitting PbS quantum dots for in vivo fluorescence imaging of the thrombotic state in septic mouse brain. Molecules. 2016;21(8): 1080.
72.Li, R., J. Tong, Y. Tan, S. Zhu, J. Yang, and M. Ji, Low molecular weight heparin prevents lipopolysaccharide induced‐hippocampus‐dependent cognitive impairments in mice. Int J Clin Exp Pathol. 2015;8(8): 8881‐8891.
73.Chen, Q., W. Yu, J. Shi, J. Shen, T. Gao, J. Zhang,et al., Insulin alleviates the inflammatory response and oxidative stress injury in cerebral tissues in septic rats. J Inflamm (Lond). 2014;11: 18, DOI: 10.1186/1476‐9255‐11‐18.
74.Hernandes, M.S., J.C. D’Avila, S.C. Trevelin, P.A. Reis, E.R. Kinjo, L.R. Lopes,et al., The role of Nox2‐derived ROS in the development of cognitive impairment after sepsis. J Neuroinflammation. 2014;11: 36, DOI: 10.1186/1742‐2094‐11‐36.
75.Lin, H.C. and F.J. Wan, Hyperbaric oxygenation reduces overexpression of c‐Fos and oxidative stress in the brain stem of experimental endotoxemic rats. Intensive Care Med. 2008;34: 1122‐1132.
76.Li, L., Q. Sun, Y. Li, Y. Yang, Y. Yang, T. Chang,et al., Overexpression of SIRT1 induced by resveratrol and inhibitor of miR‐204 suppresses activation and proliferation of microglia. J Mol Neurosci. 2015;56(4): 858-867. DOI: 10.1007/s12031‐015‐0526‐5.
77.Hamed, S.A., E.A. Hamed, and M.M. Abdella, Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S‐100B protein. Neuropediatrics. 2009;40: 66‐72.
78.Liu, J., D. Zhao, C. Liu, T. Ding, L. Yang, X. Yin,et al., Prion protein participates in the protection of mice from lipopolysaccharide infection by regulating the inflammatory process. J Mol Neurosci. 2015;55(1): 279‐287, DOI: 10.1007/s12031‐014‐0319‐2.
79.Kondo, S., S. Kohsaka, and S. Okabe, Long‐term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo. Mol Brain. 2011;4: 27.
80.Freund, H.R., M. Muggia‐Sullam, J. Peiser, and E. Melamed, Brain neurotransmitter profile is deranged during sepsis and septic encephalopathy in the rat. J Surg Res. 1985;38: 267‐271.
81.Davies, D.C., Blood‐brain barrier breakdown in septic encephalopathy and brain tumours. J Anat. 2002;200: 639‐646.
82.Kadoi, Y., S. Saito, F. Kunimoto, T. Imai, and T. Fujita, Impairment of the brain beta‐adrenergic system during experimental endotoxemia. J Surg Res. 1996;61: 496‐502.
83.Soejima, Y., Y. Fujii, T. Ishikawa, H. Takeshita, and T. Maekawa, Local cerebral glucose utilization in septic rats. Crit Care Med. 1990;18: 423‐427.
84.Dal‐Pizzol, F., C.D. Tomasi, and C. Ritter, Septic encephalopathy: does inflammation drive the brain crazy? Rev Bras Psiquiatr. 2014;36(3): 251‐258.
85.Zhang, Q.H., Z.Y. Sheng, and Y.M. Yao, Septic encephalopathy: when cytokines interact with acetylcholine in the brain. Mil Med Res. 2014;12: 0, DOI: 10.1186/2054‐9369‐1‐20.
86.Zhu, S.Z., W.P. Huang, L.Q. Huang, Y.L. Han, Q.P. Han, G.F. Zhu,et al., Huperzine A protects sepsis associated encephalopathy by promoting the deficient cholinergic nervous function. Neurosci Lett. 2016;631: 70‐78, DOI: 10.1016/j.neulet.2016.07.009.
87.Serantes, R., F. Arnalich, M. Figueroa, M. Salinas, E. Andres‐Mateos, R. Codoceo,et al., Interleukin‐1beta enhances GABAA receptor cell‐surface expression by a phosphatidylinositol 3‐kinase/Akt pathway: relevance to sepsis‐associated encephalopathy. J Biol Chem. 2006;281: 14632‐14643.
88.Taccone, F.S., S. Scolletta, F. Franchi, K. Donadello, and M. Oddo, Brain perfusion in sepsis. Curr Vasc Pharmacol. 2013;11(2): 170‐186.
89.Kafa, I.M., S. Bakirci, M. Uysal, and M.A. Kurt, Alterations in the brain electrical activity in a rat model of sepsis‐associated encephalopathy. Brain Res. 2010;1354: 217‐226.
90.Zauner, C., A. Gendo, L. Kramer, G.C. Funk, E. Bauer, P. Schenk,et al., Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med. 2002;30: 1136‐1139.
92.Teener, J.W. and M.M. Rich, Dysregulation of sodium channel gating in critical illness myopathy. J Muscle Res Cell Motil. 2006;27: 291‐296.
93.Iacobone, E., J. Bailly‐Salin, A. Polito, D. Friedman, R.D. Stevens, and T. Sharshar, Sepsis‐associated encephalopathy and its differential diagnosis. Crit Care Med. 2009;37(10 Suppl): S331‐S336, DOI: 10.1097/CCM.0b013e3181b6ed58.
94.Oddo, M. and F.S. Taccone, How to monitor the brain in septic patients? Minerva Anestesiol. 2015;81(7): 776‐788.
95.Kaplan, P.W. and A.O. Rossetti, EEG patterns and imaging correlations in encephalopathy: encephalopathy part II. J Clin Neurophysiol. 2011;28(3): 233‐251, DOI: 10.1097/WNP.0b013e31821c33a0.
96.Young, G.B., C.F. Bolton, Y.M. Archibald, T.W. Austin, and G.A. Wells, The electroencephalogram in sepsis‐associated encephalopathy. J Clin Neurophysiol. 1992;9: 145‐152.
98.Bragatti, J.A., A.M. Mattos, H. Bastes, and R.S. Riesgo, Alpha coma pattern in a child. Clin EEG Neurosci. 2008;39(4): 206‐209.
99.Hosokawa, K., N. Gaspard, F. Su, M. Oddo, J.L. Vincent, and F.S. Taccone, Clinical neurophysiological assessment of sepsis‐associated brain dysfunction: a systematic review. Crit Care. 2014;18(6): 674, DOI: 10.1186/s13054‐014‐0674‐y.
100.Stubbs, D.J., A.K. Yamamoto, and D.K. Menon, Imaging in sepsis‐associated encephalopathy[mdash]insights and opportunities. Nat Rev Neurol. 2013;9(10): 551‐561, DOI: 10.1038/nrneurol.2013.177.
101.Sharshar, T., R. Carlier, F. Bernard, C. Guidoux, J.‐P. Brouland, O. Nardi,et al., Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med. 2007;33(5): 798‐806, DOI: 10.1007/s00134‐007‐0598‐y.
102.Bozza, F.A., P. Garteiser, M.F. Oliveira, S. Doblas, R. Cranford, D. Saunders,et al., Sepsis‐associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab. 2010;30: 440‐448.
103.Finelli, P.F. and D.F. Uphoff, Magnetic resonance imaging abnormalities with septic encephalopathy. J Neurol Neurosurg Psychiatry. 2004;75: 1189‐1191.
104.Gotz, T., A. Gunther, O.W. Witte, F.M. Brunkhorst, G. Seidel, and F. Hamzei, Long‐term sequelae of severe sepsis: cognitive impairment and structural brain alterations ‐ an MRI study (LossCog MRI). BMC Neurol. 2014;14: 145, DOI: 10.1186/1471‐2377‐14‐145.
105.Semmler, A., S. Hermann, F. Mormann, M. Weberpals, S.A. Paxian, T. Okulla,et al., Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation. 2008;5: 38.
106.Weberpals, M., M. Hermes, S. Hermann, M.P. Kummer, D. Terwel, A. Semmler,et al., NOS2 gene deficiency protects from sepsis‐induced long‐term cognitive deficits. J Neurosci. 2009;29: 14177‐14184.
107.Joo, C., H. Balci, Y. Ishitsuka, C. Buranachai, and T. Ha, Advances in single‐molecule fluorescence methods for molecular biology. Annu Rev Biochem. 2008;77: 51‐76, DOI: 10.1146/annurev.biochem.77.070606.101543.
108.Terai, T. and T. Nagano, Fluorescent probes for bioimaging applications. Curr Opin Chem Biol. 2008;12(5): 515‐521, DOI: 10.1016/j.cbpa.2008.08.007.
109.Weissleder, R., A clearer vision for in vivo imaging. Nat Biotechnol. 2001;19(4): 316‐317, DOI: 10.1038/86684.
110.Jin, T. and Y. Imamura, Applications of highly bright PbS quantum dots to non‐invasive near‐infrared fluorescence imaging in the second optical window. ECS J Solid State Sci Technol. 2016;5(1): R3138‐R3145, DOI: 10.1149/2.0171601jss.
111.Taccone, F.S., F. Su, C. Pierrakos, X. He, S. James, O. Dewitte,et al., Cerebral microcirculation is impaired during sepsis: an experimental study. Crit Care. 2010;14: R140.
112.Blauhut, B., H. Kramar, H. Vinazzer, and H. Bergmann, Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res. 1985;39(1): 81‐89.
113.Iba, T., I. Nagaoka, and M. Boulat, The anticoagulant therapy for sepsis‐associated disseminated intravascular coagulation. Thromb Res. 2013;131(5): 383‐389, DOI: 10.1016/j.thromres.2013.03.012.
114.Semeraro, N., C.T. Ammollo, F. Semeraro, and M. Colucci, Sepsis‐associated disseminated intravascular coagulation and thromboembolic disease. Mediterr J Hematol Infect Dis. 2010;2(3): e2010024, DOI: 10.4084/MJHID.2010.024.
115.ten Cate, H., S.H. Schoenmakers, R. Franco, J.J. Timmerman, A.P. Groot, C.A. Spek,et al., Microvascular coagulopathy and disseminated intravascular coagulation. Crit Care Med. 2001;29(7 Suppl): S95‐S97; discussion S97‐98.
116.Ziaja, M., Sepsis and septic encephalopathy: characteristics and experimental models. Folia Neuropathol. 2012;50(3): 231‐239.
117.Zampieri, F.G., M. Park, F.S. Machado, and L.C. Azevedo, Sepsis‐associated encephalopathy: not just delirium. Clinics (Sao Paulo). 2011;66(10): 1825‐1831.
118.Panni, J.K. and M.K. Panni, Changes in S100B levels rather than absolute values may be a better marker of severity of septic encephalopathy. Br J Anaesth. 2008;100(3): 419; author reply 419‐420, DOI: 10.1093/bja/aen009.
119.Piazza, O., E. Russo, S. Cotena, G. Esposito, and R. Tufano, Elevated S100B levels do not correlate with the severity of encephalopathy during sepsis. Br J Anaesth. 2007;99(4): 518‐521, DOI: 10.1093/bja/aem201.
120.Spapen, H., D.N. Nguyen, J. Troubleyn, L. Huyghens, and J. Schiettecatte, Drotrecogin alfa (activated) may attenuate severe sepsis‐associated encephalopathy in clinical septic shock. Crit Care. 2010;14: R54.
121.Towner, R.A., P. Garteiser, F. Bozza, N. Smith, D. Saunders, J.C. d’ Avila,et al., In vivo detection of free radicals in mouse septic encephalopathy using molecular MRI and immuno‐spin trapping. Free Radic Biol Med. 2013;65: 828‐837, DOI: 10.1016/j.freeradbiomed.2013.08.172.
122.Yokoo, H., S. Chiba, K. Tomita, M. Takashina, H. Sagara, S. Yagisita,et al., Neurodegenerative evidence in mice brains with cecal ligation and puncture‐induced sepsis: preventive effect of the free radical scavenger edaravone. PLoS One. 2012;7(12): e51539, DOI: 10.1371/journal.pone.0051539.
123.Huang, Y.N., C.C. Lai, C.T. Chiu, J.J. Lin, and J.Y. Wang, L‐ascorbate attenuates the endotoxin‐induced production of inflammatory mediators by inhibiting MAPK activation and NF‐kappaB translocation in cortical neurons/glia Cocultures. PLoS One. 2014;9(7): e97276, DOI: 10.1371/journal.pone.0097276.
124.Voigt, K., A. Kontush, H.J. Stuerenburg, D. Muench‐Harrach, H.C. Hansen, and K. Kunze, Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res. 2002;36: 735‐739.
125.Wilson, J.X. and F. Wu, Vitamin C in sepsis. Subcell Biochem. 2012;56: 67‐83, DOI: 10.1007/978‐94‐007‐2199‐9_5.
126.Pinheiro da Silva, F., M.C. Machado, and I.T. Velasco, Neuropeptides in sepsis: from brain pathology to systemic inflammation. Peptides. 2013;44: 135‐138, DOI: 10.1016/j.peptides.2013.03.029.
127.Bakirci, S., I.M. Kafa, M. Uysal, and M. Ayberk Kurt, Increased adult neurogenesis in the subventricular zone in a rat model of sepsis. Neurosci Lett. 2011;497(1): 27‐31, DOI: 10.1016/j.neulet.2011.04.014.
Written By
Yukio Imamura, Yuki Murakami, Naoya Matsumoto, Hisatake Matsumoto, Satoko Mitani, Kentaro Shimizu, Hiroshi Ogura, Takeshi Shimazu and Takashi Jin
Submitted: October 14th, 2016Reviewed: February 20th, 2017Published: August 23rd, 2017
Open access peer-reviewed chapter
