Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review.

IntroductionSeveral studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear.MethodsWe performed a systematic search for studies evaluating EEG and/or EPs in adult (¿18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome.ResultsAmong 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated.ConclusionsAbnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.

Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases.

Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.

Effect of n-3 fatty acids on markers of brain injury and incidence of sepsis-associated delirium in septic patients.

BACKGROUND: Data regarding immunomodulatory effects of parenteral n-3 fatty acids in sepsis are conflicting. In this study, the effect of administration of parenteral n-3 fatty acids on markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients was investigated. METHODS: Fifty patients with sepsis were randomized to receive either 2 ml/kg/day of a lipid emulsion containing highly refined fish oil (equivalent to n-3 fatty acids 0.12 mg/kg/day) during 7 days after admission to the intensive care unit or standard treatment. Markers of brain injury and inflammatory mediators were measured on days 1, 2, 3 and 7. Assessment for sepsis-associated delirium was performed daily. The primary outcome was the difference in S-100β from baseline to peak level between both the intervention and the control group, compared by t-test. Changes of all markers over time were explored in both groups, fitting a generalized estimating equations model. RESULTS: Mean difference in change of S-100β from baseline to peak level was 0.34 (95% CI: -0.18-0.85) between the intervention and control group, respectively (P = 0.19). We found no difference in plasma levels of S-100β, neuron-specific enolase, interleukin (IL)-6, IL-8, IL-10, and C-reactive protein between groups over time. Incidence of sepsis-associated delirium was 75% in the intervention and 71% in the control groups (risk difference 4%, 95% CI -24-31%, P = 0.796). CONCLUSION: Administration of n-3 fatty acids did not affect markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients.

Brain perfusion in sepsis.

Brain dysfunction is a frequent complication of sepsis, usually defined as "sepsis-associated encephalopathy" (SAE). Its pathophysiology is complex and related to numerous processes and pathways, while the exact mechanisms producing neurological impairment in septic patients remain incompletely elucidated. Alterations of the cerebral blood flow (CBF) may represent a key component for the development of SAE. Reduction of CBF may be caused by cerebral vasoconstriction, either induced by inflammation or hypocapnia. Endothelial dysfunction associated with sepsis leads to impairment of microcirculation and cerebral metabolic uncoupling that may further reduce brain perfusion so that CBF becomes inadequate to satisfy brain cellular needs. The natural autoregulatory mechanisms that protect the brain from reduced/ inadequate CBF can be impaired in septic patients, especially in those with shock or delirium, and this further contributes to cerebral ischemia if blood pressure drops below critical thresholds. Sedative agents alter cerebro-vascular reactivity and may significantly reduce CBF. Although disorders of brain perfusion and alteration of CBF and cerebral autoregulation are frequently observed in humans with sepsis, their exact role in the pathogenesis of SAE remains unknown. Brain perfusion can further become inadequate due to cerebral microcirculatory dysfunction, as evidenced in the experimental setting. Microvascular alterations can be implicated in the development of electrophysiological abnormalities observed during sepsis and contribute to neurological alterations in septic animals. The aim of this review is to provide an update on the pathophysiology of brain perfusion in sepsis, with a particular focus on human clinical investigation and novel tools for CBF monitoring in septic patients.

Phthalates in the NICU: Is it safe?

AIMS: As growing concerns exist regarding phthalate exposure, which could be teratogenic, carcinogenic or induce reproductive toxicity, we aimed to review the evidence of the risks due to the use of medical devices containing di(2-ethylhexyl)phthalate in hospitalized neonates. METHODS: We reviewed the literature, searching through medical literature databases (Pubmed, MEDLINE, EBM reviews, Cochrane database, Embase and Google Scholar) using the following keywords: phthalate, di(2-ethylhexyl)phthalate, newborn and neonate. RESULTS: We identified several associations with short and long term health dangers, mainly subfertility, broncho-pulmonary dysplasia, necrotising enterocolitis, parenteral nutrition associated cholestasis and neuro-developmental disorders. These data are based mainly on animal or observational human studies. CONCLUSION: Clinicians must be aware of the potential risks due to phthalate exposure in the NICU. Di(2-ethylhexyl)phthalate containing materials should be identified and alternative devices should be considered. There is a need to improve knowledge in this area.

EEG Patterns and Imaging Correlations in Encephalopathy: Encephalopathy Part II.

SUMMARY:: The EEG patterns seen with encephalopathies can be correlated to cerebral imaging findings including head computerized tomography and MRI. Background slowing without slow-wave intrusion is seen with acute and chronic cortical impairments that spare subcortical white matter. Subcortical/white matter structural abnormalities or hydrocephalus may produce projected slow-wave activity, while clinical entities involving both cortical and subcortical regions (diffuse cerebral abnormalities) engender both background slowing and slow-wave activity. Triphasic waves are seen with hepatic and renal insufficiency or medication toxicities (e.g., lithium, baclofen) in the absence of a significant cerebral imaging abnormality, Conversely, subcortical/white matter abnormalities may facilitate the appearance of triphasic waves without significant hepatic, renal, or toxic comorbidities. More specific syndromes, such as Jakob-Creutzfeldt disease, autoimmune limbic encephalitis, autoimmune corticosteroid-responsive encephalopathy with thyroid autoimmunity, sepsis-associated encephalopathy, and acute disseminated encephalomyelitis, have imaging/EEG changes that are variable but which may include slowing and epileptiform activity. This overview highlighting EEG-imaging correlations may help the treating physician in the diagnosis, and hence the appropriate treatment, of patients with encephalopathy.

How to monitor the brain in septic patients?

Brain injury is frequently observed after sepsis and may be primarily related to the direct effects of the septic insult on the brain (e.g., brain edema, ischemia, seizures) or to secondary/indirect injuries (e.g., hypotension, hypoxemia, hypocapnia, hyperglycemia). Management of brain injury in septic patients is first focused to exclude structural intracranial complications (e.g., ischemic/hemorrhagic stroke) and possible confounders (e.g., electrolyte alterations or metabolic disorders, such as dysglycemia). Sepsis-associated brain dysfunction is frequently a heterogeneous syndrome. Despite increasing understanding of main pathophysiologic determinants, therapy is essentially limited to protect the brain against further cerebral damage, by way of "simple" therapeutic manipulations of cerebral perfusion and oxygenation and by avoiding over-sedation. Non-invasive monitoring of cerebral perfusion and oxygenation with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) is feasible in septic patients. Electroencephalography (EEG) allows detection of sepsis-related seizures and holds promise also as sedation monitoring. Brain CT-scan detects intra-cerebral structural lesions, while magnetic resonance imaging (MRI) provides important insights into primary mechanisms of sepsis-related direct brain injury, (e.g., cytotoxic vs. vasogenic edema) and the development of posterior reversible encephalopathy. Together with EEG and evoked potentials (EP), MRI is also important for coma prognostication. Emerging clinical evidence suggests monitoring of the brain in septic patients can be implemented in the ICU. The objective of this review was to summarize recent clinical data about the role of brain monitoring - including TCD, NIRS, EEG, EP, CT, and MRI - in patients with sepsis and to illustrate its potential utility for the diagnosis, management and prognostication.

Macrophage Migration Inhibitory Factor Deficiency Is Associated With Impaired Killing of Gram-Negative Bacteria by Macrophages and Increased Susceptibility to Klebsiella pneumoniae Sepsis.

The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.

Gas6 and its receptors are implicated in sepsis as modulators of innate immunity

Gas6 downregulates the activation state of macrophages and thereby their production of proinflammatory cytokines induced by various stimuli. We aimed to determine whether Gas6 is involved in sepsis. We measured Gas6 plasma levels in 13 healthy subjects, 29 patients with severe sepsis, and 18 patients with non-infectious inflammatory diseases. Gas6 level was higher in septic patients than in control groups (P 0.0001). The sensitivity and specificity of Gas6 levels to predict fatal outcome were 83% and 88%. We next investigated whether Gas6 affects cytokine production and outcome in experimental models of endotoxemia and peritonitis in wild-type (WT) and Gas6-/- mice. Circulating levels of Gas6 after LPS 25mg/kg i.p. peaked at 1 hour (P<0.001). Similarly, TNF- was higher in Gas6-/- than in WT mice 1 hour after LPS (P<0.05). Furthermore, 62 anti- and pro-inflammatory cytokines were quantified in plasma after LPS injection. Their levels were globally higher in Gas6-/- plasma after LPS, 47/62 cytokines being at least 50% higher in Gas6-/- than in WT plasma after 1 hour. Mortality induced by 25mg/kg LPS was 25% in WT versus 87% in Gas6-/- mice (P<0.05). LPS-induced mortality in Gas6 receptors Axl-/-, Tyro3-/- and Merkd was also enhanced when compared to WT mice (P<0.001). In peritonitis models (cecal ligation and puncture, CLP, and i.p. injection of E. coli), Gas6 plasma levels increased and remained elevated at least 24 hours. CLP increased mortality in Gas6-/- mice. Finally, we explored the role of Gas6 in LPS-treated macrophages. We found that Gas6 was released by LPS-stimulated WT macrophages and that Gas6-/- macrophages produced more TNF- and IL-6 than WT macrophages. Cytokine release by Gas6-/- macrophages was higher than by WT macrophages (cytokine array). Adjunction of recombinant Gas6 to the culture medium of Gas6-/- macrophages diminished the cytokine production to WT levels. In LPS-treated Gas6-/- macrophages, Akt and Erk1/2 phosphorylation was reduced whereas p38 and NF B activation was enhanced. Thus, in septic patients, elevated Gas6 levels were associated with fatal outcome. In mice, they raised in experimental endotoxemia and peritonitis models, and correlated also with sepsis severity. However, Gas6-/- mice survival in these models was reduced compared to WT. Gas6 secreted by macrophages in response to LPS activated Akt and restrained p38 and NF B activation, thereby dampening macrophage activation. Altogether these data suggest that, during endotoxemia, Gas6-/- mice phenotype resembles that of mice which have undergone PI3K inhibition, indicating that Gas6 is a major modulator of innate immunity.

Hépatopathies gravidiques [Pregnancy-associated liver diseases]

Les hépatopathies sont rares au cours de la grossesse, mais peuvent avoir des conséquences dramatiques pour la mère et l'enfant si elles ne sont pas diagnostiquées à temps. On différencie principalement les hépatopathies spécifiquement secondaires à la grossesse des intercurrentes. Parmi les premières, on peut citer les manifestations hépatiques de l'hyperemesis gravidarum, la cholestase intrahépatique gravidique, les atteintes hépatiques lors d'une (pré-)éclampsie, y compris le syndrome HELLP, et la stéatose hépatique aiguë gravidique. Le diagnostic différentiel est basé sur l'anamnèse (stade de la grossesse), la clinique, quelques examens de laboratoire et l'échographie comme imagerie de première intention. Le traitement d'une cholestase intrahépatique gravidique par acide ursodésoxycholique améliore le prurit et les tests hépatiques maternels. Une surveillance rapprochée de la grossesse reste cependant indispensable. Lors d'un syndrome HELLP ou d'une stéatose hépatique aiguë gravidique, il faut procéder à l'accouchement le plus vite possible. Toutes les hépatopathies déjà connues nécessitent un suivi strict durant la grossesse. While liver diseases are a rare occurrence in pregnancy, they may have dramatic implications for mother and child if not detected in good time. A distinction is drawn between pregnancy-specific liver diseases and intercurrent liver diseases during pregnancy. The former include hepatic manifestations of hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, hepatic involvement in preeclampsia or eclampsia, including the HELLP syndrome, and acute fatty liver of pregnancy. Differential diagnosis of pregnancy-associated liver disorders is based on history (stage of pregnancy), clinical findings, a few laboratory tests and ultrasound as the primary imaging technique. Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid improves pruritus and maternal liver tests. Close monitoring of pregnancy remains however indispensable. In HELLP syndrome and acute fatty liver of pregnancy the aim should be rapid delivery. Preexisting liver diseases require intensified monitoring during pregnancy.

Brain dysfunction in sepsis: what can we learn from cerebral perfusion studies?

Investigations on the relationship between sepsis, brain dysfunction, and cerebral perfusion are methodologically very difficult to perform. It is important to interpret the results of such studies in view of our limited ability to diagnose and quantify brain dysfunction and to consider our limited understanding of the mechanisms that lead to or are associated with brain dysfunction in sepsis.

Schwangerschaftsassoziierte Lebererkrankungen [Pregnancy-associated liver diseases]

Lebererkrankungen treten in der Schwangerschaft selten auf, können jedoch für Mutter und Kind dramatische Folgen haben, wenn sie nicht rechtzeitig erkannt werden. Prinzipiell unterscheidet man schwangerschaftsspezifische Lebererkrankungen von interkurrierenden Lebererkrankungen während der Schwangerschaft. Zu ersteren gehören die hepatischen Manifestationen der Hyperemesis gravidarum, die intrahepatische Schwangerschaftscholestase, die Leberbeteiligung bei Präeklampsie bzw. Eklampsie inkl. HELLP-Syndrom und die akute Schwangerschaftsfettleber. Die Differentialdiagnose schwangerschaftsassoziierter Lebererkrankungen basiert auf der Anamnese (Stadium der Schwangerschaft), der Klinik, wenigen Laboruntersuchungen und einer Ultrasonographie als primärem bildgebendem Verfahren. Die Behandlung der intrahepatischen Schwangerschaftscholestase mit Ursodeoxycholsäure verbessert den Pruritus und die mütterlichen Leberwerte. Eine engmaschige Überwachung der Schwangerschaft bleibt jedoch unabdingbar. Beim HELLP-Syndrom und der akuten Schwangerschaftsfettleber ist die rasche Entbindung anzustreben. Vorbestehende Lebererkrankungen bedürfen in der Schwangerschaft einer intensivierten Kontrolle. While liver diseases are a rare occurrence in pregnancy, they may have dramatic implications for mother and child if not detected in good time. A distinction is drawn between pregnancy-specific liver diseases and intercurrent liver diseases during pregnancy. The former include hepatic manifestations of hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, hepatic involvement in preeclampsia or eclampsia, including the HELLP syndrome, and acute fatty liver of pregnancy. Differential diagnosis of pregnancy-associated liver disorders is based on history (stage of pregnancy), clinical findings, a few laboratory tests and ultrasound as the primary imaging technique. Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid improves pruritus and maternal liver tests. Close monitoring of pregnancy remains however indispensable. In HELLP syndrome and acute fatty liver of pregnancy the aim should be rapid delivery. Preexisting liver diseases require intensified monitoring during pregnancy.

Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management.

ABSTRACT: INTRODUCTION: Biomarkers, such as C-reactive protein [CRP] and procalcitonin [PCT], are insufficiently sensitive or specific to stratify patients with sepsis. We investigate the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections. METHODS: PSP/reg, CRP, PCT, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL1-β), IL-6 and IL-8 were prospectively measured in cohort of patients ≥ 18 years of age with severe sepsis or septic shock within 24 hours of admission in a medico-surgical intensive care unit (ICU) of a community and referral university hospital, and the ability to predict in-hospital mortality was determined. RESULTS: We evaluated 107 patients, 33 with severe sepsis and 74 with septic shock, with in-hospital mortality rates of 6% (2/33) and 25% (17/74), respectively. Plasma concentrations of PSP/reg (343.5 vs. 73.5 ng/ml, P < 0.001), PCT (39.3 vs. 12.0 ng/ml, P < 0.001), IL-8 (682 vs. 184 ng/ml, P < 0.001) and IL-6 (1955 vs. 544 pg/ml, P < 0.01) were significantly higher in patients with septic shock than with severe sepsis. Of note, median PSP/reg was 13.0 ng/ml (IQR: 4.8) in 20 severely burned patients without infection. The area under the ROC curve for PSP/reg (0.65 [95% CI: 0.51 to 0.80]) was higher than for CRP (0.44 [0.29 to 0.60]), PCT 0.46 [0.29 to 0.61]), IL-8 (0.61 [0.43 to 0.77]) or IL-6 (0.59 [0.44 to 0.75]) in predicting in-hospital mortality. In patients with septic shock, PSP/reg was the only biomarker associated with in-hospital mortality (P = 0.049). Risk of mortality increased continuously for each ascending quartile of PSP/reg. CONCLUSIONS: Measurement of PSP/reg concentration within 24 hours of ICU admission may predict in-hospital mortality in patients with septic shock, identifying patients who may benefit most from tailored ICU management.

Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities.

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.