Search

Background and objectives Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to determine whether pro- and anti-inflammatory T cells are involved in the local immune response to lung inflammation. Methods Bronchoalveolar lavage (BAL) was performed in 15 healthy volunteers, after which Escherichia coli LPS (4 ng/kg) was administered. BAL was repeated at 2, 4, 6, 8 or 24 h after instillation of LPS. Results BALF CD4+ and CD8+ T cells were characterized by expression of activation markers (HLA-DR+CD38+), the proportion of cells expressing naive markers (CD45RA+CD27+CCR7+) was lower, and that of cells expressing effector memory markers (CD45RA-CD27+CCR7-) was higher, compared with peripheral blood. Bronchial LPS induced a local inflammatory response with recruitment of CD4+ (P = 0.014), CD8+ T cells (P = 0.034), an increase in the proportion of CD4+CD25+CD127lowFoxp3+ regulatory T cells (Tregs) (P = 0.045) and a tendency towards an increase in CD4+CD161+ cells (P = 0.071) were observed. Conclusions A unique distribution of T cells with little day-to-day variation was found in human airways. An increase in Tregs after endobronchial LPS suggests a role for Tregs during early stages of pulmonary inflammation.

Assessment of the default mode network (DMN) using resting-state functional magnetic resonance imaging (fMRI) may improve assessment of the level of consciousness in chronic brain injury, and therefore, fMRI may also have prognostic value in acute brain injury. However, fMRI is much more challenging in critically ill patients because of cardiovascular vulnerability, intravenous sedation, and artificial ventilation. Using resting-state fMRI, we investigated the DMN in a convenience sample of patients with acute brain injury admitted to the intensive care unit. The DMN was classified dichotomously into “normal” and “grossly abnormal.” Clinical outcome was assessed at 3 months. Seven patients with acute brain injury (4 females; median age 37 years [range 14–71 years]; 1 traumatic brain injury [TBI]; 6 non-TBI) were investigated by fMRI a median of 15 days after injury (range 5–25 days). Neurological presentation included 2 coma, 1 vegetative state/unresponsive wakefulness syndrome (VS/UWS), 3 minimal conscious state (MCS) minus, and 1 MCS plus. Clinical outcomes at 3 months included 1 death, 1 VS/UWS, 1 MCS plus, and 4 conscious states (CS; 1 modified Rankin Scale 0; 2 mRS 4; 1 mRS 5). Normal DMNs were seen in 4 out of 7 patients (1 MCS plus, 3 CS at follow-up). It is feasible to assess the DMN by resting-state fMRI in patients with acute brain injury already in the very early period of intensive care unit admission. Although preliminary data, all patients with a preserved DMN regained consciousness levels at follow-up compatible with MCS+ or better.

Background The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased 90-day mortality with hydroxyethyl starch (HES) 130/0.42 vs. Ringer's acetate. To explore the underlying pathophysiology, we compared early changes in plasma cytokine concentrations between patients resuscitated with HES vs. Ringer's acetate. Methods In a subgroup of 226 patients from the 6S trial, we calculated delta plasma concentrations of tumour necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-10 from randomization to day 2. We used multiple linear and logistic regression analyses to assess differences between the groups and associations between delta cytokine concentrations and 90-day mortality, respectively. Results Baseline characteristics and day 2 mortality were comparable between the groups. We observed similar delta cytokine concentrations in the HES vs. Ringer's group (mean difference in delta TNF-α: -1.5 pg/ml (95% CI, -4.9 to 1.9), P = 0.39; IL-6: 36.0 pg/ml (-24.1 to 96.1), P = 0.24; IL-10: -3.9 pg/ml (-21.1 to 28.9), P = 0.76). In all included patients, we observed a linear relationship between increases in TNF-α and 90-day mortality (P = 0.005). Conclusion Resuscitation with HES 130/0.42 vs. Ringer's acetate did not appear to affect plasma concentrations of TNF-α, IL-6 or IL-10 differently during the first days after randomization into the 6S trial. In the overall cohort, increases in TNF-α were associated with increased 90-day mortality. Although interpretation should be done with caution, it seems unlikely that the increased mortality observed with the use HES in the 6S trial is signalled by early changes in three biomarkers of systemic inflammation.

Corticosteroid-binding globulin (CBG) cleavage promotes local cortisol delivery in inflammation. Enzymatic cleavage of high-affinity CBG to low-affinity CBG (haCBG to laCBG) occurs at inflammatory sites and is now measurable in vivo; however, the time kinetics of haCBG depletion following an inflammatory stimulus is unknown. Hence our aim was to determine the immediate effect of the key pro-inflammatory cytokine TNF-α on CBG levels and cleavage. We performed a crossover study of 12 healthy males receiving a TNF-α versus saline infusion, measuring total CBG, haCBG, laCBG and free and total cortisol hourly for 6 h. There was no change in total CBG or haCBG levels in the first 6 h of inflammation between the groups, suggesting that CBG cleavage is not activated nor is hepatic CBG production affected by TNF-α in this time frame. There was an early increase in the ratio of free:total cortisol, in association with pyrexia. This accords with data indicating that CBG acts a thermocouple in vivo, increasing free cortisol levels independent of elastase-driven cleavage.

Supplemental Digital Content is available in the text., Background and Purpose— Delayed cerebral ischemia (DCI) accounts for a major part of the morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are pathophysiologically involved in acute cerebral ischemia. This study compared miRNA profiles in cerebrospinal fluid from neurologically healthy patients, as well as SAH patients with and without subsequent development of DCI. Methods— In a prospective case–control study of SAH patients treated with external ventricular drainage and neurologically healthy patients, miRNA profiles in cerebrospinal fluid were screened and validated using 2 different high-throughput real-time quantification polymerase chain reaction techniques. The occurrence of DCI was documented in patient charts and subsequently reviewed independently by 2 physicians. Results— MiRNA profiles from 27 SAH patients and 10 neurologically healthy patients passed quality control. In the validation, 66 miRNAs showed a relative increase in cerebrospinal fluid from SAH patients compared with neurologically healthy patients (P

Dialysis disequilibrium syndrome (DDS) is a serious neurological complication of hemodialysis, and patients with acute brain injury are at increased risk. We report a case of DDS leading to intracranial hypertension in a patient with anoxic brain injury and discuss the subsequent dialysis strategy. A 13-year-old girl was admitted after prolonged resuscitation from cardiac arrest. Computed tomography (CT) revealed an inferior vena cava aneurysm and multiple pulmonary emboli as the likely cause. An intracranial pressure (ICP) monitor was inserted, and, on day 3, continuous renal replacement therapy (CRRT) was initiated due to acute kidney injury, during which the patient developed severe intracranial hypertension. CT of the brain showed diffuse cerebral edema. CRRT was discontinued, sedation was increased, and hypertonic saline was administered, upon which ICP normalized. Due to persistent hyperkalemia and overhydration, ultrafiltration and intermittent hemodialysis were performed separately on day 4 with a small dialyzer, low blood and dialysate flow, and high dialysate sodium content. During subsequent treatments, isolated ultrafiltration was well tolerated, whereas hemodialysis was associated with increased ICP necessitating frequent pauses or early cessation of dialysis. In patients at risk of DDS, hemodialysis should be performed with utmost care and continuous monitoring of ICP should be considered.

Objectives:Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following lipopolysaccharide

Summary Background Continuous monitoring of cerebral blood flow (CBF) may be valuable in critically ill patients with sepsis. In this study, we compared spatially resolved near-infrared spectroscopy (NIRS) to transcranial Doppler ultrasound (TCD)-derived estimates of noradrenaline-associated changes in CBF in such patients. Methods Mean arterial blood pressure (MAP) was elevated by increasing the noradrenaline infusion rate in eight mechanically ventilated, critically ill patients diagnosed with severe sepsis or septic shock. The associated changes in CBF were assessed by simultaneous ipsilateral NIRS (ScO2) and TCD (middle cerebral artery blood flow velocity, MCAv) measurements. Results A total of fifteen simultaneous NIRS- and TCD-derived assessments of noradrenaline-associated changes in CBF were obtained. MAP was increased from 74 (median; interquartile range (IQR), 71–90) to 100 (median; IQR, 93–115) mmHg (P

Background Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. Methods We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m2). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. Results TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. Conclusion In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. Copyright © 2013 John Wiley & Sons, Ltd.

Critical illness afflicts millions of people worldwide and is associated with a high risk of organ failure and death or an adverse outcome with persistent physical or cognitive deficits. Spontaneous hyperglycemia is common in critically ill patients and is associated with an adverse outcome compared to normoglycemia. Insulin is used for treating hyperglycemia in the critically ill patients but may be complicated by hypoglycemia, which is difficult to detect in these patients and which may lead to serious neurological sequelae and death. The incretin hormone, glucagon-like peptide (GLP) 1, stimulates insulin secretion and inhibits glucagon release both in healthy individuals and in patients with type 2 diabetes (T2DM). Compared to insulin, GLP-1 appears to be associated with a lower risk of severe hypoglycemia, probably because the magnitude of its insulinotropic action is dependent on blood glucose (BG). This is taken advantage of in the treatment of patients with T2DM, for whom GLP-1 analogs have been introduced during the recent years. Infusion of GLP-1 also lowers the BG level in critically ill patients without causing severe hypoglycemia. The T2DM and critical illness share similar characteristics and are, among other things, both characterized by different grades of systemic inflammation and insulin resistance. The GLP-1 might be a potential new treatment target in critically ill patients with stress-induced hyperglycemia.

SummaryHuman brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT.

It is a central principle in medical ethics that vulnerable patients are entitled to a degree of protection that reflects their vulnerability. In critical care research, this protection is often established by means of so-called proxy consent. Proxy consent for research participation constitutes a substituted judgement by a close relative or friend, based on knowledge of patient's values, preferences, and view of life. For the consent to be genuine, the proxy must be informed of and understand three fundamental aspects of research practice: (1) that participation is voluntary and the consent can be withdrawn at any time; (2) that the research is designed to benefit future patients and society as a whole, and not the individual study participant; and (3) that participation involves an incremental non-therapeutic risk. If this is not fulfilled because the research is to be conducted under circumstances where the proxy is unavailable, adequate protection of the patient must be ensured by other means. Thus, the research must be designed specifically to benefit critically ill patients, and the incremental non-therapeutic risk must only comprise a minimal risk.

ICU admission is associated with decreased physical function for years after discharge. The underlying mechanisms responsible for this muscle function impairment are undescribed. The aim of this study was to describe the biomechanical properties of the quadriceps muscle in ICU survivors 12 months after ICU discharge.Case-control study with consecutive inclusion of ICU survivors and age- and sex-matched controls.Patients were treated at a mixed 18-bed ICU at a tertiary care university hospital and tested at a biomechanical university laboratory.We included 16 male ICU patients (Acute Physiology and Chronic Health Evaluation II score 20 ± 7, mean ± SD), who had stayed in the ICU72 hrs and survived to 12 months and 15 age- and sex-matched controls.None.An extensive battery of biomechanical tests, including maximum, fast, and endurance contractions, was administered during isometric knee extensions while simultaneously recording surface electromyography (quadriceps and hamstrings). Compared to controls, ICU survivors had reduced maximal voluntary torque (22%, 179 ± 64 Nm vs. 230 ± 57 Nm, p = 0.03), absolute rate of force development (50%, 868 ± 372 Nm/sec vs. 1739 ± 470 Nm/sec, p0.001) and relative rate of force development (32%, 512 ± 260% maximum voluntary contraction/sec vs. 754 ± 189% maximum voluntary contraction/sec, p0.01), and endurance time (40%, 136 ± 84 sec vs. 226 ± 111 sec, p0.02). Rate of force development, but not maximal voluntary torque, was significantly reduced after adjusting for muscle mass. Electromyography data indicated no impairment of motor activation strategy or central motor drive. Also, no difference in reaction time was found between patients and controls.ICU survivors had reduced rate of force development and muscular endurance 1 yr after ICU discharge. Our data indicate that the functional deficits experienced by ICU survivors originate in muscle tissue rather than the nervous system. Also, increased attention to velocity-orientated exercise during rehabilitation of ICU patients may have the potential to better physical outcome after critical illness.

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment by overlapping mechanisms. The purpose of this study was to test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after 8 consecutive days in bed. Healthy, lean men ( n = 20) were randomized to 1) 8 days of bed rest with three daily isoenergetic meals (control group, n = 10); and 2) 8 days of bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, dual-energy X-ray absorptiometry (DXA) scans, magnetic resonance imaging of the abdomen and brain, V̇o2max, and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24-h glucose profiles by continuous glucose monitoring system were assessed during the 8 days of bed rest period. Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared with the control group, ADCR was associated with improved and steadier glycemic control on fasting days and higher glycemic fluctuation and indexes of insulin resistance on overeating days. In contrast to our hypothesis, the metabolic impairment induced by 8 days of bed rest was not counteracted by ADCR with overall energy balance. NEW & NOTEWORTHY Alternate-day caloric restriction without overall energy reduction does not ameliorate the metabolic impairment induced in lean men by 8 days of bed rest.

We aimed to study the relationship between pain perception and cytokine release during systemic inflammation. We present a randomized crossover trial in healthy volunteers ( n = 17) in 37 individual trials. Systemic inflammation was induced by an i.v. bolus of Escherichia coli LPS (2 ng/kg) on two separate trial days, with or without a nicotine patch applied 10 h previously. Pain perception at baseline, and 2 and 6 h after LPS was assessed by pressure algometry and tonic heat stimulation at an increasing temperature (45–48℃) during both trials. Compared with baseline, pain pressure threshold was reduced 2 and 6 h after LPS, while heat pain perception was accentuated at all testing temperatures after 2 but not 6 h. The magnitude of changes in pain perception did not correlate to cytokine release. No effect of transdermal nicotine or training status was observed. In conclusion, LPS administration in healthy human volunteers leads to reduction in pain pressure threshold and an increase in pain perception to heat stimuli, supporting a relationship between acute systemic inflammation and pain perception.

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

Sepsis is frequently complicated by brain dysfunction, which may be associated with disturbances in cerebral autoregulation, rendering the brain susceptible to hypoperfusion and hyperperfusion. The purpose of the present study was to assess static and dynamic cerebral autoregulation 1) in a human experimental model of the systemic inflammatory response during early sepsis and 2) in patients with advanced sepsis. Cerebral autoregulation was tested using transcranial Doppler ultrasound in healthy volunteers ( n = 9) before and after LPS infusion and in patients with sepsis ( n = 16). Static autoregulation was tested by norepinephrine infusion and dynamic autoregulation by transfer function analysis (TFA) of spontaneous oscillations between mean arterial blood pressure and middle cerebral artery blood flow velocity in the low frequency range (0.07–0.20 Hz). Static autoregulatory performance after LPS infusion and in patients with sepsis was similar to values in healthy volunteers at baseline. In contrast, TFA showed decreased gain and an increased phase difference between blood pressure and middle cerebral artery blood flow velocity after LPS (both P < 0.01 vs. baseline); patients exhibited similar gain but lower phase difference values ( P < 0.01 vs. baseline and LPS), indicating a slower dynamic autoregulatory response. Our findings imply that static and dynamic cerebral autoregulatory performance may disassociate in sepsis; thus static autoregulation was maintained both after LPS and in patients with sepsis, whereas dynamic autoregulation was enhanced after LPS and impaired with a prolonged response time in patients. Hence, acute surges in blood pressure may adversely affect cerebral perfusion in patients with sepsis.

Corticosteroids are used as an adjunct to antibiotics in the treatment of bacterial meningitis in an attempt to attenuate the intrathecal inflammatory response and thereby reduce mortality and morbidity. The purpose of the present paper is to provide a review of clinical studies of corticosteroids in the treatment of bacterial meningitis. Relevant literature was found in PubMed, the Cochrane databases, and references in studies. Forty-four publications of relevance were identified, comprising 29 publications of randomised studies, 10 publications reporting either non- or quasi-randomised studies, and five reporting retrospective studies, and nine meta-analyses. Taken together, dexamethasone treatment may be associated with a lower mortality in adults and fewer neurological and auditory sequelae in adults and children from high-income countries, in particular in adults suffering from pneumococcal meningitis. In contrast, studies conducted in developing countries have yielded less favourable results.

We report 2 cases of Capnocytophaga canimorsus-induced septicaemia complicated by purpura fulminans in previously healthy individuals, both of whom had been exposed to dog saliva prior to disease. They both presented with purpuric skin lesions, as well as the tetrad of abdominal symptoms, haemolytic anaemia, metabolic acidosis, and renal failure, which may be common in C. canimorsus-associated purpura fulminans. The patients survived after treatment with broad-spectrum antibiotics and supportive intensive care. C. canimorsus should be considered as a possible cause of infectious purpura fulminans in the unresolved critically ill patient with a history of dog exposure.

Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P

Background Minimally invasive monitoring systems of central haemodynamics are gaining increasing popularity. The present study investigated the precision of the endotracheal cardiac output monitor (ECOM) system and its agreement with pulmonary artery catheter thermodilution (PAC TD) for measuring cardiac output (CO) during steady state and with induced haemodynamic changes in patients scheduled for elective cardiac surgery. Methods Twenty-five patients were enrolled. After induction of anaesthesia, endotracheal intubation using a dedicated ECOM tube, and insertion of the pulmonary artery catheter (PAC), the patient was placed in the following successive positions: (a) supine, (b) head-down tilt, (c) head-up tilt, (d) supine, (e) supine with phenylephrine administration. CO was measured simultaneously using the ECOM and the PAC. Results Both methods showed an equally good precision

To the Editor: As noted by Asfar et al. (April 24 issue),1 a major concern related to targeting a relatively low mean arterial blood pressure in patients with septic shock is that the brain is at risk for ischemia in this condition. The risk of potential brain ischemia is particularly pertinent among patients with a history of arterial hypertension, because their cerebral autoregulatory curve may be shifted to the right.2 Indeed, cerebral ischemia may contribute to sepsis-associated encephalopathy and persistent neurocognitive dysfunction.3 However, neither the primary nor the secondary outcomes in the study by Asfar et al. involved any measures of neurocognitive function. A mean arterial blood pressure of approximately 65 to 90 mm Hg describes the lower limit of autoregulation in healthy persons,4 and the same level appears to be present in critically ill patients with sepsis who do not have a history of hypertension.5 Before the findings by Asfar et al. are implemented in major guidelines, we think that further studies should address the way in which cerebral hemodynamics are specifically affected in patients with sepsis and a history of hypertension, as well as whether targeting a relatively high mean arterial blood pressure improves long-term neurocognitive function.

TACE/ADAM17-mediated shedding of CD163 likely explains the empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity. CD163 is expressed specifically in the monocyte/macrophage lineage, where it mediates uptake of haptoglobin-hemoglobin complexes, leading to metabolism of the oxidative heme molecule. Shedding of the CD163 ectodomain from the cell surface produces a sCD163 plasma protein, and a positive correlation is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity.

The objective of this study was to develop a personalized inflammatory model and estimate subject-specific parameters that could be related to changes in heart rate variability (HRV), a measure that can be obtained non-invasively in real time. An inflammatory model was developed and calibrated to measurements of interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), interleukin-8 (IL-8) and interleukin-10 (IL-10) over 8 hours in 20 subjects administered a low dose of lipopolysaccharide. For this model, we estimated 11 subject-specific parameters for all 20 subjects. Estimated parameters were correlated with changes in HRV, computed from ECG measurements using a built-in HRV module available in Labchart. Results revealed that patients could be separated into two groups expressing normal and abnormal responses to endotoxin. Abnormal responders exhibited increased HRV, most likely as a result of increased vagal firing. The observed correlation between the inflammatory response and HRV brings us a step further towards understanding if HRV predictions can be used as a marker for inflammation. Analyzing HRV parameters provides an easy, non-invasively obtained measure that can be used to assess the state of the subject, potentially translating to identifying a non-invasive marker that can be used to detect the onset of sepsis.

Background: Limited information is available on physical function after septic shock. The aim of the present study was to assess the physical outcome in survivors 1 year after septic shock. Methods: The outcome status of all 174 adult patients admitted to a mixed ICU with the diagnosis septic shock in a 1-year period was registered. Survivors were interviewed about physical function and socioeconomic status using a questionnaire including the Short Form-36 survey. The pre-ICU-admission Functional Comorbidity Index (FCI) was also registered. Results: Of the 80 survivors, two were still hospitalised; thus, 78 were invited to participate and 70 replied (inclusion-rate 88%). Patients were followed up at median 351 days after hospital discharge. At follow-up the patients had a markedly reduced physical component summary score (PCS) compared with age- and sex-adjusted general population controls (36 vs. 47, P

Static cerebral blood flow (CBF) autoregulation maintains a constant CBF despite changes in cerebral perfusion pressure (CPP) within certain limits; this is achieved through adaptive responses in the cerebrovascular resistance, i.e. arteriolar vasoconstriction and vasodilation. This system may protect the brain from hyper- and hypoperfusion upon CPP challenges. CBF autoregulation appears to be mediated through myogenic and metabolic feedback systems, which may involve the vasoconstrictor 20-hydroxyeicosatetraenoic acid as well as an oxygen-sensing mechanism that may involve nitric oxide signalling. Static CBF autoregulation is modulated or impaired in various pathological conditions. In chronic arterial hypertension, both the lower and upper limit of CBF autoregulation are shifted towards higher CPPs; however, CBF autoregulation may be readapted to normal by antihypertensive therapy. Furthermore, CBF autoregulation is impaired in a wide range of clinical conditions, including cerebral ischaemia, traumatic brain injury, intracranial space-occupying processes, subarachnoid haemorrhage, acute bacterial meningitis, fulminant hepatic failure and diabetes. In some of these conditions, CBF autoregulation may be restored by means of hyperventilation and/or induced hypothermia. At present, the clinical impact of CBF autoregulation impairment and of treatment strategies that aim to restore CBF autoregulation remains unclear.

We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood–brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O2) and following 6 h passive exposure to hypoxia (12% O2). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS–). A more marked increase in the venous concentration of the ascorbate radical (A•−), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS–). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS–). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07–0.20Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS–). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal–parenchymal damage as indicated by a lack of change in MCAv, S100β and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

Background: The Kety–Schmidt method is the reference method for measuring global cerebral blood flow (CBF), cerebral metabolic rates (CMR) and flux, especially where scanners are unavailable or impractical. Our primary objective was to assess the repeatability of the Kety–Schmidt method in a variety of different approaches using inhaled nitrous oxide (N2O) as the tracer, combined with photoacoustic spectrometry. A secondary objective was to assess the impact of this tracer on the systemic vascular concentration of nitrite (NO2−). Methods: Twenty-nine healthy male volunteers underwent 61 CBF measurements by breathing a normoxic gas mixture containing 5% N2O until tension equilibrium. Paired blood samples were collected from an arterial and a jugular bulb catheter in the saturation or desaturation phase, by continuous or the discontinuous sampling. N2O concentration was measured with photoacoustic spectrometry after equilibration of blood samples with air. CBF was calculated by the Kety–Schmidt equation. CMR of oxygen (CMRO2) was determined by the Fick principle. NO2− in plasma and red blood cells (RBC) was measured by ozone-based chemiluminescence. Results: The most robust approach for CBF measurement was achieved by discontinuous sampling in the desaturation phase [CBF, 64 (95% confidence interval, 59–71 ml)] 100 g/min; CMRO2 1.8 (1.7–2.0) μmol/g/min). The tracer did not influence plasma or RBC NO2− (P>0.05 vs. baseline). Conclusion: These findings confirm the reliability and robustness of the Kety–Schmidt method using inhaled N2O for the measurement of global CBF and CMR. At the low tracer concentration used, altered NO metabolism is unlikely to have affected cerebral haemodynamic function.

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.

IL-6 is a key modulator of immune function and suggested to be involved in skeletal muscle wasting as seen in sepsis.Our objective was to determine the role of IL-6 in human in vivo systemic and skeletal muscle amino acid metabolism and protein turnover.There were 12 healthy men infused for 3 h with saline (saline, n = 6) or recombinant human IL (rhIL)-6 (n = 6). Systemic and muscle protein turnover was determined with a combination of tracer dilution methodology, primed constant infusion of L-[ring-(2)H(5)]phenylalanine, and femoral arterial-venous blood differences and m. vastus lateralis biopsies after 2-h basal, 3-h infusion, and 3 h after infusion.The IL-6 concentration after 30-min infusion was approximately 4 (saline) and 140 pg/ml (rhIL-6). Three-hour rhIL-6 infusion caused an approximate 50% decrease in muscle protein turnover, albeit synthesis was more suppressed than breakdown, causing a small increase in net muscle protein breakdown. Furthermore, rhIL-6 decreased arterial amino acid concentration with 20-40%, despite the increase net release from muscle.We demonstrated that IL-6 profoundly alters amino acid turnover. A substantial decrease in plasma amino acids was observed with a concomitant 50% decrease in muscle protein turnover, however, modest increase in net muscle degradation. We hypothesize that the profound reduction in muscle protein turnover and modest increase in net degradation are primarily caused by the reduced plasma amino acid availability and not directly mediated by IL-6.

SummaryThe aim of this study was to investigate to what extent single nucleotide polymorphisms (SNPs) in promoter regions of genes of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF)-α, interleukin (IL)-18, interferon (IFN)-γ, IL-6 and IL-10 affect the cytokine response during a controlled low-grade inflammatory response in vivo. Two hundred healthy young male volunteers were genotyped, and cytokine levels were measured in response to a low-dose intravenous bolus of Escherichia coli endotoxin. No association was detected between SNPs (TLR-4299, TLR-4399, TNF-308, IL-18-137, IL-18-607, IFN-γ+874, IL-6-174, IL-10-592 and IL-10-1082) and endotoxin-induced changes in plasma levels of TNF-α, IL-6 and IL-10. IL-18 levels were unaffected by endotoxin. In conclusion, the investigated SNPs did not affect endotoxin-induced low-grade cytokine production of TNF-α, IL-6, IL-18 or IL-10 in healthy young men. Previous reports of a major heritability factor in the inflammatory response may be due to other target genes or effects in older age groups or women.

To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O2 delivery with O2 demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 μg (kg body mass)−1 min−1) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 ± 1.0 versus 7.9 ± 1.0 l min−1) and femoral arterial oxygen delivery (1.2 ± 0.2 versus 1.3 ± 0.2 l min−1; control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 ± 14.2 versus 83.3 ± 16.0 mmHg, P < 0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 ± 5.3 to 72.0 ± 10.2% (P < 0.05), and the corresponding venous O2 content was increased from 25.5 ± 10.0 to 46.3 ± 18.5 ml l−1 (control and ATP, respectively, P < 0.05). With ATP, leg arterial–venous O2 difference was decreased (P < 0.05) from 139.3 ± 9.0 to 116.9 ± 8.4−1 and leg was 20% lower compared to the control trial (1.1 ± 0.2 versus 0.9 ± 0.1 l min−1) (P= 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O2 delivery with O2 demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg is not limited by restricted vasodilatation in the altitude-acclimatized human.

In the present study, we studied the effect of bacteremia on cerebral blood flow (CBF) autoregulation in a rat model of pneumococcal bacteremia and meningitis. Anesthetized rats were divided into five groups (A to E) and inoculated with pneumococci intravenously and normal saline intracisternally (group A, N = 10); saline intravenously and pneumococci intracisternally (group B, N = 10); pneumococci intravenously and pneumococci intracisternally (group C, N = 5); saline intravenously, antipneumococcal antibody intravenously (to prevent bacteremia), and pneumococci intracisternally (group D, N = 10); or saline intravenously and saline intracisternally (group E, N = 10), respectively. Positive cultures occurred in the blood for all rats in groups A, B, and C, and in the cerebrospinal fluid for all rats in groups D and E. Twenty-four hours after inoculation, CBF was measured with laser-Doppler ultrasound during incremental reductions in cerebral perfusion pressure (CPP) by controlled hemorrhage. Autoregulation was preserved in all rats without meningitis (groups A and E) and was lost in 24 of 25 meningitis rats (groups B, C, and D) ( P

When travellers return from malaria-endemic areas and present to hospital with fever, microscopy of blood smears remains the leading method to verify a suspected diagnosis of malaria. Additional laboratory abnormalities may, however, also be indicative of acute malaria infection. We monitored prospectively a group of patients with imported Plasmodium falciparum (n=28) or P. vivax/P. ovale (n=12) infection, respectively, and assessed haemoglobin, leucocytes, thrombocytes, C-reactive protein, coagulation factor II-VII-X, lactate dehydrogenase and bilirubin during 7 d of admission and weekly until d 28. For comparison, admission values of a group of febrile patients with suspected malaria, but with negative blood slides, were also assessed (n=66). The thrombocyte, leucocyte counts and coagulation factor II-VII-X were significantly lower in the malaria group compared to the non-malaria group, whereas the C-reactive protein, lactate dehydrogenase and bilirubin were significantly higher in the malaria group. The differences were particularly strong with falciparum malaria. By contrast, haemoglobin levels were not affected. In conclusion, our study emphasizes the role of a few commonly analysed laboratory parameters, in particular thrombocyte counts, in guiding the clinician managing a returning traveller with fever.

Background Cerebral hemodynamic disturbances in the peri- or postoperative period may contribute to postoperative cognitive dysfunction (POCD) in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We therefore examined dynamic cerebral autoregulation (dCA) post-CPB and changes in neurocognitive function in patients that had undergone CABG. Materials and Methods We assessed dCA by transfer function analysis of spontaneous oscillations between arterial blood pressure and middle cerebral artery blood flow velocity measured by transcranial Doppler ultrasound in eight patients 6 hours after the cessation of CPB; 10 healthy volunteers served as controls. Neurocognitive function was assessed by four specific tests 1 day prior to and 3 days after CPB. Results Even though patients exhibited systemic inflammation and anemic hypoxemia, dCA was similar to healthy volunteers (gain: 1.24 [0.94–1.49] vs. 1.22 [1.06–1.34] cm mm Hg −1 s −1 , p = 0.97; phase: 0.33 [0.15–0.56] vs. 0.69 [0.50–0.77] rad, p = 0.09). Neurocognitive testing showed a perioperative decline in the Letter Digit Coding Score ( p = 0.04), while weaker dCA was associated with a lower Stroop Color Word Test (rho = − 0.90; p = 0.01). Discussion and Conclusion We found no changes in dCA 6 hours after CPB. However, based on the data at hand, it cannot be ruled out that changes in dCA predispose to POCD, which calls for larger studies that assess the potential impact of dCA in the early postoperative period on POCD.

Admission to the hospital, and particularly to the intensive care unit, leads to a dramatic reduction in physical activity level, which alters the glucose metabolism towards a pre-diabetic state [1]. Critically ill patients often develop spontaneous hyperglycemia, which is related to an increase in morbidity and mortality [2, 3]. The incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP) are secreted from the gut in response to a glucose load and stimulate up to 70 % of the insulin secretion from the pancreatic beta cell in healthy persons, which is named the incretin effect [4]. The incretin effect is reduced in critically ill patients [5], but the underlying mechanism has not yet been determined.

This report explores how public sector support promotes the locomotive model, which is understood as partnerships between locomotive companies and SMEs in order to facilitate export of cleantech an ...

Active, passive and resting state paradigms using functional MRI (fMRI) or EEG may reveal consciousness in the vegetative (VS) and the minimal conscious state (MCS). A meta-analysis was performed to assess the prevalence of preserved consciousness in VS and MCS as revealed by fMRI and EEG, including command following (active paradigms), cortical functional connectivity elicited by external stimuli (passive paradigms) and default mode networks (resting state). Studies were selected from multiple indexing databases until February 2015 and evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. 37 studies were identified, including 1041 patients (mean age 43 years, range 16-89; male/female 2.1:1; 39.5% traumatic brain injuries). MCS patients were more likely than VS patients to follow commands during active paradigms (32% vs 14%; OR 2.85 (95% CI 1.90 to 4.27; p

Background. Critical illness is associated with muscle weakness leading to long-term functional limitations.Objectives. To assess the reliability of a novel method for evaluating fatigability of the quadriceps muscle in noncooperating healthy subjects.Methods. On two occasions, separated by seven days, nonvoluntary isometric contractions (twitch and tetanic) of the quadriceps femoris muscle evoked by transcutaneous electrical muscle stimulation were recorded in twelve healthy adults. For tetanic contractions, the Fatigue Index (ratio of peak torque values) and the slope of the regression line of peak torque values were primary outcome measures. For twitch contractions, maximum peak torque and rise time were calculated. Relative (intraclass correlation, ICC3.1) and absolute (standard error of measurement, SEM) reliability were assessed and minimum detectable change was calculated using a 95% confidence interval (MDC95%).Results. The Fatigue Index (ICC3.1, 0.84; MDC95%, 0.12) and the slope of the regression line (ICC3.1, 0.99; MDC95%, 0.03) showed substantial relative and absolute reliability during the first 15 and 30 contractions, respectively.Conclusion. This method for assessing fatigability of the quadriceps muscle produces reliable results in healthy subjects and may provide valuable data on quantitative changes in muscle working capacity and treatment effects in patients who are incapable of producing voluntary muscle contractions.

We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.7 +/- 1.3 micromol min(-1) (mean +/-s.e.m.) in the placebo trial and 2.5 +/- 1.0 micromol min(-1) in the glucose trial (P < 0.05 compared to rest, not different across trials). At rest, CSF ammonia was below the detection limit of 2 microm in all subjects, but it increased to 5.3 +/- 1.1 microm following exercise with glucose, and further to 16.1 +/- 3.3 microm after the placebo trial (P < 0.05). Correlations were established between both the cerebral uptake (r2 = 0.87; P < 0.05) and the CSF concentration (r2 = 0.72; P < 0.05) and the arterial ammonia level and, in addition, a weaker correlation (r2 = 0.37; P < 0.05) was established between perceived exertion and CSF ammonia at the end of exercise. The results let us suggest that during prolonged exercise the cerebral uptake and accumulation of ammonia may provoke fatigue, e.g. by affecting neurotransmitter metabolism.

Background and Purpose— In patients with severe bacterial meningitis, norepinephrine is often infused to increase mean arterial pressure (MAP). This increases cerebral blood flow (CBF), but it is unknown if this increase is caused by impaired cerebral autoregulation or by a cerebral effect of norepinephrine through increased cerebral metabolism. The latter possibility implies a CBF–metabolism coupling. This has not been studied during meningitis. We studied the effect of norepinephrine and propofol on CBF and oxidative metabolism in patients with severe bacterial meningitis. Methods— In seven patients with pneumococcal meningitis and 7 healthy subjects, norepinephrine was infused intravenously; patients also underwent intravenous propofol infusion. Global CBF was measured by the Kety–Schmidt technique; cerebral oxidative metabolism and net flux of norepinephrine and epinephrine were calculated from measured arterial-to-jugular venous concentration differences (a-vD). Results— During norepinephrine infusion, MAP increased from a median value of 79 (range, 70 to 89) to 99 (98 to 129) mm Hg in patients, and from 87 (72 to 103) to 123 (112 to 132) mm Hg in controls. CBF increased in patients (51 [48 to 60] to 59 [54 to 77] mL/100 g per minute) but remained unchanged in controls. The cerebral metabolic rate of oxygen (CMRO 2 ) decreased in patients and remained unchanged in controls. No cerebral net flux of norepinephrine or epinephrine was found at any time in the 2 groups. During propofol infusion, CMRO 2 , and the a-vDO 2 decreased whereas CBF was unchanged. Conclusions— In patients with severe bacterial meningitis, norepinephrine increases both MAP and CBF but not CMRO 2 , indicating impaired autoregulation. Propofol reduces CBF relatively less than cerebral metabolism, suggesting a resetting of the CBF–CMRO 2 relationship.