Oligomalt, a New Slowly Digestible Carbohydrate, Is Well Tolerated in Healthy Young Men and Women at Intakes Up to 180 Gram per Day: A Randomized, Double-Blind, Crossover Trial.

In this randomized, double-blind triple-crossover study (NCT05142137), the digestive tolerance and safety of a novel, slowly digestible carbohydrate (SDC), oligomalt, an α-1,3/α-1,6-glucan α-glucose-based polymer, was assessed in healthy adults over three separate 7-day periods, comparing a high dose of oligomalt (180 g/day) or a moderate dose of oligomalt (80 g/day in combination with 100 g maltodextrin/day) with maltodextrin (180 g/day), provided as four daily servings in 300 mL of water with a meal. Each period was followed by a one-week washout. A total of 24 subjects (15 females, age 34 years, BMI 22.2 kg/m2, fasting blood glucose 4.9 mmol/L) were recruited, of whom 22 completed the course. The effects on the primary endpoint (the Gastrointestinal Symptom Rating Score (GSRS)) showed a statistically significant dose dependency, albeit of limited clinical relevance, between a high dose of oligomalt and maltodextrin (mean (95% CI) 2.29 [2.04, 2.54] vs. 1.59 [1.34, 1.83], respectively; difference: [-1.01, -0.4], p < 0.0001), driven by the GSRS-subdomains "Indigestion" and "Abdominal pain". The GSRS difference ameliorated with product exposure, and the GSRS in those who received high-dose oligomalt as their third intervention period was similar to pre-intervention (mean ± standard deviation: 1.6 ± 0.4 and 1.4 ± 0.3, respectively). Oligomalt did not have a clinically meaningful impact on the Bristol Stool Scale, and it did not cause serious adverse events. These results support the use of oligomalt across various doses as an SDC in healthy, normal weight, young adults.

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

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-ß), 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.

Effect of Different Nutritional Supplements on Glucose Response of Complete Meals in Two Crossover Studies.

Postprandial hyperglycemia is an important risk factor in the development and progression of type-2 diabetes and cardiometabolic diseases. Therefore, maintaining a low postprandial glucose response is key in preventing these diseases. Carbohydrate-rich meals are the main drivers of excessive glycemic excursions during the day. The consumption of whey protein premeals or mulberry leaf extract was reported to reduce postprandial glycemia through different mechanisms of action. The efficacy of these interventions was shown to be affected by the timing of the consumption or product characteristics. Two randomised crossover studies were performed, aiming to identify the optimal conditions to improve the efficacy of these nutritional supplements in reducing a glycemic response. The acute postprandial glycemic response was monitored with a continuous glucose monitoring device. The first study revealed that a preparation featuring 10 g of whey protein microgel reduced the postprandial glucose response by up to 30% (p = 0.001) and was more efficient than the whey protein isolates, independently of whether the preparation was ingested 30 or 10 min before a complete 320 kcal breakfast. The second study revealed that a preparation featuring 250 mg mulberry leaf extract was more efficient if it was taken together with a complete 510 kcal meal (−34%, p < 0.001) rather than ingested 5 min before (−26%, p = 0.002). These findings demonstrate that the efficacy of whey proteins premeal and mulberry leaf extracts can be optimised to provide potential nutritional solutions to lower the risk of type-2 diabetes or its complications.

A Decentralized Study Setup Enables to Quantify the Effect of Polymerization and Linkage of α-Glucans on Post-Prandial Glucose Response.

The complexity of the carbohydrate structure is associated with post-prandial glucose response and diverse health benefits. The aim of this study was to determine whether, thanks to the usage of minimally invasive glucose monitors, it was possible to evaluate, in a decentralized study setup, the post-prandial glycemic response (PPGR) of α-glucans differing systematically in their degree of polymerization (DP 3 vs. DP 60) and in their linkage structure (dextrin vs. dextran). Ten healthy subjects completed a double-blind, randomized, decentralized crossover trial, testing at home, in real life conditions, four self-prepared test beverages consisting of 25 g α-glucan dissolved in 300 mL water. The incremental area under the curve of the 120 min PPGR (2h-iAUC) was the highest for Dextrin DP 3 (163 ± 27 mmol/L*min), followed by Dextrin DP 60 (-25%, p = 0.208), Dextran DP 60 (-59%, p = 0.002), and non-fully caloric Resistant Dextrin (-68%, p = 0.002). These results show that a fully decentralized crossover study can be successfully used to assess the influence of both polymerization and structure of α-glucans on PPGR.

Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest.

OBJECTIVE: Hypothermia impairs blood glucose homeostasis and insulin sensitivity. However, the impact of therapeutic hypothermia on blood glucose levels and insulin requirements is unknown. We analyzed blood glucose variability during therapeutic hypothermia in patients with coma after cardiac arrest and examined its impact on outcome. DESIGN: Prospective observational study. SETTING: Two university hospital medical/surgical intensive care units. PATIENTS: Comatose cardiac arrest patients treated with therapeutic hypothermia (33°C, 24 hrs). INTERVENTIONS: Insulin therapy (blood glucose target 6-8 mmol/L [110-150 mg/dL]), according to a written algorithm, with nurse-driven adjustment of insulin dose. MEASUREMENTS AND MAIN RESULTS: Two-hundred and twenty patients (median age 61 yrs, median time to return of spontaneous circulation 20 min) were studied. Two time periods, comparable in duration, were categorized: therapeutic hypothermia (stable maintenance phase) and normothermia (after rewarming). Blood glucose variability was defined as the difference between maximum and minimum blood glucose concentration during each time period. Mean blood glucose (8.3±2.3 vs. 7.1±1.3 mmol/L), blood glucose variability (5.7±3.9 vs. 3.7±3.6 mmol/L), and insulin dose (2±2 vs. 1±1 U/h) were higher during therapeutic hypothermia compared to normothermia (all p<.001). Higher mean blood glucose (7.9±1.8 mmol/L in survivors vs. 8.7±2.6 mmol/L in nonsurvivors, p=.02) and increased blood glucose variability (4.9±3.5 vs. 6.5±4.1 mmol/L, p=.003) during therapeutic hypothermia were associated with mortality. After adjusting for time to return of spontaneous circulation, initial arrest rhythm, and cardiac arrest etiology, increased blood glucose variability during therapeutic hypothermia, but not mean blood glucose level, was an independent predictor of inhospital mortality (odds ratio for death 1.10 [confidence interval 1.02-1.19], p=.016). CONCLUSIONS: Mild therapeutic hypothermia is associated with higher blood glucose levels, increased blood glucose variability, and greater insulin requirements compared to the postrewarming normothermic phase. Increased blood glucose variability during therapeutic hypothermia is a predictor of inhospital mortality after cardiac arrest, independent of injury severity and mean blood glucose levels.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

INTRODUCTION: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. METHODS: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). CONCLUSIONS: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

Agreement between activated partial thromboplastin time and anti-Xa activity in critically ill patients receiving therapeutic unfractionated heparin.

BACKGROUND: No study supports the use of either aPTT or anti-Xa activity for heparin monitoring in critical care patients. There are no strong data on the agreement between aPTT and anti-Xa. The aims of this study were to: 1. Analyse the agreement between aPTT and anti-Xa in a large population of critically ill patients under unfractionated heparin therapy (UFH), 2. Identify clinical and biological factors associated to agreement or disagreement, and 3. Analyse the impact of anti-Xa availability on the use of aPTT and UFH therapy. METHODS: Retrospective study in a 35 beds mixed-ICU population between 2006 and 2016 in a University teaching hospital. INCLUSION CRITERIA: delivery of a UFH dose >15,000 U/24 h during at least one day with one anti-Xa determination. DATA: demographic variables, aPTT, anti-Xa, laboratory variables, presence of extracorporeal devices (ECD). Pairs of simultaneously dosed aPTT and anti-Xa [aPTT:anti-Xa] were analysed on the basis of their agreement within the sub-therapeutic, therapeutic (aPTT 50-80″, anti-Xa 0.3-0.7 U/ml) or supra-therapeutic ranges. RESULTS: 2283 patient admissions (2085 patients) were analysed. 35,595 [aPTT:anti-Xa] pairs were found. The overall [aPTT:anti-Xa] agreement was 59.6% and lowest (54.3%) in presence of ECD compared to non-ECD patients (61.6%; p < 0.001). Sixteen demographic and biological variables were analysed and were not predictive of [aPTT:anti-Xa] agreement. No significant difference in administered UFH dose was observed after anti-Xa introduction. CONCLUSION: In this large cohort, the [aPTT:anti-Xa] agreement is <60% and significantly lower in patients with ECD. None of the variables identified as potentially affecting the agreement were predictive. Availability of anti-Xa had neither effect on aPTT use nor on UFH-dose. These results call for a prospective study to determine the optimal UFH-therapy monitoring tool.

Effects of protein quantity and type on diet induced thermogenesis in overweight adults: A randomized controlled trial.

BACKGROUND & AIMS: Protein content of a meal is hypothesized to drive DIT dose-dependently. However, no single meal study exists comparing two different doses of protein on DIT. In addition, the source of protein, particularly whey protein, was shown to have a higher DIT than casein and soy in the acute setting, however the mechanism behind this difference is not yet clear. The aim of the present work is therefore to evaluate the efficacy of two different doses and types of protein (whey protein and casein) on DIT in overweight adults. METHODS: Randomized, double blind crossover including seventeen overweight men and women assigned to four isocaloric study treatments where protein and carbohydrate were exchanged: control, 30 g of whey protein microgels (WPM30), 50 g WPM (WPM50) or 50 g micellar casein (MC50). Energy expenditure was measured by indirect calorimetry. Blood, breath and urine samples were collected in order to measure substrate oxidation, amino acid profile, glucose and insulin, protein turnover and other metabolic parameters. RESULTS: DIT was 6.7 ± 3.7%, 13.0 ± 5.0%, 18.0 ± 5.0% and 16.0 ± 5.0% for control, WPM30, WPM50 and MC50, respectively. There was a significant difference between WPM50 and WPM30 (p < 0.005) and a trend was observed between WPM50 and MC50 (p = 0.06). WPM50 resulted in the highest total, essential, and branched-chain plasma amino acid concentrations when compared with the other study treatments (p < 0.005) and a higher insulin concentration than MC50 (p < 0.005). Protein oxidation was higher for WPM50 than MC50. Protein turnover was significantly correlated with DIT through total leucine oxidation (r = 0.52, p = 0.005). CONCLUSIONS: Our findings show that DIT does increase at a dose beyond 30 g of WPM and that the type of dairy protein may have an effect on DIT with WPM tending towards a higher DIT than casein. Although further research is required to understand the mechanism behind the effect of different protein sources on thermogenesis, we suggest that amongst the components of protein turnover, protein oxidation may be an important driver of thermogenesis at doses higher than 30 g. These results have concrete implications when choosing a dose of protein to optimize its thermogenic effect. CLINICAL TRIAL REGISTRY NUMBER: NCT02303080 www.clinicaltrials.gov.

Moderate glycemic control safe in critically ill adult burn patients: A 15 year cohort study.

INTRODUCTION: Hyperglycemia is a metabolic alteration in major burn patients associated with complications. The study aimed at evaluating the safety of general ICU glucose control protocols applied in major burns receiving prolonged ICU treatment. METHODS: 15 year retrospective analysis of consecutive, adult burn patients admitted to a single specialized centre. EXCLUSION CRITERIA: death or length of stay <10 days, age <16 years. VARIABLES: demographic variables, burned surface (TBSA), severity scores, infections, ICU stay, outcome. Metabolic variables: total energy, carbohydrate and insulin delivery/24h, arterial blood glucose and CRP values. Analysis of 4 periods: 1, before protocol; 2, tight doctor driven; 3, tight nurse driven; 4, moderate nurse driven. RESULTS: 229 patients, aged 45 ± 20 years (mean ± SD), burned 32 ± 20% TBSA were analyzed. SAPSII was 35 ± 13. TBSA, Ryan and ABSI remained stable. Inhalation injury increased. A total of 28,690 blood glucose samples were analyzed: the median value remained unchanged with a narrower distribution over time. After the protocol initiation, the normoglycemic values increased from 34.7% to 65.9%, with a reduction of hypoglycaemic events (no extreme hypoglycemia in period 4). Severe hyperglycemia persisted throughout with a decrease in period 4 (9.25% in period 4). Energy and glucose deliveries decreased in periods 3 and 4 (p<0.0001). Infectious complications increased during the last 2 periods (p=0.01). CONCLUSION: A standardized ICU glucose control protocol improved the glycemic control in adult burn patients, reducing glucose variability. Moderate glycemic control in burns was safe specifically related to hypoglycemia, reducing the incidence of hypoglycaemic events compared to the period before. Hyperglycemia persisted at a lower level.

Incorporation and washout of n-3 PUFA after high dose intravenous and oral supplementation in healthy volunteers.

BACKGROUND & AIMS: Although the physiological effects of n-3 polyunsaturated fatty acids (n-3PUFA) are generally thought to require several weeks of exposure to allow their incorporation into plasma membranes, intravenous (IV) n-3PUFA attenuate the cardiovascular and neuroendocrine response to stress within 3 h. Whether oral n-3 PUFA exert similar early effects remains unknown. OBJECTIVE: To assess whether acute IV or short term oral n-3PUFA administration reproduces the metabolic effects of long term oral supplements during exercise, and how it relates to their incorporation into platelets and red blood cells (RBC) membranes. DESIGN: Prospective single center open label study in 8 healthy subjects receiving a 3-h infusion of 0.6 g/kg body weight n-3PUFA emulsion, followed one week later by an oral administration of 0.6 g/kg over 3 consecutive days. Maximal power output (cycling exercise), maximal heart rate (HR), blood lactate at exhaustion, and platelet function were measured at baseline and after IV or 3-day oral supplementation; platelet and RBC membrane composition were assessed until 15 days after n-3PUFA administration. RESULTS: Both IV and oral n-3PUFA significantly decreased maximal HR (-6% and -5%), maximal power output (-10%) and peak blood lactate (-47% and -52%) Platelet function tests were unchanged. The EPA and DHA membrane contents of RBC and platelets increased significantly, but only to 1.7-1.9% of fatty acid content. CONCLUSION: The cardiovascular and metabolic effects of n-3 PUFA during exercise occur already within 1-3 days of exposure, and may be unrelated to changes in membranes composition. Effects occur within hours of administration and are unrelated to lipid membrane composition. Trial registered at clinicaltrials.gov as NCT00516178.

Serum procalcitonin as a marker of post-cardiac arrest syndrome and long-term neurological recovery, but not of early-onset infections, in comatose post-anoxic patients treated with therapeutic hypothermia.

OBJECTIVE: To examine the relationship of early serum procalcitonin (PCT) levels with the severity of post-cardiac arrest syndrome (PCAS), long-term neurological recovery and the risk of early-onset infections in patients with coma after cardiac arrest (CA) treated with therapeutic hypothermia (TH). METHODS: A prospective cohort of adult comatose CA patients treated with TH (33°C, for 24h) admitted to the medical/surgical intensive care unit, Lausanne University Hospital, was studied. Serum PCT was measured early after CA, at two time-points (days 1 and 2). The SOFA score was used to quantify the severity of PCAS. Diagnosis of early-onset infections (within the first 7 days of ICU stay) was made after review of clinical, radiological and microbiological data. Neurological recovery at 3 months was assessed with Cerebral Performance Categories (CPC), and was dichotomized as favorable (CPC 1-2) vs. unfavorable (CPC 3-5). RESULTS: From December 2009 to April 2012, 100 patients (median age 64 [interquartile range 55-73] years, median time from collapse to ROSC 20 [11-30]min) were studied. Peak PCT correlated with SOFA score at day 1 (Spearman's R=0.44, p<0.0001) and was associated with neurological recovery at 3 months (peak PCT 1.08 [0.35-4.45]ng/ml in patients with CPC 1-2 vs. 3.07 [0.89-9.99] ng/ml in those with CPC 3-5, p=0.01). Peak PCT did not differ significantly between patients with early-onset vs. no infections (2.14 [0.49-6.74] vs. 1.53 [0.46-5.38]ng/ml, p=0.49). CONCLUSIONS: Early elevations of serum PCT levels correlate with the severity of PCAS and are associated with worse neurological recovery after CA and TH. In contrast, elevated serum PCT did not correlate with early-onset infections in this setting.

Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: a randomized controlled trial.

BACKGROUND: Fish oil (FO) has antiinflammatory effects, which might reduce systemic inflammation induced by a cardiopulmonary bypass (CPB). OBJECTIVE: We tested whether perioperative infusions of FO modify the cell membrane composition, inflammatory responses, and clinical course of patients undergoing elective coronary artery bypass surgery. DESIGN: A prospective randomized controlled trial was conducted in cardiac surgery patients who received 3 infusions of 0.2 g/kg FO emulsion or saline (control) 12 and 2 h before and immediately after surgery. Blood samples (7 time points) and an atrial biopsy (during surgery) were obtained to assess the membrane incorporation of PUFAs. Hemodynamic data, catecholamine requirements, and core temperatures were recorded at 10-min intervals; blood triglycerides, nonesterified fatty acids, glucose, lactate, inflammatory cytokines, and carboxyhemoglobin concentrations were measured at selected time points. RESULTS: Twenty-eight patients, with a mean ± SD age of 65.5 ± 9.9 y, were enrolled with no baseline differences between groups. Significant increases in platelet EPA (+0.86%; P = 0.0001) and DHA (+0.87%; P = 0.019) were observed after FO consumption compared with at baseline. Atrial tissue EPA concentrations were higher after FO than after control treatments (+0.5%; P < 0.0001). FO did not significantly alter core temperature but decreased the postoperative rise in IL-6 (P = 0.018). Plasma triglycerides increased transiently after each FO infusion. Plasma concentrations of glucose, lactate, and blood carboxyhemoglobin were lower in the FO than in the control group on the day after surgery. Arrhythmia incidence was low with no significant difference between groups. No adverse effect of FO was detected. CONCLUSIONS: Perioperative FO infusions significantly increased PUFA concentrations in platelet and atrial tissue membranes within 12 h of the first FO administration and decreased biological and clinical signs of inflammation. These results suggest that perioperative FO may be beneficial in elective cardiac surgery with CPB.

Functional late outgrowth endothelial progenitors isolated from peripheral blood of burned patients.

BACKGROUND: Bioengineered skin substitutes are increasingly considered as a useful option for the treatment of full thickness burn injury. Their viability following grafting can be enhanced by seeding the skin substitute with late outgrowth endothelial progenitor cells (EPCs). However, it is not known whether autologous EPCs can be obtained from burned patients shortly after injury. METHODS: Late outgrowth EPCs were isolated from peripheral blood sampled obtained from 10 burned patients (extent 19.6±10.3% TBSA) within the first 24h of hospital admission, and from 7 healthy subjects. Late outgrowth EPCs were phenotyped in vitro. RESULTS: In comparison with similar cells obtained from healthy subjects, growing colonies from burned patients yielded a higher percentage of EPC clones (46 versus 17%, p=0.013). Furthermore, EPCs from burned patients secreted more vascular endothelial growth factor (VEGF) into the culture medium than did their counterparts from healthy subjects (85.8±56.2 versus 17.6±14pg/mg protein, p=0.018). When injected to athymic nude mice 6h after unilateral ligation of the femoral artery, EPCs from both groups of subjects greatly accelerated the reperfusion of the ischaemic hindlimb and increased the number of vascular smooth muscle cells. CONCLUSIONS: The present study supports that, in patients with burns of moderate extension, it is feasible to obtain functional autologous late outgrowth EPCs from peripheral blood. These results constitute a strong incentive to pursue approaches based on using autotransplantation of these cells to improve the therapy of full thickness burns.

Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia.

OBJECTIVE: Therapeutic temperature modulation is recommended after cardiac arrest (CA). However, body temperature (BT) regulation has not been extensively studied in this setting. We investigated BT variation in CA patients treated with therapeutic hypothermia (TH) and analyzed its impact on outcome. METHODS: A prospective cohort of comatose CA patients treated with TH (32-34°C, 24h) at the medical/surgical intensive care unit of the Lausanne University Hospital was studied. Spontaneous BT was recorded on hospital admission. The following variables were measured during and after TH: time to target temperature (TTT=time from hospital admission to induced BT target <34°C), cooling rate (spontaneous BT-induced BT target/TTT) and time of passive rewarming to normothermia. Associations of spontaneous and induced BT with in-hospital mortality were examined. RESULTS: A total of 177 patients (median age 61 years; median time to ROSC 25 min) were studied. Non-survivors (N=90, 51%) had lower spontaneous admission BT than survivors (median 34.5 [interquartile range 33.7-35.9]°C vs. 35.1 [34.4-35.8]°C, p=0.04). Accordingly, time to target temperature was shorter among non-survivors (200 [25-363]min vs. 270 [158-375]min, p=0.03); however, when adjusting for admission BT, cooling rates were comparable between the two outcome groups (0.4 [0.2-0.5]°C/h vs. 0.3 [0.2-0.4]°C/h, p=0.65). Longer duration of passive rewarming (600 [464-744]min vs. 479 [360-600]min, p<0.001) was associated with mortality. CONCLUSIONS: Lower spontaneous admission BT and longer time of passive rewarming were associated with in-hospital mortality after CA and TH. Impaired thermoregulation may be an important physiologic determinant of post-resuscitation disease and CA prognosis. When assessing the benefit of early cooling on outcome, future trials should adjust for patient admission temperature and use the cooling rate rather than the time to target temperature.

Metabolic and physiologic effects of an endotoxin challenge in healthy obese subjects.

AIM: The obesity epidemic has increased the number of obese patients admitted to the ICU. In vitro studies suggest that adipose tissue response to inflammation is enhanced: in vivo data are not conclusive yet. The aim of this study was to test the physiologic response of healthy obese subjects to a standardized intravenous LPS challenge. METHODS: Prospective single-blind, randomized, cross-over study in eight subjects (four men, four women), aged 34 ± 7 years, BMI 34·7 ± 4·2, without glucose intolerance and lipid abnormalities, testing the impact of intravenous LPS (2 ng kg(-1) of actual body weight) versus placebo. RESULTS: Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-α, IL-6, stress hormones, hs-CRP) were collected. After LPS temperature, heart rate, TNF-α and Il-6 concentrations and stress hormones (cortisol and glucagon) increased significantly, with maximal responses between 120 and 240 min after the injection. The pattern, the timing and the magnitude of change were similar to those observed in lean subjects. CONCLUSION: This study shows that healthy obese subjects have a similar response pattern to intravenous LPS as described in lean subjects.

Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans.

Nitric oxide (NO) is crucial for the microvascular homeostasis, but its role played in the microvascular alterations during sepsis remains controversial. We investigated NO-dependent vasodilation in the skin microcirculation and plasma levels of asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of the NO synthases, in a human model of sepsis. In this double-blind, randomized, crossover study, microvascular NO-dependent (local thermal hyperemia) and NO-independent vasodilation (post-occlusive reactive hyperemia) assessed by laser Doppler imaging, plasma levels of ADMA, and l-arginine were measured in seven healthy obese volunteers, immediately before and 4 h after either a i.v. bolus injection of Escherichia coli endotoxin (LPS; 2 ng/kg) or normal saline (placebo) on two different visits at least 2 weeks apart. LPS caused the expected systemic effects, including increases in heart rate (+43%, P < 0.001), cardiac output (+16%, P < 0.01), and rectal temperature (+1.4°C, P < 0.001), without change in arterial blood pressure. LPS affected neither baseline skin blood flow nor post-occlusive reactive hyperemia but decreased the NO-dependent local thermal hyperemia response, l-arginine, and, to a lesser extent, ADMA plasma levels. The changes in NO-dependent vasodilation were not correlated with the corresponding changes in the plasma levels of ADMA, l-arginine, or the l-arginine/ADMA ratio. Our results show for the first time that experimental endotoxemia in humans causes a specific decrease in endothelial NO-dependent vasodilation in the microcirculation, which cannot be explained by a change in ADMA levels. Microvascular NO deficiency might be responsible for the heterogeneity of tissue perfusion observed in sepsis and could be a therapeutic target.