The rapid and accurate categorisation of critically ill patients (RACE) to identify outcomes of interest for longitudinal studies: a feasibility study.

The capacity to measure the impact of an intervention on long-term functional outcomes might be improved if research methodology reflected our clinical approach, which is to individualise goals of care to what is achievable for each patient. The objective of this multicentre inception cohort study was to evaluate the feasibility of rapidly and accurately categorising patients, who were eligible for simulated enrolment into a clinical trial, into unique categories based on premorbid function. Once a patient met eligibility criteria a rapid 'baseline assessment' was conducted to categorise patients into one of eight specified groups. A subsequent 'gold standard' assessment was made by an independent blinded assessor once patients had recovered sufficiently to allow such an assessment to occur. Accuracy was predefined as agreement in >80% of assessments. One hundred and twenty-two patients received a baseline assessment and 104 (85%) were categorised to a unique category. One hundred and six patients survived to have a gold standard assessment performed, with 100 (94%) assigned to a unique category. Ninety-two patients had both a baseline and gold standard assessment, and these agreed in 65 (71%) patients. It was not feasible to rapidly and accurately categorise patients according to premorbid function.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

Weekend days are not required to accurately measure oral intake in hospitalised patients.

BACKGROUND: Nutrition studies in patients admitted to hospital frequently disregard oral intake because measurement is time-intensive and logistically challenging. In free-living populations, weighed food records (WFR) are the gold-standard and are conducted on weekend and weekdays to capture variations in intake, although this may not translate during hospitalisation. The present study aimed to determine whether oral intake differs between weekends and weekdays in hospitalised patients. METHODS: For adult patients initially admitted to the intensive therapy unit with a moderate-severe head injury over a 12-month period, WFR were conducted each week on Tuesday, Thursday and Saturday throughout hospitalisation. Meal components were weighed before and after consumption, and energy and protein intakes were calculated using specialised software. Data are reported as the mean (SD). Differences were assessed using paired t-tests and agreement using Bland-Altman plots. RESULTS: Thirty-two patients had WFR collected on 220 days, 68% (n = 149) on weekdays and 32% (n = 71) on weekends. Overall, daily intakes were 5.72 (3.67) MJ [1367 (877) kcal] and 62 (40) g protein. There were no differences in intake across all days (P = 0.937 energy, P = 0.797 protein), nor between weekdays and weekends, in weeks 1-3 of oral intake (all P > 0.1). Limits of agreement between mean intakes across days were wide for energy [range -11.20 to 9.55 MJ (-2680 to 2283 kcal)] and protein (range -125 to 110 g). CONCLUSIONS: Grouped energy and protein intakes from WFR in hospitalised patients are similar on weekdays and weekends, although large intra-patient variations occur. Future quantification of oral intake during hospitalisation should include as many days as feasible, although not necessarily weekend days, to reflect true intake.

The effect of augmenting early nutritional energy delivery on quality of life and employment status one year after ICU admission.

Augmenting energy delivery during the acute phase of critical illness may reduce mortality and improve functional outcomes. The objective of this sub-study was to evaluate the effect of early augmented enteral nutrition (EN) during critical illness, on outcomes one year later. We performed prospective longitudinal evaluation of study participants, initially enrolled in The Augmented versus Routine approach to Giving Energy Trial (TARGET), a feasibility study that randomised critically ill patients to 1.5 kcal/ml (augmented) or 1.0 kcal/ml (routine) EN administered at the same rate for up to ten days, who were alive at one year. One year after randomisation Short Form-36 version 2 (SF-36v2) and EuroQol-5D-5L quality of life surveys, and employment status were assessed via telephone survey. At one year there were 71 survivors (1.5 kcal/ml 38 versus 1.0 kcal/ml 33; P=0.55). Thirty-nine (55%) patients consented to this follow-up study and completed the surveys (n = 23 and 16, respectively). The SF-36v2 physical and mental component summary scores were below normal population means but were similar in 1.5 kcal/ml and 1.0 kcal/ml groups (P=0.90 and P=0.71). EuroQol-5D-5L data were also comparable between groups (P=0.70). However, at one-year follow-up, more patients who received 1.5 kcal/ml were employed (7 versus 2; P=0.022). The delivery of 1.5 kcal/ml for a maximum of ten days did not affect self-rated quality of life one year later.

Peri-operative nutrition.

Patients are frequently malnourished or are at risk of malnutrition before surgery. Peri-operative nutritional support can improve their outcomes. This review focuses on new developments in peri-operative nutrition, including: patient preparation and pre-operative fasting; the role of nutritional supplementation; the optimal route and timing of nutrient delivery; and the nutritional management of specific groups including critically ill, obese and elderly patients.

Enhanced Protein-Energy Provision via the Enteral Route Feeding (PEPuP) protocol in critically ill surgical patients: a multicentre prospective evaluation.

Suboptimal levels of feeding in critically ill patients are associated with poor clinical outcomes. The Enhanced Protein-Energy Provision via the Enteral Route Feeding (PEPuP) protocol was developed to improve nutritional delivery in the critically ill and has been studied in several hospitals. However, the experience with this protocol in surgical patients is limited to date. The objective of this analysis was to describe the experience with this protocol in surgical patients. We analysed observational patient data obtained from the 2013 International Nutrition Survey. We compared nutritional practices and outcomes of patients admitted for surgical and medical reasons to ICUs in sites that implemented the PEPuP protocol. We used surgical ICU patients in non-PEPuP sites as a concurrent control group. In sites that implemented the PEPuP protocol, surgical patients received a smaller proportion of prescribed calories (43% versus 61%, P=0.004) and protein (38% versus 57%, P=0.002) compared to medical patients. When compared to the cohort of surgical patients from control sites, the surgical patients from PEPuP sites received similar amounts of calories and protein. Although surgical PEPuP patients were more likely to receive trophic and volume-based feeds compared to surgical patients in control sites, other aspects of the PEPuP protocol were not adequately implemented. We conclude that nutritional delivery to surgical patients remains inadequate and the PEPuP protocol seems ineffective in improving nutritional intake in this population. Further research to determine methods of optimising PEPuP protocol implementation and adherence in surgery patients is needed.

Overcoming barriers to the mobilisation of patients in an intensive care unit.

We conducted a quality improvement project aimed at increasing the frequency of mobilisation in our ICU. We designed a four-part quality improvement project comprising: an audit documenting the baseline frequency of mobilisation; a staff survey evaluating perceptions of the barriers to mobilisation; identification of barriers that were amenable to change and implementation of strategies to address these; and a follow-up audit to determine their effectiveness. The setting was a tertiary care, urban, public hospital ICU in South Australia. All patients admitted to the ICU during the two audit periods were included in the audits, while all permanent/semi-permanent ICU staff were eligible for inclusion in the staff survey. We found that patient- and institution-related factors had the greatest impact on the mobilisation of patients in our ICU. Barriers identified as being amenable to change included insufficient staff education about the benefits of mobilisation, poor interdisciplinary communication and lack of leadership regarding mobilisation. Various strategies were implemented to address these barriers over a three-month period. Multivariable analyses showed that three out of four mobility outcomes did not significantly change between the baseline and follow-up audits, with a significant difference in favour of the baseline audit found for the fourth mobility outcome (maximum level of mobility). We concluded that implementing relatively simple measures to improve staff education, interdisciplinary communication and leadership regarding early progressive mobilisation was ineffective at improving mobility outcomes for patients in a large tertiary-level Australian ICU. Other strategies, such as changing sedation practices and/or increasing staffing, may be required to improve mobility outcomes of these patients.

Anti-seizure prophylaxis in critically ill patients with traumatic brain injury in an intensive care unit.

The objectives of this prospective observational study were to determine the proportion of patients with traumatic brain injury who received effective anti-seizure prophylaxis. The study was conducted in a tertiary level ICU of a major trauma referral centre between February 2012 and August 2013. A total of 2361 patients were admitted to the ICU in this study period, of whom125 patients (index) with traumatic head injury were included in this study. The patients had a mean age of 45 years (SD=19), a mean score on the Glasgow Coma Scale of 9 (SD=4), a mean injury severity score of 27 (SD=13) and a mean APACHE III score of 55 (SD=27). Only 13.6 % (17 of 125) of patients were given anti-seizure prophylaxis and phenytoin levels were measured in 9.6% (12 of 125). Although all 12 patients achieved an effective concentration for phenytoin therapy (>40 µmol/l) after the loading dose, no patient had their target concentration consistently maintained in the recommended therapeutic range (40 to 80 µmol/l) throughout the seven-day monitoring period. There was wide fluctuation in phenytoin levels in the patients in this study. Twenty-two (18%) of the index patients had post-traumatic seizures, indicating a high prevalence for this study. Poor compliance with guidelines could possibly explain this phenomenon. Future studies are needed to look at the dosing and monitoring of phenytoin and/or alternative anti-seizure prophylaxis in patients with traumatic brain injury.

Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications.

OBJECTIVE: Corticosteroid-binding globulin (CBG) is cleaved by neutrophil elastase converting the high-affinity (haCBG) conformation of CBG to a low-affinity (laCBG) conformation with a ninefold reduced cortisol-binding affinity. These in vitro data suggest that cortisol release by CBG cleavage results in the targeted delivery of cortisol to areas of inflammation. Our objective was to determine whether CBG cleavage alters circulating levels of haCBG and laCBG in vivo in proportion to sepsis severity. DESIGN: Prospective, observational cohort study in an adult tertiary level Intensive Care Unit in Adelaide, Australia. PATIENTS: Thirty-three patients with sepsis or septic shock grouped by illness severity [sepsis, septic shock survivors, septic shock nonsurvivors and other shock]. MEASUREMENTS: Plasma levels of haCBG and laCBG were assessed using a recently developed in-house assay in patients. Plasma total and free cortisol levels were also measured. RESULTS: Plasma total CBG and haCBG levels fell significantly, in proportion to disease severity (P < 0·0001 for both). There was a nonsignificant increase in free and total cortisol as illness severity worsened (P = 0·19 and P = 0·39, respectively). Illness severity was better correlated with haCBG levels than either free or total cortisol levels. CONCLUSIONS: Increasing illness severity in sepsis and septic shock is associated with markedly reduced circulating haCBG concentrations in vivo. We propose that low levels of haCBG in chronic inflammation may limit the availability of cortisol to inflammatory sites, perpetuating the inflammatory process.

An overview of the new frontiers in the treatment of atherogenic dyslipidemias.

Cardiovascular diseases (CVDs) are the leading cause of morbidity/mortality worldwide. Dyslipidemia is a major risk factor for premature atherosclerosis and CVD. Lowering low-density-lipoprotein cholesterol (LDL-C) levels is well established as an intervention for the reduction of CVDs. Statins are the first-line drugs for treatment of dyslipidemia, but they do not address all CVD risk. Development of novel therapies is ongoing and includes the following: (i) reduction of LDL-C concentrations using antibodies to proprotein convertase subtilisin/kexin-9, antisense oligonucleotide inhibitors of apolipoprotein B production, microsomal transfer protein (MTP) inhibitors, and acyl-coenzyme A cholesterol acyl transferase inhibitors; (ii) reduction in levels of triglyceride-rich lipoproteins with ω-3 fatty acids, MTP inhibitors, and diacylglycerol acyl transferase-1 inhibitors; and (iii) increase of high-density-lipoprotein (HDL) cholesterol levels, HDL particle numbers, and/or HDL functionality using cholesteryl ester transfer protein inhibitors, HDL-derived agents, apolipoprotein AI mimetic peptides, and microRNAs. Large prospective outcome trials of several of these emerging therapies are under way, and thrilling progress in the field of lipid management is anticipated.

Dietary supplementation contributes to lifestyle improvement in hypercholesterolemic patients in real-life contexts.

AIMS: Assess the evolution of cardiovascular lifestyle behaviors in hypercholesterolemic patients concomitantly with changes in their daily intake of phytosterol-supplemented yoghurt (Phyto-SY). METHODS: Nationwide prospective observational study conducted in general practices across France and Spain. Each practitioner suggested lifestyle changes to five consecutive patients with hypercholesterolemia (whether or not they were taking hypocholesterolemic drugs) and recommended daily consumption of Phyto-SY. The study design involved an inclusion visit, a patient's self-monitoring assessment after 1 month, and a final visit after 4 months. Primary evaluation criterion: changes in dietary habits assessed by a standardized Nutritional Lifestyle score. Secondary criteria: changes in lipid profile, anthropometry (waist circumference) and lifestyle behavior. RESULTS: A total of 2376 hypercholesterolemic patients (of whom 54.8% were women) were included. The average age was 56.2 years old. The Nutritional Lifestyle score improved from 15.4 ± 5.4 to 8.7 ± 4.0 (p < 0.0001). Total cholesterol decreased by 10.6% (<0.0001), HDL-C increased by 8.0% (<0.0001), and LDL-C fell by 12.7% (<0.0001). Similar results were observed in patients treated with statins and those who were not. Frequency of walking (>30 min) increased from 59.3% to 78.3% (p < 0.0001). The overweight rate decreased from 22.8% to 17.5% (p < 0.0001) and waist circumference from 94.6 ± 13.3 cm to 93.0 ± 12.8 cm (p < 0.0001). Nutritional Lifestyles and other lifestyle markers' improvement were parallel to adherence to Phyto-SY adherence. CONCLUSION: Improvements in Nutritional Lifestyle scores, which included regular consumption of Phyto-SY over 4 months, was significantly linked to healthier lifestyles and to beneficial modifications in atherogenic lipid profiles, which reflected patient empowerment in a 'real life' context.

Endogenous amylin and glucagon-like peptide-1 concentrations are not associated with gastric emptying in critical illness.

BACKGROUND: In health, the hormones amylin and glucagon-like peptide-1 (GLP-1) slow gastric emptying (GE) and modulate glycaemia. The aims of this study were to determine amylin and GLP-1 concentrations in the critically ill and their relationship with GE, glucose absorption and glycaemia. METHODS: In fasted critically ill and healthy subjects (n = 26 and 23 respectively), liquid nutrient, containing 100 mg (13) C-sodium octanoate and 3 g 3-O-methlyglucose (3-OMG), was administered via a nasogastric tube. Amylin, GLP-1, glucose and 3-OMG concentrations were measured in blood samples taken during fasting, and 30 min and 60 min after the 'meal'. Breath samples were taken to determine gastric emptying coefficient (GEC). Intolerance to intragastric feeding was defined as a gastric residual volume of ≥ 250 ml and/or vomiting within the 24 h prior to the study. RESULTS: Although GE was slower (GEC: critically ill 2.8 ± 0.9 vs. health, 3.4 ± 0.2; P = 0.002), fasting blood glucose was higher (7.0 ± 1.9 vs. 5.7 ± 0.2 mmol/l; P = 0.005) and overall glucose absorption was reduced in critically ill patients (3-OMG: 9.4 ± 8.0 vs. 17.7 ± 4.9 mmol/l.60 min; P < 0.001), there were no differences in fasting or postprandial amylin concentrations. Furthermore, although fasting [1.7 (0.4-7.2) vs. 0.7 (0.3-32.0) pmol/l; P = 0.04] and postprandial [3.0 (0.4-8.5) vs. 0.8 (0.4-34.3) pmol/l; P = 0.02] GLP-1 concentrations were increased in the critically ill and were greater in feed intolerant when compared with those tolerating feed [3.7 (0.4-7.2) vs. 1.2 (0.7-4.6) pmol/l; P = 0.02], there were no relationships between GE and fasting amylin or GLP-1 concentrations. CONCLUSION: In the critically ill, fasting GLP-1, but not amylin, concentrations are elevated and associated with feed intolerance. Neither amylin nor GLP-1 appears to substantially influence the rate of GE.

Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies.

AIMS: Statin treatment may impair glucose homeostasis and increase the risk of new-onset diabetes mellitus, although this may depend on the statin, dose and patient population. We evaluated the effects of pitavastatin 4 mg/day on glucose homeostasis in patients with metabolic syndrome in the CAPITAIN trial. Findings were validated in a subset of patients enrolled in PREVAIL-US. METHODS: Participants with a well defined metabolic syndrome phenotype were recruited to CAPITAIN to reduce the influence of confounding factors. Validation and comparison datasets were selected comprising phenotypically similar subsets of individuals enrolled in PREVAIL-US and treated with pitavastatin or pravastatin, respectively. Mean change from baseline in parameters of glucose homeostasis (fasting plasma glucose [FPG], glycated hemoglobin [HbA1c], insulin, quantitative insulin-sensitivity check index [QUICKI] and homeostasis model of assessment-insulin resistance [HOMA-IR]) and plasma lipid profile were assessed at 6 months (CAPITAIN) and 3 months (PREVAIL-US) after initiating treatment. RESULTS: In CAPITAIN (n = 12), no significant differences from baseline in HbA1c, insulin, HOMA-IR and QUICKI were observed at day 180 in patients treated with pitavastatin. A small (4%) increase in FPG from baseline to day 180 (P < 0.05), was observed. In the validation dataset (n = 9), no significant differences from baseline in glycemic parameters were observed at day 84 (all comparisons P > 0.05). Similar results were observed for pravastatin in the comparison dataset (n = 14). CONCLUSIONS: Other than a small change in FPG in the CAPITAIN study, neutral effects of pitavastatin on glucose homeostasis were observed in two cohorts of patients with metabolic syndrome, independent of its efficacy in reducing levels of atherogenic lipoproteins. The small number of patients and relatively short follow-up period represent limitations of the study. Nevertheless, these data suggest that statin-induced diabetogenesis may not represent a class effect.

Mesenteric blood flow, glucose absorption and blood pressure responses to small intestinal glucose in critically ill patients older than 65 years.

PURPOSE: To compare nutrient-stimulated changes in superior mesenteric artery (SMA) blood flow, glucose absorption and glycaemia in individuals older than 65 years with, and without, critical illness. METHODS: Following a 1-h 'observation' period (t (0)-t (60)), 0.9 % saline and glucose (1 kcal/ml) were infused directly into the small intestine at 2 ml/min between t (60)-t (120), and t (120)-t (180), respectively. SMA blood flow was measured using Doppler ultrasonography at t (60) (fasting), t (90) and t (150) and is presented as raw values and nutrient-stimulated increment from baseline (Δ). Glucose absorption was evaluated using serum 3-O-methylglucose (3-OMG) concentrations during, and for 1 h after, the glucose infusion (i.e. t (120)-t (180) and t (120)-t (240)). Mean arterial pressure was recorded between t (60)-t (240). Data are presented as median (25th, 75th percentile). RESULTS: Eleven mechanically ventilated critically ill patients [age 75 (69, 79) years] and nine healthy volunteers [70 (68, 77) years] were studied. The magnitude of the nutrient-stimulated increase in SMA flow was markedly less in the critically ill when compared with healthy subjects [Δt (150): patients 115 (-138, 367) versus health 836 (618, 1,054) ml/min; P = 0.001]. In patients, glucose absorption was reduced during, and for 1 h after, the glucose infusion when compared with health [AUC(120-180): 4.571 (2.591, 6.551) versus 11.307 (8.447, 14.167) mmol/l min; P < 0.001 and AUC(120-240): 26.5 (17.7, 35.3) versus 40.6 (31.7, 49.4) mmol/l min; P = 0.031]. A close relationship between the nutrient-stimulated increment in SMA flow and glucose absorption was evident (3-OMG AUC(120-180) and ∆SMA flow at t (150): r (2) = 0.29; P < 0.05). CONCLUSIONS: In critically ill patients aged >65 years, stimulation of SMA flow by small intestinal glucose infusion may be attenuated, which could account for the reduction in glucose absorption.

Pharmacokinetics of oxycodone after subcutaneous administration in a critically ill population compared with a healthy cohort.

This study aimed to characterise and compare the absorption pharmacokinetics of a single subcutaneous dose of oxycodone in critically ill patients and healthy subjects. Blood samples taken at intervals from two minutes to eight hours after a subcutaneous dose of oxycodone in patients (5 mg) and healthy volunteers (10 mg) were assayed using high performance liquid chromatography. Data were analysed using a non-compartmental approach and presented as mean (SD). Parameters were corrected for dose differences between the groups assuming linear kinetics. Ten patients (eight male, two female) and seven healthy male subjects were included. Maximum venous concentration and area under the concentration curve were approximately two-fold lower in the patient group for an equivalent dose, suggesting either reduced bioavailability or increased clearance: maximum venous concentration 0.14 ± 0.06 vs 0.05 ± 0.02 µg/ml (P <0.0001); area under the concentration curve 19.50 ± 9.15 vs 9.72 ± 2.71 µg/ml/minute (P <0.001) respectively. However, time to maximum venous concentration and mean residence time were not different, suggesting similar absorption rates: time to maximum venous concentration 22.10 ± 18.0 vs 20.50 ± 16.10 minutes (P=0.81); mean residence time 353 ± 191 vs 291 ± 80 minutes (P=0.26). Kinetic parameters were less variable in patients than in volunteers. The patients therefore had reduced exposure to subcutaneous oxycodone. This warrants further model-based analysis and experimentation. Dose regimens for subcutaneous oxycodone developed in healthy volunteers cannot be directly translated to critically ill patients.

Gastric emptying of a liquid nutrient meal in the critically ill: relationship between scintigraphic and carbon breath test measurement.

OBJECTIVE: It is assumed that delayed gastric emptying (GE) occurs frequently in critical illness; however, the prevalence of slow GE has not previously been assessed using scintigraphy. Furthermore, breath tests could potentially provide a convenient method of quantifying GE, but have not been validated in this setting. The aims of this study were to (i) determine the prevalence of delayed GE in unselected, critically ill patients and (ii) evaluate the relationships between GE as measured by scintigraphy and carbon breath test. DESIGN: Prospective observational study. SETTING: Mixed medical/surgical intensive care unit. PATIENTS: 25 unselected, mechanically ventilated patients (age 66 years (49-72); and 14 healthy subjects (age 62 years (19-84)). INTERVENTIONS: GE was measured using scintigraphy and (14)C-breath test. A test meal of 100 ml Ensure (standard liquid feed) labelled with (14)C octanoic acid and (99m)Technetium sulphur colloid was placed in the stomach via a nasogastric tube. MAIN OUTCOME MEASURES: Gastric 'meal' retention (scintigraphy) at 60, 120, 180 and 240 min, breath test t(50) (BTt(50)), and GE coefficient were determined. RESULTS: Of the 24 patients with scintigraphic data, GE was delayed at 120 min in 12 (50%). Breath tests correlated well with scintigraphy in both patients and healthy subjects (% retention at 120 min vs BTt(50); r(2)=0.57 healthy; r(2)=0.56 patients; p≤0.002 for both). CONCLUSIONS: GE of liquid nutrient is delayed in approximately 50% of critically ill patients. Breath tests correlate well with scintigraphy and are a valid method of GE measurement in this group.

Serum levels of adhesion molecules ICAM-1 and VCAM-1 and tissue inhibitor of metalloproteinases, TIMP-1, are elevated in patients with autoimmune thyroid disorders: relevance to vascular inflammation.

Serum levels of ICAM-1 (Inter Cellular Adhesion Molecule-1), VCAM-1 (Vascular cell Adhesion Molecule-1-I), TIMP-1 (tissue inhibitor of metalloproteinases 1) and MMP-9 (Metalloproteinase 9) are well established markers of inflammation. The physiopathological link between inflammation, atherosclerosis and autoimmunity is well demonstrated. However, serum levels of these biomarkers in patients with autoimmune-mediated dysthyroidism, including their evolution after improvement of the thyroid disorder have not been assessed. So, we evaluated the circulating levels of these markers in autoimmune and in non-autoimmune-mediated dysthyroid patients, and their evolution after treatment of thyroid disease. We conducted a prospective study to evaluate these markers before and after treatment in hyperthyroid patients (n = 33; 28 patients with autoimmune disease), hypothyroid patients (n = 38; 33 patients with autoimmune disease) and euthyroid subjects (n = 33). At baseline, serum levels of ICAM-1, VCAM-1 and TIMP-1 were significantly elevated in patients with hyperthyroidism as compared to euthyroid and hypothyroid patients (respectively p = 0.0005 and p < 0.0001). In multivariate analysis, the differences remained significant for VCAM-1 and TIMP-1. Median levels of ICAM-1, VCAM-1 and TIMP-1 were significantly higher in patients with autoimmune-mediated dysthyroidism compared to euthyroid patients (respectively p < 0.0001 and p = 0.002). In hyperthyroid patients, ICAM-1, VCAM-1 and TIMP-1 concentrations fell significantly after they had become euthyroid (respectively p = 0.0006; p < 0.0001 and p = 0.0009), although VCAM-1 values remained higher than those observed in the control group (p = 0.005). We found that autoimmune-mediated dysthyroidism were associated with increased peripheral blood concentrations of VCAM-1, ICAM-1 and TIMP-1. Whether these biological abnormalities translate into increase intima remodelling and atherosclerosis remains to be studied.

Relationship between alcohol intake, health and social status and cardiovascular risk factors in the Urban Paris-Ile-de-France Cohort: is the cardioprotective action of alcohol a myth?

BACKGROUND/OBJECTIVES: Observational studies document the inverse relationship between cardiovascular disease (CVD) and moderate alcohol intake. However, the causal role for alcohol in cardioprotection remains uncertain as such protection may be caused by confounders and misclassification. The aim of our study was to evaluate potential confounders, which may contribute to putative cardioprotection by alcohol. SUBJECTS/METHODS: We evaluated clinical and biological characteristics, including cardiovascular (CV) risk factors and health status, of 149,773 subjects undergoing examination at our Center for CVD Prevention (The Urban Paris-Ile-de-France Cohort). The subjects were divided into four groups according to alcohol consumption: never, low (30 g/day); former drinkers were analyzed as a separate group. RESULTS: After adjustment for age, moderate male drinkers were more likely to display clinical and biological characteristics associated with lower CV risk, including low body mass index, heart rate, pulse pressure, fasting triglycerides, fasting glucose, stress and depression scores together with superior subjective health status, respiratory function, social status and physical activity. Moderate female drinkers equally displayed low waist circumference, blood pressure and fasting triglycerides and low-density lipoprotein-cholesterol. Alcohol intake was strongly associated with plasma high-density lipoprotein-cholesterol in both sexes. Multivariate analysis confirmed that moderate and low drinkers displayed better health status than did never drinkers. Importantly, few factors were causally related to alcohol intake. CONCLUSIONS: Moderate alcohol drinkers display a more favorable clinical and biological profile, consistent with lower CV risk as compared with nondrinkers and heavy drinkers. Therefore, moderate alcohol consumption may represent a marker of higher social level, superior health status and lower CV risk.

Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levels.

Objectives Nitric oxide (NO) concentrations are elevated in sepsis and their vasodilatory action may contribute to the development of hyperdynamic circulatory failure. Hydrocortisone infusion has been reported to reduce nitric oxide metabolite (NOx) concentrations and facilitate vasopressor withdrawal in septic shock. Our aim was to determine whether NOx concentrations relate to (i) protocol-driven vasopressor initiation and withdrawal and (ii) plasma cortisol concentrations, from endogenous and exogenous sources. Demonstration of a relation between NOx, cortisol and vasopressor requirement may provide an impetus towards the study of hydrocortisone-mediated NOx suppression as a tool in sepsis management. Design A prospective study of 62 patients with severe sepsis admitted to the intensive care unit. Measurements Plasma NOx, total and free cortisol, and corticosteroid-binding globulin (CBG) concentrations were measured and related to protocol-driven vasopressor use for 7 days following admission. Results Patients who developed septic shock (n = 35) had higher plasma NOx, total and free cortisol, and lower CBG concentrations than the nonseptic shock group (n = 27). Cortisol, CBG and NOx concentrations correlated with illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx concentrations, predicted septic shock. NOx concentrations were higher in nonsurvivors, and the concentrations were characteristically stable within individuals but marked interindividual differences were only partly accounted for by illness severity or renal dysfunction. NOx concentrations did not correlate with cortisol, did not relate to vasopressor requirement and did not fall after standard dose hydrocortisone, given for clinical indications. Conclusions Nitric oxide production increased with sepsis severity but did not correlate with plasma cortisol or vasopressor requirement. NOx levels were not suppressed reproducibly by hydrocortisone. High interindividual variability of NOx levels suggests that absolute NOx levels may not be a suitable target for individualized hydrocortisone therapy.