Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

AIMS: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. MATERIALS/METHODS: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. RESULTS: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. CONCLUSIONS: GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Reducing pre-operative fasting while preserving operating room scheduling flexibility: feasibility and impact on patient discomfort.

BACKGROUND: The need to preserve operating room (OR) scheduling flexibility can challenge adherence to the 2-h pre-operative fasting period recommendation before elective surgery. Our primary objective was to assess the feasibility of a pre-operative carbohydrate (CHO) drink delivery strategy preserving OR scheduling flexibility. METHODS: During the 1st study phase, patients admitted for elective surgery fasted overnight (Control group); during the 2nd phase, patients fasted overnight and received a pre-operative CHO drink (CHO group). CHO delivery time was set to allow any patient to be ready for surgery 30 min ahead of the scheduled time and any patient with an operation scheduled in the afternoon to be ready at 13:00 hours; patients admitted the morning of an early morning operation would not be allowed to take a CHO drink. RESULTS: We included 194 patients in the Control group and 199 in the CHO group. In the CHO group, the morning CHO dose was delivered to 66.3% of the patients (95% CI 59.3-72.9%), with a median pre-operative fasting time period of 4 h 57 min. After excluding patients admitted the morning of an operation scheduled before 10:00 hours, the delivery rate was 77.2% (70.2-83.3%). Patients in the CHO group experienced significantly less pre-operative thirst (median 2 vs. 5 on a 0-10 scale, P < 0.0001) and hunger (0 vs. 2, P < 0.0001) than those in the Control group. CONCLUSION: Although preservation of OR scheduling flexibility resulted in a longer fasting time than recommended, CHO drink can be made available to a large proportion of patients with significantly reduced perioperative discomfort.

Dopamine D2 receptors contribute to increased avidity for sucrose in obese rats lacking CCK-1 receptors.

Accumulating evidence has indicated a link between dopamine signaling and obesity in both animals and humans. We have recently demonstrated heightened avidity to sapid sweet solutions in the obese cholecystokinin (CCK)-1 receptor deficient Otsuka Long Evans Tokushima fatty (OLETF) rat. To investigate the dopamine dependence and the respective contribution of D1 and D2 receptor subtypes in this phenomenon, real and sham intake of 0.3 M sucrose solution was compared between prediabetic, obese OLETF and age-matched lean Long-Evans Tokushima Otsuka (LETO) cohorts following peripheral (i.p.) administration of equimolar doses (50-800 nmol/kg) of the D1 (R-(+) 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, SCH23390) and D2 (raclopride) selective receptor antagonists. Both antagonists were potent in reducing sucrose intake in both strains with both drugs suppressing sham intake starting at lower doses than real intake (200 nmol/kg vs. 400 nmol/kg for SCH23390, and 400 nmol/kg vs. 600 nmol/kg for raclopride, respectively). Furthermore, when percent suppression of intake, a measure that controlled for the higher baseline sucrose intake by obese rats was analyzed, OLETF rats expressed an increased sensitivity to raclopride in reducing ingestion of sucrose with a 1.7- and 2.9-fold lower inhibitory dose threshold (ID50) for real and sham intake conditions, respectively, compared with LETO controls. In contrast, SCH23390 caused no differential strain effect with respect to dosage whether sucrose was real or sham fed. These findings demonstrate that D2 receptors are involved in heightened increased consumption of sucrose observed in the OLETF obese rat.

[Neuromuscular abnormalities in critical illness]. / Neuvièmes Journées des Maladies du Système Nerveux Périphérique.

Critical illness neuromuscular abnormalities (CINMA) are found in 25 percent of ITU patients who recover consciousness and are characterized by a bilateral and symmetric weakness that involves the four limbs but spares the facial muscles. Electrophysiological testing shows an axonal sensory motor polyneuropathy and/or myopathy. The main risk factors of CINMA are prolonged durations of multiple organ failure and mechanical ventilation, use of corticosteroids and hyperglycaemia. CINMA contribute also to increase the duration of mechanical ventilation, this effect being mediated by diaphragm weakness. The median duration of limb weakness is 21 days, although it can exceed several months in some patients. Few preventive measures have been assessed. Whether the benefit of strict blood glucose control in ITU patients recovering from heart surgery on CINMA incidence can be extended to medical ICU patients needs to be determined.

"Colonization pressure" and risk of acquisition of methicillin-resistant Staphylococcus aureus in a medical intensive care unit.

OBJECTIVE: To determine the roles of "colonization pressure," work load or patient severity in patient acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs). DESIGN: Prospectively collected data from October 1996 through December 1998. SETTING: A 12-bed medical ICU in a university-affiliated general hospital. PATIENTS: Patients with risk factors for MRSA admitted to the ICU were screened within 72 hours of admission and weekly thereafter. MRSA was considered imported if detected during the first 72 hours of admission and nosocomial if detected only thereafter. Three screening strategies were used on admission during three consecutive periods. INTERVENTIONS: The unit of time chosen for measurements was the week. Weekly colonization pressure (WCP) was defined as the number of MRSA-carrier patient-days/total number of patient-days. Patient severity (number of deaths, Simplified Acute Physiologic Score [SAPS] II), work load (number of admis sions, Omega score), and colonization pressure (number of MRSA carriers at the time of admission, WCP) were compared with the number of MRSA-nosocomial cases during the following week. RESULTS: Of the 1,016 patients admitted over 116 weeks, 691 (68%) were screened. MRSA was imported in 91 (8.9%) admitted patients (13.1% of screened patients) and nosocomial in 46 (4.5%). The number of MRSA-nosocomial cases was correlated to the SAPS II (P=.007), the Omega 3 score (P=.007), the number of MRSA-imported cases (P=.01), WCP (P<.0001), and the screening period (P<.0001). In multivariate analysis, WCP was the only independent predictive factor for MRSA acquisition (P=.0002). Above 30% of WCP, the risk of acquisition of MRSA was approximately fivefold times higher (relative risk, 4.9; 95% confidence interval, 1.2-19.9; P<.0001). CONCLUSION: Acquisition of MRSA in ICU patients is strongly and independently influenced by colonization pressure.

Using and understanding sedation scoring systems: a systematic review.

OBJECTIVE: To systematically review instruments for measuring the level and effectiveness of sedation in adult and pediatric ICU patients. STUDY IDENTIFICATION: We searched MEDLINE, EMBASE, the Cochrane Library and reference lists of the relevant articles. We selected studies if the sedation instrument reported items related to consciousness and one or more additional items related to the effectiveness or side effects of sedation. DATA ABSTRACTION: We extracted data on the description of the instrument and on their measurement properties (internal consistency, reliability, validity and responsiveness). RESULTS: We identified 25 studies describing relevant sedation instruments. In addition to the level of consciousness, agitation and synchrony with the ventilator were the most frequently assessed aspects of sedation. Among the 25 instruments, one developed in pediatric ICU patients (the Comfort Scale), and 3 developed in adult ICU patients (the Ramsay scale, the Sedation-Agitation-Scale and the Motor Activity Assessment Scale), were tested for both reliability and validity. None of these instruments were tested for their ability to detect change in sedation status over time (responsiveness). CONCLUSION: Many instruments have been used to measure sedation effectiveness in ICU patients. However, few of them exhibit satisfactory clinimetric properties. To help clinicians assess sedation at the bedside, to aid readers critically appraise the growing number of sedation studies in the ICU literature, and to inform the design of future investigations, additional information about the measurement properties of sedation effectiveness instruments is needed.

Acquired neuromuscular disorders in critically ill patients: a systematic review. Groupe de Reflexion et d'Etude sur les Neuromyopathies En Reanimation.

OBJECTIVE: To summarize the prospective clinical studies of neuromuscular abnormalities in intensive care unit (ICU) patients. STUDY IDENTIFICATION AND SELECTION: Studies were identified through MEDLINE, EMBASE, references in primary and review articles, personal files, and contact with authors. Through duplicate independent review, we selected prospective cohort studies evaluating ICU-acquired neuromuscular disorders. DATA ABSTRACTION: In duplicate, independently, we abstracted key data regarding design features, the population, clinical and laboratory diagnostic tests, and clinical outcomes. RESULTS: We identified eight studies that enrolled 242 patients. Inception cohorts varied; some were mechanically ventilated patients for > or = 5 days, others were based on a diagnosis of sepsis, organ failure, or severe asthma while others were selected on the basis of exposure to muscle relaxants, or because of participation in muscle biochemistry studies. Weakness was systematically assessed in two of the eight studies, concerning patients with severe asthma, with a reported frequency of 36 and 70%, respectively. Electrophysiologic and histologic abnormalities consisted of both peripheral nerve and muscle involvement and were frequently reported, even in non-selected ICU patients. In a population of patients mechanically ventilated for more than 5 days, electrophysiologic abnormalities were reported in 76 % of cases. Two studies showed a clinically important increase (5 and 9 days, respectively) in duration of mechanical ventilation and a mortality twice as high in patients with critical illness neuromuscular abnormalities, compared to those without. CONCLUSIONS: Prospective studies of ICU-acquired neuromuscular abnormalities include a small number of patients with various electrophysiologic findings but insufficiently reported clinical correlations. Evaluation of risk factors for these disorders and studies examining their contribution to weaning difficulties and long-term disability are needed.

Mechanical ventilation in patients with acute ischemic stroke: survival and outcome at one year.

OBJECTIVE: To assess the prognosis of patients with acute ischemic stroke who require mechanical ventilation and to determine early factors influencing mortality. DESIGN: Prospective observational study. SETTING: Medical intensive care unit with a cerebrovascular emergency unit in a university-affiliated hospital. PATIENTS: Fifty-eight consecutive patients (mean age 65+/-13 years) requiring mechanical ventilation in the early course of an acute ischemic stroke. MEASUREMENTS AND RESULTS: Clinical data were recorded before intubation according to a standardized procedure. Mortality and functional outcome were assessed after a 1-year follow-up. Mechanical ventilation was started within 48 h after admission in 53 patients (91.4%). The mean duration of ventilation was similar in survivors (9.7+/-9.0 days) and non-survivors (8.6+/-8.7 days). Mortality was 72.4% at 1 year. Among the 16 survivors, none were in a persistent vegetative state and 11 had a Barthel index of 60, reflecting good functional status. Bilateral absence of corneal reflex and bilateral absence of pupillary light reflex had a positive predictive value of death of 1 (95% CI 0.78-1.00 and 0.74-1.00, respectively). After Cox regression analysis, presence of stupor or coma (OR 2.6, 95% CI 1.5-5.0), bilateral absence of corneal reflex before intubation (OR 3.4, 95% CI 1.4-8.7) and presence of ischemic cardiopathy (OR 2.8, 95% CI 1.4-5.5) were independent predictors of mortality. CONCLUSIONS: Systematic withholding of endotracheal intubation in patients with AIS is not recommended. Careful and rigorous neurologic examination, including assessment of brain stem reflexes, might help to identify patients with a very high probability of death despite mechanical ventilation.

Candida albicans prosthetic arthritis treated with fluconazole alone.

Conventional treatment of Candida prosthetic joint infection usually includes surgery followed by a long period of antifungal medication. We report a case of Candida albicans prosthetic arthritis successfully treated with fluconazole alone.

Relationship between blood lactate and early hepatic dysfunction in acute circulatory failure.

PURPOSE: The purpose of this study was to assess the influence of early hepatic dysfunction on lactate level in patients with acute circulatory failure in a retrospective study. MATERIALS AND METHODS: Blood lactate was compared between patients in acute circulatory failure (systolic blood pressure < or = 80 mm Hg despite fluid challenge) with or without early hepatic dysfunction (bilirubin > 60 micromol/L or SGOT > 100 IU/L during the first 48 hours). Univariate and multivariate analysis were performed to assess the effects of early hepatic dysfunction and other clinical and biological data on serum lactate levels in patients with acute circulatory failure. RESULTS: The study included 92 patients, mean age 64+/-15 years, mean simplified acute physiology score (SAPS) 18.4+/-4.1. Early hepatic dysfunction was identified in 29 patients (32%). Mean initial blood lactate was 5.54+/-4.78 mmol/L. Overall intensive care unit mortality was 67.3%. Although patients with and without hepatic dysfunction showed no significant difference in terms of mean SAPS, mean lowest systolic blood pressure, and mortality, serum lactate was higher in the group with hepatic dysfunction than in the group without hepatic dysfunction (8.24+/-6.49 mmol/L v4.29+/-3.09 mmol/L, P < .001). Factors independently associated with serum lactate were the existence of early hepatic dysfunction (P < .01), a nondistributive type of shock (P < .05), and the mean initial amount of epinephrine (P < .05). CONCLUSIONS: This study suggests that early hepatic dysfunction plays an important role in serum lactate elevation in acute circulatory failure.

[Management of adult refractory convulsive status epilepticus in the intensive care unit]. / Prise en charge des états de mal épileptiques convulsifs réfractaires en réanimation.

Patients with convulsive status epilepticus in whom first line treatment is not rapidly effective, or with a persistent delay in recovering consciousness must be admitted in an ICU even if assisted, mechanical ventilation is not performed. Continuous EEG monitoring performed in close collaboration with a neurophysiologist/epileptologist is mandatory to detect and treat subtle status epilepticus and to exclude post-anoxic encephalopathy. A number of drugs and anaesthetic agents have been proposed to control refractory status epilepticus. Midazolam and/or propofol have been recently recommended before performing general barbiturate anaesthesia. However, this approach is not rigorously assessed, because patients and series are heterogeneous, and controlled studies are difficult to design. Prognosis is closely related to the quality of initial management, to the development of subtle status epilepticus and, above all, to aetiology.

[Severe forms of rubella encephalitis: arguments for a better vaccination policy]. / Formes sévères d'encéphalites au décours d'une infection rubéolique: arguments pour une meilleure couverture vaccinale.

BACKGROUND: Two cases of rubella encephalitis in young adults are reported. CASES REPORTS: 2 patients, 19 and 16-year-old, presented with severe encephalitis. One required mechanical ventilation. Neither were vaccinated against rubella. MRI scan of the brain was normal. The diagnosis was confirmed by serology. Good recovery was noted in both patients. DISCUSSION: Both cases of rubella encephalitis occurring in young adults illustrate the severity of this rare disease. As already shown in Finland, improvement with the French vaccination policy should lead to the prevention of rubella encephalitis.

[Current use of sedation and analgesia: 218 resuscitations in France services practices survey]. / La sédation-analgésie au quotidien : enquête de pratiques auprès de 218 services de réanimation en France.

OBJECTIVES: To assess the current use of sedation and analgesia in a large sample of French intensive care units (ICUs) and to define structural characteristics of the units that use a written procedure. STUDY DESIGN: Self-reported survey. PARTICIPANTS: Three hundred and sixty French ICUs were presented the questionnaire in September 2007. RESULTS: Surveys were received from 228 (60.6%) ICUs. Midazolam was used in more than 50% of the patients in 79.2% of the ICUs and propofol in 22.2% of the ICUs. Sufentanil was the most frequently used morphinic. A sedation-scale was used in 68.8% of the units (80.3% Ramsay score). Sedation was assessed at least every 4hours in 61% of ICUs. A pain-scale was used in 88.9% of the ICUs, but only 12.5% in the non-communicant patients. A written procedure was used in 29.4% of the units only. In multivariate analysis, use in the ICU of a written procedure for the early management of patients with septic shock and/or intensive insulin therapy was the single variable significantly associated with presence of a written procedure for sedation and analgesia (respectively OR 4.37; p<0.0001 and OR 5.64; p=0.032). CONCLUSION: Although more than two-third of the responding ICUs reported the use of sedation-and-pain-scales, frequency of assessment was low, and objective assessment of pain in the non-communicating patients was extremely uncommon. Similarly, the use of written procedure was low. The use of sedation-analgesia written procedure in an ICU seems strongly influenced by a more global involvement of the ICU in the protocolisation of complex care. These findings support the reinforcement of educational programs.

[Management of the sedated patient]. / Prise en charge du patient sédaté.

A sedation strategy aimed at minimizing alteration of consciousness once comfort, analgesia and adaptation to the ventilator have been ensured is feasible in critically-ill patients requiring mechanical ventilation, even if, in patients with severe ARDS or ICH, the high dosages of sedatives and analgesics transiently required to provide perfect adaptation to the ventilator often preclude preservation of consciousness. The main components of a sedation algorithm include a clear objective of sedation-analgesia, regular assessments of patient status using validated clinical tools and a precise yet simple dosage adaptation schedule. Development and implementation of a sedation algorithm requires a multidisciplinary approach and an important input from both physicians and nurses. However, several methodologically-correct interventional studies have shown that using an algorithm to administrate sedatives and analgesics results in a significant reduction of MV duration, reaching 50% in some studies. This might translate into a real benefit for the patient point of view provided that preserving patient's comfort remains a constant concern for the caregivers. There is no reliable evidence to date to use propofol rather than midazolam as a sedative agent. Indeed, the way the sedative drug is used, as part of a sedation algorithm, is very likely more important than the selection of the drug itself. Analgesia-based sedation, promoting the use of morphinics alone before the adjunction of hypnotics, represents a new alternative to the traditional combined administration of hypnotics and morphinics. However data on the impact of analgesia-based sedation on patients' outcomes remain sparse to date.

Neisseria meningitidis C:2b:P1.2,5 with decreased susceptibility to penicillin isolated from a patient with meningitis and purpura fulminans.

This report describes the case of an 18-year-old woman with meningococcal meningitis and purpura fulminans. Cerebrospinal fluid culture revealed Neisseria meningitidis serogroup-serotype-serosubtype C:2b:P1.2,5 as the pathogenic organism. Following treatment with cefotaxime and management of multiple organ failure, the patient survived without sequelae. To the best of our knowledge this report represents the first case of a meningococcal strain with a minimum inhibitory concentration of 1.5 mug/ml for penicillin, without beta-lactamase production, to be documented in France. The prevalence of meningococci with reduced susceptibility to penicillin is increasing. The emergence of such strains might represent a serious problem affecting the empirical antibiotic treatment of meningococcal disease.