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.

[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.

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.

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.

[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.

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.

Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial.

CONTEXT: Whether venous catheterization at the femoral site is associated with an increased risk of complications compared with that at the subclavian site is debated. OBJECTIVE: To compare mechanical, infectious, and thrombotic complications of femoral and subclavian venous catheterization. DESIGN AND SETTING: Concealed, randomized controlled clinical trial conducted between December 1997 and July 2000 at 8 intensive care units (ICUs) in France. PATIENTS: Two hundred eighty-nine adult patients receiving a first central venous catheter. INTERVENTIONS: Patients were randomly assigned to undergo central venous catheterization at the femoral site (n = 145) or subclavian site (n = 144). MAIN OUTCOME MEASURES: Rate and severity of mechanical, infectious, and thrombotic complications, compared by catheterization site in 289, 270, and 223 patients, respectively. RESULTS: Femoral catheterization was associated with a higher incidence rate of overall infectious complications (19.8% vs 4.5%; P<.001; incidence density of 20 vs 3.7 per 1000 catheter-days) and of major infectious complications (clinical sepsis with or without bloodstream infection, 4.4% vs 1.5%; P =.07; incidence density of 4.5 vs 1.2 per 1000 catheter-days), as well as of overall thrombotic complications (21.5% vs 1.9%; P<.001) and complete thrombosis of the vessel (6% vs 0%; P =.01); rates of overall and major mechanical complications were similar between the 2 groups (17.3% vs 18.8 %; P =.74 and 1.4% vs 2.8%; P =.44, respectively). Risk factors for mechanical complications were duration of insertion (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.08 per additional minute; P<.001); insertion in 2 of the centers (OR, 4.52; 95% CI, 1.81-11.23; P =.001); and insertion during the night (OR, 2.06; 95% CI, 1.04-4.08; P =.03). The only factor associated with infectious complications was femoral catheterization (hazard ratio [HR], 4.83; 95% CI, 1.96-11.93; P<.001); antibiotic administration via the catheter decreased risk of infectious complications (HR, 0.41; 95% CI, 0.18-0.93; P =.03). Femoral catheterization was the only risk factor for thrombotic complications (OR, 14.42; 95% CI, 3.33-62.57; P<.001). CONCLUSION: Femoral venous catheterization is associated with a greater risk of infectious and thrombotic complications than subclavian catheterization in ICU patients.

Severe acute asthma with bowel infarction and pneumatosis intestinalis in a young adult.

A young patient presented with a small bowel infarction with pneumatosis intestinalis in the early course of life-threatening severe acute asthma. Low cardiac output with severe congestive right heart failure combined with the use of high doses of epinephrine to reverse the near-fatal bronchospasm probably contributed to this previously unreported complication. The presence of gas collections in the submucosal space was possibly the consequence of diffuse small bowel mucosal disruption. Early recognition of this unusual complication is of major importance to ensure appropriate therapeutic management.

A prospective survey of nutritional support practices in intensive care unit patients: what is prescribed? What is delivered?

OBJECTIVES: To assess the amount of nutrients delivered, prescribed, and required for critically ill patients and to identify the reasons for discrepancies between prescriptions and requirements and between prescriptions and actual delivery of nutrition. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university-affiliated general hospital. PATIENTS: Fifty-one consecutive patients, receiving nutritional support either enterally or intravenously for > or = 2 days. We followed patients for the first 14 days of nutritional delivery. MEASUREMENTS AND MAIN RESULTS: The amount of calories prescribed and the amount actually delivered were recorded daily and compared with the theoretical energy requirements. A combined regimen of enteral and parenteral nutrition was administered on 58% of the 484 nutrition days analyzed, and 63.5% of total caloric intake was delivered enterally. Seventy-eight percent of the mean caloric amount required was prescribed, and 71% was effectively delivered. The amount of calories actually delivered compared with the amount prescribed was significantly lower in enteral than in parenteral administration (86.8% vs. 112.4%, p < .001). Discrepancies between prescription and delivery of enterally administered nutrients were attributable to interruptions caused by digestive intolerance (27.7%, mean daily wasted volume 641 mL), airway management (30.8%, wasted volume 745 mL), and diagnostic procedures (26.6%, wasted volume 567 mL). Factors significantly associated with a low prescription rate of nutritional support were the administration of vasoactive drugs, central venous catheterization, and the need for extrarenal replacement. CONCLUSIONS: An inadequate delivery of enteral nutrition and a low rate of nutrition prescription resulted in low caloric intake in our intensive care unit patients. A large volume of enterally administered nutrients was wasted because of inadequate timing in stopping and restarting enteral feeding. The inverse correlation between the prescription rate of nutrition and the intensity of care required suggests that physicians need to pay more attention to providing appropriate nutritional support for the most severely ill patients.

"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.

Outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay.

OBJECTIVE: To examine the outcome, functional autonomy, and quality of life of elderly patients (> or = 70 yrs old) hospitalized for >30 days in an intensive care unit (ICU). DESIGN: Prospective cohort study. SETTING: A ten-bed, medical-surgical ICU in a 460-bed, acute care, tertiary, university hospital. PATIENTS: A consecutive cohort of 75 patients, >70 yrs old, admitted to the ICU from January 1, 1993, to August 1, 1998, for >30 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Severity at admission and of the underlying disease was estimated according to the Simplified Acute Physiologic Score (SAPS II), the Organ Dysfunction and/or Infection (ODIN) score, the McCabe score, and the Knaus classification. Therapeutic intensity was measured through the French Omega scoring system. All patients were mechanically ventilated during their ICU stay. Outcome measurements were made by two cross-sectional studies using telephone interviews on the first week of September 1996 and 1998 with a questionnaire including measures of functional capacity by Katz's Activities of Daily Living, modified Patrick's Perceived Quality of Life score, and the Nottingham Health Profile. The survival rate was 67% in the ICU and 47% in the hospital. A total of 30 patients were alive and able to participate in at least one of the cross-sectional studies. Independence in activities of daily living was decreased significantly after the ICU stay, except for feeding. However, most of the 30 patients remained independent (class A of the Activities of Daily Living index) with the possibility of going home. Perceived Quality of Life scores remained good, even if the patients estimated a decrease in their quality of life for health and memory. Return to society appeared promising regarding patient self respect and happiness with life. The estimated cost by survivor was of 55,272 EUR ($60,246 US). CONCLUSIONS: This study suggests that persistent high levels of ICU therapeutic intensity were associated with a reasonable hospital survival in elderly patients experiencing prolonged mechanical ventilatory support. These patients presented a moderate disability that influenced somewhat their perceived quality of life. These results are sufficient to justify prolonged ICU stays for elderly patients.

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.

Procalcitonin (PCT) is useful in predicting the bacterial origin of an acute circulatory failure in critically ill patients.

OBJECTIVE: To evaluate the accuracy of procalcitonin (PCT) in predicting bacterial infection in ICU medical and surgical patients. SETTING: A 10-bed medical surgical unit. DESIGN: PCT, C-reactive protein (CRP), interleukin 6 (IL-6) dosages were sampled in four groups of patients: septic shock patients (SS group), shock without infection (NSS group), patients with systemic inflammatory response syndrome related to a proven bacterial infection (infect. group) and ICU patients without shock and without bacterial infection (control group). RESULTS: Sixty patients were studied (SS group:n=16, NSS group,n=18, infect. group,n=16, control group,n=10). The PCT level was higher in patients with proven bacterial infection (72+/-153 ng/ml vs 2.9+/-10 ng/ml,p=0.0003). In patients with shock, PCT was higher when bacterial infection was diagnosed (89 ng/ml+/-154 vs 4.6 ng/ml+/-12,p=0.0004). Moreover, PCT was correlated with severity (SAPS:p=0.00005, appearance of shock:p=0.0006) and outcome (dead: 71.3 g/ml, alive: 24.0 g/ml,p=0.006). CRP was correlated with bacterial infection (p<10(-5)) but neither with SAPS nor with day 28 mortality. IL-6 was correlated with neither infection nor day 28 mortality but was correlated with SAPS. Temperature and white blood cell count were unable to distinguish shocked patients with or without infection. Finally, when CRP and PCT levels were introduced simultaneously in a stepwise logistic regression model, PCT remained the unique marker of infection in patients with shock (PCT> or =5 ng/ml, OR: 6.2, 95% CI: 1.1-37,p=0.04). CONCLUSION: The increase of PCT is related to the appearance and severity of bacterial infection in ICU patients. Thus, PCT might be an interesting parameter for the diagnosis of bacterial infections in ICU patients.