Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.

Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. AIM OF THE STUDY: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O₂) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. CONCLUSIONS: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms.

Albuterol delivery in an in vitro pediatric ventilator lung model: comparison of jet, ultrasonic, and mesh nebulizers.

OBJECTIVE: : To determine the influence of nebulizer types and nebulization modes on bronchodilator delivery in a mechanically ventilated pediatric lung model. DESIGN: : In vitro, laboratory study. SETTING: : Research laboratory of a university hospital. INTERVENTIONS: : Using albuterol as a marker, three nebulizer types (jet nebulizer, ultrasonic nebulizer, and vibrating-mesh nebulizer) were tested in three nebulization modes in a nonhumidified bench model mimicking the ventilatory pattern of a 10-kg infant. The amounts of albuterol deposited on the inspiratory filters (inhaled drug) at the end of the endotracheal tube, on the expiratory filters, and remaining in the nebulizers or in the ventilator circuit were determined. Particle size distribution of the nebulizers was also measured. MEASUREMENTS AND MAIN RESULTS: : The inhaled drug was 2.8% ± 0.5% for the jet nebulizer, 10.5% ± 2.3% for the ultrasonic nebulizer, and 5.4% ± 2.7% for the vibrating-mesh nebulizer in intermittent nebulization during the inspiratory phase (p < 0.01). The most efficient nebulizer was the vibrating-mesh nebulizer in continuous nebulization (13.3% ± 4.6%, p < 0.01). Depending on the nebulizers, a variable but important part of albuterol was observed as remaining in the nebulizers (jet and ultrasonic nebulizers), or being expired or lost in the ventilator circuit (all nebulizers). Only small particles (range 2.39-2.70 µm) reached the end of the endotracheal tube. CONCLUSIONS: : Important differences between nebulizer types and nebulization modes were seen for albuterol deposition at the end of the endotracheal tube in an in vitro pediatric ventilator-lung model. New aerosol devices, such as ultrasonic and vibrating-mesh nebulizers, were more efficient than the jet nebulizer.

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation (1) indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak recommendations (2) indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B), targeting a blood glucose < 150 mg/dL after initial stabilization (2C); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); and a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSIONS: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Residual antimalarials in malaria patients from Tanzania--implications on drug efficacy assessment and spread of parasite resistance.

Repeated antimalarial treatment for febrile episodes and self-treatment are common in malaria-endemic areas. The intake of antimalarials prior to participating in an in vivo study may alter treatment outcome and affect the interpretation of both efficacy and safety outcomes. We report the findings from baseline plasma sampling of malaria patients prior to inclusion into an in vivo study in Tanzania and discuss the implications of residual concentrations of antimalarials in this setting. In an in vivo study conducted in a rural area of Tanzania in 2008, baseline plasma samples from patients reporting no antimalarial intake within the last 28 days were screened for the presence of 14 antimalarials (parent drugs or metabolites) using liquid chromatography-tandem mass spectrometry. Among the 148 patients enrolled, 110 (74.3%) had at least one antimalarial in their plasma: 80 (54.1%) had lumefantrine above the lower limit of calibration (LLC = 4 ng/mL), 7 (4.7%) desbutyl-lumefantrine (4 ng/mL), 77 (52.0%) sulfadoxine (0.5 ng/mL), 15 (10.1%) pyrimethamine (0.5 ng/mL), 16 (10.8%) quinine (2.5 ng/mL) and none chloroquine (2.5 ng/mL). The proportion of patients with detectable antimalarial drug levels prior to enrollment into the study is worrying. Indeed artemether-lumefantrine was supposed to be available only at government health facilities. Although sulfadoxine-pyrimethamine is only recommended for intermittent preventive treatment in pregnancy (IPTp), it was still widely used in public and private health facilities and sold in drug shops. Self-reporting of previous drug intake is unreliable and thus screening for the presence of antimalarial drug levels should be considered in future in vivo studies to allow for accurate assessment of treatment outcome. Furthermore, persisting sub-therapeutic drug levels of antimalarials in a population could promote the spread of drug resistance. The knowledge on drug pressure in a given population is important to monitor standard treatment policy implementation.

Appropriateness of respiratory care: evidence-based guidelines.

PRINCIPLES: Respiratory care is universally recognised as useful, but its indications and practice vary markedly. In order to improve the appropriateness of respiratory care in our hospital, we developed evidence-based local guidelines in a collaborative effort involving physiotherapists, physicians and health service researchers. METHODS: Recommendations were developed using the standardised RAND appropriateness method. A literature search was conducted based on terms associated with guidelines and with respiratory care. A working group prepared proposals for recommendations which were then independently rated by a multidisciplinary expert panel. All recommendations were then discussed in common and indications for procedures were rated confidentially a second time by the experts. The recommendations were then formulated on the basis of the level of evidence in the literature and on the consensus among these experts. RESULTS: Recommendations were formulated for the following procedures: non-invasive ventilation, continuous positive airway pressure, intermittent positive pressure breathing, intrapulmonary percussive ventilation, mechanical insufflation-exsufflation, incentive spirometry, positive expiratory pressure, nasotracheal suctioning and non-instrumental airway clearance techniques. Each recommendation referred to a particular medical condition and was assigned to a hierarchical category based on the quality of the evidence from the literature supporting the recommendation and on the consensus among the experts. CONCLUSION: Despite a marked heterogeneity of scientific evidence, the method used allowed us to develop commonly agreed local guidelines for respiratory care. In addition, this work fostered a closer relationship between physiotherapists and physicians in our institution.

The role of teriparatide in sequential and combination therapy of osteoporosis.

Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.

Survey on current practices for neurological prognostication after cardiac arrest.

PURPOSE: To investigate current practices and timing of neurological prognostication in comatose cardiac arrest patients. METHODS: An anonymous questionnaire was distributed to the 8000 members of the European Society of Intensive Care Medicine during September and October 2012. The survey had 27 questions divided into three categories: background data, clinical data, decision-making and consequences. RESULTS: A total of 1025 respondents (13%) answered the survey with complete forms in more than 90%. Twenty per cent of respondents practiced outside of Europe. Overall, 22% answered that they had national recommendations, with the highest percentage in the Netherlands (>80%). Eighty-nine per cent used induced hypothermia (32-34 °C) for comatose cardiac arrest patients, while 11% did not. Twenty per cent had separate prognostication protocols for hypothermia patients. Seventy-nine per cent recognized that neurological examination alone is not enough to predict outcome and a similar number (76%) used additional methods. Intermittent electroencephalography (EEG), brain computed tomography (CT) scan and evoked potentials (EP) were considered most useful. Poor prognosis was defined as cerebral performance category (CPC) 3-5 (58%) or CPC 4-5 (39%) or other (3%). When prognosis was considered poor, 73% would actively withdraw intensive care while 20% would not and 7% were uncertain. CONCLUSION: National recommendations for neurological prognostication after cardiac arrest are uncommon and only one physician out of five uses a separate protocol for hypothermia treated patients. A neurological examination alone was considered insufficient to predict outcome in comatose patients and most respondents advocated a multimodal approach: EEG, brain CT and EP were considered most useful. Uncertainty regarding neurological prognostication and decisions on level of care was substantial.

Obstructive Sleep Apnea Severity and Overnight Body Fluid Shift before and after Hemodialysis.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea is associated with significantly increased cardiovascular morbidity and mortality. Fluid overload may promote obstructive sleep apnea in patients with ESRD through an overnight fluid shift from the legs to the neck soft tissues. Body fluid shift and severity of obstructive sleep apnea before and after hemodialysis were compared in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seventeen patients with hemodialysis and moderate to severe obstructive sleep apnea were included. Polysomnographies were performed the night before and after hemodialysis to assess obstructive sleep apnea, and bioimpedance was used to measure fluid overload and leg fluid volume. RESULTS: The mean overnight rostral fluid shift was 1.27±0.41 L prehemodialysis; it correlated positively with fluid overload volume (r=0.39; P=0.02) and was significantly lower posthemodialysis (0.78±0.38 L; P<0.001). There was no significant difference in the mean obstructive apnea-hypopnea index before and after hemodialysis (46.8±22.0 versus 42.1±18.6 per hour; P=0.21), but obstructive apnea-hypopnea index was significantly lower posthemodialysis (-10.1±10.8 per hour) in the group of 12 patients, with a concomitant reduction of fluid overload compared with participants without change in fluid overload (obstructive apnea-hypopnea index +8.2±16.1 per hour; P<0.01). A lower fluid overload after hemodialysis was significantly correlated (r=0.49; P=0.04) with a lower obstructive apnea-hypopnea index. Fluid overload-assessed by bioimpedance-was the best predictor of the change in obstructive apnea-hypopnea index observed after hemodialysis (standardized r=-0.68; P=0.01) in multivariate regression analysis. CONCLUSIONS: Fluid overload influences overnight rostral fluid shift and obstructive sleep apnea severity in patients with ESRD undergoing intermittent hemodialysis. Although no benefit of hemodialysis on obstructive sleep apnea severity was observed in the whole group, the change in obstructive apnea-hypopnea index was significantly correlated with the change in fluid overload after hemodialysis. Moreover, the subgroup with lower fluid overload posthemodialysis showed a significantly lower obstructive sleep apnea severity, which provides a strong incentive to further study whether optimizing fluid status in patients with obstructive sleep apnea and ESRD will improve the obstructive apnea-hypopnea index.

Étude de faisabilité pour une mesure fiable de la mobilité après fracture du membre inférieur chez l'enfant

Introduction : Les fractures du membre inférieur (MI) de l'enfant traitées par immobilisation plâtrée engendrent une modification significative de la mobilité exacerbée en cas d'obésité. L'accéléromètre est un outil d'évaluation du degré d'activité physique (AP) de l'enfant scientifiquement validé. Il n'a jamais fait l'objet d'étude chez un enfant ayant souffert d'une fracture du MI. Le but de ce travail était d'identifier les problèmes dans l'utilisation d'un accéléromètre comme moyen de mesure de l'AP après fracture nécessitant une décharge du MI. Une adaptation de la réhabilitation post-traumatique en fonction du BMI pourrait alors être proposée. Méthode : Identification d'enfants âgés de 8 et 15 ans, victimes d'une fracture du membre inférieur, consultant aux urgences de l'Hôpital de l'Enfance d'octobre 2013 à mai 2014 et nécessitant une décharge post-traumatique. Etaient exclus les enfants polytraumatisés ou souffrants d'un déficit mental. Données pré-requises des patients: âge, poids, taille, sexe, mécanisme de l'accident, type de fracture et traitement. Proposition de port d'un Actiwatch® Spectrum au poignet et cheville pour la période de remobilisation en décharge. Identification des avantages et problèmes liés à l'usage de l'appareil durant les premiers 30 jours de la période de réhabilitation. Importance : L'absence totale d'étude sur la mobilité post-fracture, la complexité des problèmes liés à la marche en décharge, les contraintes de l'immobilisation plâtrée et la prévalence grandissante de l'obésité pédiatrique justifient la recherche d'un moyen fiable pour quantifier la mobilité d'un enfant en décharge après traumatisme du MI. Résultats : Sur 43 fractures du MI traitées à l'HEL durant la période de l'étude, 13 enfants identifiés, dont 1 exclu pour maladie psychiatrique, 1 refus de participation, 2 transferts immédiats, 2 non inclus pour causes pratiques. Sept garçons âgés de 11 à 16 ans ont accepté le port de l'Actiwatch® pour une durée variant entre 7 et 27 jours (moyenne 15). Nombre d'activités (NA) médians de 5 enfants: 171,79 ±105,37 [cpm]* à J1 et 219,48 ±145,52 [cpm] à J5. NA totales médianes sur 24h : 114'072±44'791 [cpm] à J1 et 234'452 ±134'775 [cpm] à J5. Une dynamique de regain de mobilité est mise en évidence avec intensités maximales et minimales du nombre d'activités pour chacun. La médiane du temps de sommeil des 5 enfants était de 716± 45,5 [mn]. Les problèmes rencontrés ont été d'ordre mécanique (Un Actiwatch® fut défectueux), d'ordre pratique (un perdu et rendu tardivement, un port intermittent, une réaction allergique au bracelet à 4j de port). Conclusions La compliance à l'utilisation de l'Actiwatch® sur toute la durée de la décharge n'était pas optimale. La mobilité moyenne des enfants était objectivable de par leur dynamique, leur intensité maximale et minimale et comparables vis-à-vis de certaines études. Une différence avec les sujets en surpoids est observable. La durée de sommeil de chaque enfant suggère que l'antalgie administrée en cours de traitement est suffisante. Utiliser ce capteur de manière prolongée et sur un grand collectif d'enfants serait un moyen fiable et simple d'objectiver la dynamique de reprise de l'activité physique chez ces patients. Profil de l'étude : observation de cas.