Pressure-volume curves with and without muscle paralysis in acute respiratory distress syndrome

Objective Pressure-volume (PV) curves are recorded after induction of complete muscle paralysis, which may limit their clinical use. The feasibility of recording PV curves without paralysis has not been tested. In 19 patients with acute respiratory distress syndrome (ARDS) and no hemodynamic instability we prospectively evaluated whether PV curves can be safely and reliably recorded under deep sedation without neuromuscular blockade.Methods After standardized sedation (continuous infusion of midazolam and fentanyl) PV curves were recorded during apneic sedation, defined as absence of respiratory effort during a 6-s expiratory pause and during paralysis induced by cis-atracurium.Measurements and results Agreement between PV curve parameters in the two conditions was evaluated. Curves were obtained from 10 cmH₂O and from zero end-expiratory pressure in all patients under apneic sedation. In five patients propofol was given in addition to midazolam and fentanyl, and in two of them fluid resuscitation was needed. A strong agreement was found for respiratory system compliance and the lower inflection point and for chest wall compliance in the five patients whose esophageal pressure was measured. The variability of the measurements, however, should be taken into account in clinical practice.Conclusion Neuromuscular blockade can be dispensed with when recording PV curves in many ARDS patients. Reliable PV curves can be obtained under anesthesia alone, with no serious adverse effects.Electronic supplementary material The electronic reference of this article is . The online full-text version of this article includes electronic supplementary material. This material is available to authorised users and can be accessed by means of the ESM button beneath the abstract or in the structured full-text article. To cite or link to this article you can use the above reference.     

Urinary cystatin C as a specific marker of tubular dysfunction.

BACKGROUND: Cystatin C (CST3), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized, with the remainder then eliminated in urine. In tubular diseases, it seems sensible to postulate that CST3 degradation would be reduced and consequently an increase in its urinary elimination would be observed. METHODS: We report here the development of an automatic quantitative assay to measure CST3 concentrations in urine using a Behring N-Latex Cystatin C kit on a BNII laser nephelometer. We tested its clinical relevance on several kidney disease patients. RESULTS: This assay is sensitive (limit of detection 0.008 mg/L) and precise (within- and between-day CVs < 4%). Reference values for freshly collected urine samples range from 0.03 to 0.18 mg/L. Mean urine CST3 concentrations obtained from 52 patients with kidney tubular disease (4.31 +/- 3.85 mg/L) were significantly higher than those for 60 controls (0.096 +/- 0.044 mg/L; p < 0.0001) and 47 glomerular disease patients (0.106 +/- 0.133 mg/L; p < 0.0001). CONCLUSION: Increased urinary CST3 concentrations allow the accurate detection of tubular dysfunction among pure and mixed nephropathies. Because of its ability to be processed on automated clinical chemistry analyzers, this assay could easily be used as an adjunct to the standard panel used to screen kidney pathologies, even in emergency situations.     

Be careful with triage in emergency departments: interobserver agreement on 1,578 patients in France

Background

For several decades, emergency departments (EDs) utilization has increased, inducing ED overcrowding in many countries. This phenomenon is related partly to an excessive number of nonurgent patients. To resolve ED overcrowding and to decrease nonurgent visits, the most common solution has been to triage the ED patients to identify potentially nonurgent patients, i.e. which could have been dealt with by general practitioner. The objective of this study was to measure agreement among ED health professionals on the urgency of an ED visit, and to determine if the level of agreement is consistent among different sub-groups based on following explicit criteria: age, medical status, type of referral to the ED, investigations performed in the ED, and the discharge from the ED.

Methods

We conducted a multicentric cross-sectional study to compare agreement between nurses and physicians on categorization of ED visits into urgent or nonurgent. Subgroups stratified by criteria characterizing the ED visit were analyzed in relation to the outcome of the visit.

Results

Of 1,928 ED patients, 350 were excluded because data were lacking. The overall nurse-physician agreement on categorization was moderate (kappa = 0.43). The levels of agreement within all subgroups were variable and low. The highest agreement concerned three subgroups of complaints: cranial injury (kappa = 0.61), gynaecological (kappa = 0.66) and toxicology complaints (kappa = 1.00). The lowest agreement concerned two subgroups: urinary-nephrology (kappa = 0.09) and hospitalization (kappa = 0.20). When categorization of ED visits into urgent or nonurgent cases was compared to hospitalization, ED physicians had higher sensitivity and specificity than nurses (respectively 94.9% versus 89.5%, and 43.1% versus 30.9%).

Conclusions

The lack of physician-nurse agreement and the inability to predict hospitalization have important implications for patient safety. When urgency screening is used to determine treatment priority, disagreement might not matter because all patients in the ED are seen and treated. But using assessments as the basis for refusal of care to potential nonurgent patients raises legal, ethical, and safety issues. Managed care organizations should be cautious when applying such criteria to restrict access to EDs.     

Displaying Fel d1 on virus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: a novel therapy for cat allergy

Allergen-specific desensitization is the only disease-modifying therapy currently available for the treatment of allergies. These therapies require application of allergen over several years and some may induce life-threatening anaphylactic reactions. An ideal vaccine for desensitization should be highly immunogenic and should alleviate allergic symptoms upon few injections while being nonreactogenic. We describe such a vaccine for the treatment of cat allergy, consisting of the major cat allergen Fel d1 coupled to bacteriophage Qβ-derived virus-like particles (Qβ–Fel d1). Qβ–Fel d1 was highly immunogenic, and a single vaccination was sufficient to induce protection against type I allergic reactions. Allergen-specific immunoglobulin G antibodies were shown to be the critical effector molecules and alleviated symptoms by two distinct mechanisms. Although allergen-induced systemic basophil degranulation was inhibited in an FcγRIIb-dependent manner, inhibition of local mast cell degranulation in tissues occurred independently of FcγRIIb. In addition, treatment with Qβ–Fel d1 abolished IgE memory responses upon antigen recall. Despite high immunogenicity, the vaccine was essentially nonreactogenic and vaccination induced neither local nor systemic anaphylactic reactions in sensitized mice. Moreover, Qβ–Fel d1 did not induce degranulation of basophils derived from human volunteers with cat allergies. These data suggest that vaccination with Qβ–Fel d1 may be a safe and effective treatment for cat allergy.Allergic reactions are associated with several hypersensitivity diseases including asthma, rhinoconjunctivitis, contact dermatitis, urticaria, anaphylaxis, and insect, drug, and food allergy. These diseases can affect all age groups and have reached epidemic proportions worldwide with increasing incidence over the last decades (Holgate, 1999). The most common forms of allergies, such as pollen, house dust, or animal dander allergies, are dependent on type 2 T cell responses (Georas et al., 2005), leading to the generation of IL-4 and IgE. IgE antibodies have a short half-life in serum but are stable if bound to Fcε receptors on circulating basophils and, in particular, tissue mast cells (Vieira and Rajewsky, 1988). Cross-linking of the IgE–FcεI receptor complex on these cells by allergen leads to degranulation within seconds, liberating a variety of preformed inflammatory mediators. The clinical effects attended by such allergic reactions vary according to the site of basophil and mast cell activation. Although inhalation or ingestion of allergens activates mucosal mast cells, i.v. or s.c. antigen entry activates circulating basophils and connective tissue mast cells.Most current therapies for the treatment of allergies block mast cell effector molecules (e.g., histamines) or nonspecifically suppress immune responses (e.g., steroids). Although effective, these treatments fail to affect the immunological conditions causing the allergies. In addition, different vaccination or desensitization strategies have been investigated, including the usage of allergen-derived peptides (Francis and Larché, 2005), recombinant hypoallergenic derivates (Niederberger et al., 2004; Saarne et al., 2005), oligonucleotides with CpG motives (Hessel et al., 2005), or allergen conjugated to carbohydrate-based particles (Andersson et al., 2004). However, only a few disease-modifying therapies for allergy have been approved so far. These immunotherapies consist of either multiple s.c. injections of increasing doses of allergen or multiple sublingual or oral administration of the allergen, resulting in long-term desensitization (Till et al., 2004). Although these allergen-specific immunotherapies have shown successes (Durham and Till, 1998), the procedures are time consuming and require 1–3 yr of regular treatments (Hedlin et al., 1986, 1991). Moreover, this therapy bears a high risk for anaphylactic reactions, especially after administration of higher allergen doses (Cox and Coulter, 1997; Bousquet et al., 1998).The mechanism by which this specific immunotherapy affects allergies is poorly understood. The reduction in allergic symptoms by this treatment has been hypothesized to be at least partly mediated by a shift from Th2 toward a Th1 response or the induction of regulatory T (T reg) cells (Akdis et al., 2005). Alternatively, and not mutually exclusive, the balance between allergen-specific IgE and IgG antibodies may regulate mast cell and basophil activity. In fact, Hulett et al. (1993) identified an FcR, with a binding site for IgG, which regulates high affinity IgE receptor–mediated mast cell activation (Daëron et al., 1995b). It is well established that the FcγRIIb (FcγIIb receptor), expressed on mouse and human basophils and mast cells (Bischoff, 2007), can down-regulate FcεRI signaling by cross-linking of the FcεRI–IgE and FcγRIIb–IgG-Ag complex (Daëron et al., 1995a; Katz, 2002; Bruhns et al., 2005; Kraft and Kinet, 2007; Nimmerjahn and Ravetch, 2008). Indeed, a fusion molecule between the cat allergen Fel d1 and the constant part of IgG1 has recently been shown to inhibit allergic symptoms by cross-linking of FcγRIIb with FcεRI in a mouse model of asthma (Zhu et al., 2005; Terada et al., 2006). In addition to signaling through FcγRIIb, allergen-specific IgG antibodies may sequester allergens and hence prevent their binding to IgE–FcεRI complexes. Moreover, it has been shown that the ratio of allergen-specific IgE and IgG antibodies may affect presentation of allergen-derived epitopes to T cells (Wachholz and Durham, 2004). Thus, allergen-specific antibodies may have multiple ways to modulate allergic responses.We have previously shown that antigens displayed in a repetitive fashion on virus-like particles (VLPs) derived from the coat protein of the bacteriophage Qβ are highly immunogenic in mice (Jegerlehner et al., 2002a,b; Lechner et al., 2002; Spohn et al., 2005) and humans (Maurer et al., 2005; Kündig et al., 2006; Ambühl et al., 2007; Tissot et al., 2008). Because bacterial host RNA is incorporated into the VLPs during self-assembly inside bacteria, Qβ-VLPs provide Toll-like receptor ligands, which induce strong IgG2a/c-dominated antibody responses (Forsbach et al., 2007, 2008; Jegerlehner et al., 2007). In the present study, the major cat allergen Fel d1 was coupled in an oriented fashion to Qβ-VLPs, resulting in a highly repetitive form of the allergen. This vaccine was strongly immunogenic in mice, yielding high and long-lasting antigen-specific serum IgG titers after only a single immunization. Vaccination with Qβ–Fel d1 resulted in strongly reduced immediate type I allergic responses in a mouse model of mast cell degranulation, vascular leakage, and anaphylaxis and completely abolished IgE B cell memory responses upon antigen recall. Strikingly, coupling of Fel d1 to Qβ-VLPs essentially abrogated its ability to induce allergic responses in mice or the degranulation of human basophils derived from allergic individuals. Thus, displaying Fel d1 on VLPs enhanced its immunogenicity and therapeutic efficacy while strongly reducing its reactogenicity.     

Overstenting the hypogastric artery during endovascular aneurysm repair with and without prior coil embolization: A comparative analysis from the ENGAGE Registry

Background

Endovascular aneurysm repair of aortoiliac or iliac aneurysms is often performed with stent graft coverage of the origin of the hypogastric artery (HA) to ensure adequate distal seal. It is considered common practice to perform adjunctive coiling of the HA to prevent a type II endoleak. Our objective was to question the necessity of pre-emptive coiling by comparing the outcomes of HA coverage with and without prior coil embolization.

Any nonadherence to instructions for use predicts graft-related adverse events in patients undergoing elective endovascular aneurysm repair

Background

A variety of devices exist for endovascular aneurysm repair (EVAR). Device-specific instructions for use (IFU) detail anatomic constraints to application and deployment of devices and are developed from rigorous bench testing. Nonadherence to IFU occurs frequently to avoid open surgery. The purpose of this study was to determine if IFU violations are associated with increased risk of graft-related adverse events (GRAEs) during follow-up.