Enhanced care team response to incidents involving major trauma at night: are helicopters the answer?

INTRODUCTION: Challenges exist in how to deliver enhanced care to patients suffering severe injury in geographically remote areas within regionalised trauma networks at night. The physician led Enhanced Care Teams (ECTs) in the West Midlands region of England do not currently utilise helicopters to respond to incidents at night. This study describes this remote trauma workload at night within the regional network in terms of incident location; injury profile and patient care needs and discusses various solutions to the delivery of ECTs to such incidents, including the need for helicopter based platforms. METHODS: We present a retrospective analysis of incidents involving Major Trauma occurring in the West Midlands Regional Trauma Network in England over a one year period (1st April 2012 until the 31st March 2013). Anonymised patient records from the Trauma Audit and Research Network (TARN) for patients that had been conveyed to hospital by ambulance/air ambulance were cross-referenced with the West Midlands Ambulance Service NHS Foundation Trust (WMAS) Computer Assisted Dispatch (CAD) archive for the same period. Data were abstracted from the combined dataset relating to injury severity (ISS/ICU admission/death at scene or as inpatient); ECT resource activations/scene attendances; incident location and the need for enhanced level care. RESULTS: A total of 603 incidents involving Major Trauma were identified during night time hours. Enhanced Care Team resources attended scene in 167 cases (27.7%). Of the incidents not attended by an ECT 179 (41.1%) were due to falls and 91 (20.9%) involved a 'Road Traffic Collision'. A total of 36 incidents (6.0% of total at night) occurred in locations identified as being greater than 45min by road from the nearest major trauma centre. In these cases 13 patients had enhanced care needs that could not be addressed at scene by the attending ambulance service personnel. CONCLUSIONS: There is limited evidence to support the need for night HEMS operations in the West Midlands regional trauma network. The potential role of night HEMS in other regional trauma networks in England requires further evaluation with specific reference to the incidence of Major Trauma and efficiency of existing road based systems.

A mouse Fcgamma-Fcepsilon protein that inhibits mast cells through activation of FcgammaRIIB, SH2 domain-containing inositol phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases.

BACKGROUND: A human Fcgamma-Fcepsilon fusion protein (GE2) designed to inhibit FcepsilonRI signaling by coaggregating FcepsilonRI with the inhibitory receptor FcgammaRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcgammaRIIB. OBJECTIVE: Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. METHODS: The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow-derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum-sensitized cynomolgus monkeys. RESULTS: mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcgammaRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcgammaRIIB phosphorylation and the subsequent recruitment of SH2 domain-containing inositol polyphosphate 5' phosphatase (SHIP) 1 and SH2 domain-containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. CONCLUSION: mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcgammaRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.

An intermediate pH unfolding transition abrogates the ability of IgE to interact with its high affinity receptor FcepsilonRIalpha.

The interaction between IgE-Fc (Fcepsilon) and its high affinity receptor FcepsilonRI on the surface of mast cells and basophils is a key event in allergen-induced allergic inflammation. Recently, several therapeutic strategies have been developed based on this interaction, and some include Fcepsilon-containing moieties. Unlike well characterized IgG therapeutics, the stability and folding properties of IgE are not well understood. Here, we present comparative biophysical analyses of the pH stability and thermostability of Fcepsilon and IgG1-Fc (Fcgamma). Fcepsilon was found to be significantly less stable than Fcgamma under all pH and NaCl conditions tested. Additionally, the Cepsilon3Cepsilon4 domains of Fcepsilon were shown to become intrinsically unfolded at pH values below 5.0. The interaction between Fcepsilon and an Fcgamma-FcepsilonRIalpha fusion protein was studied between pH 4.5 and 7.4 using circular dichroism and a combination of differential scanning calorimetry and isothermal titration calorimetry. Under neutral pH conditions, the apparent affinity of Fcepsilon for the dimeric fusion protein was extremely high compared with published values for the monomeric receptor (KD < 10(-12) m). Titration to pH 6.0 did not significantly change the binding affinity, and titration to pH 5.5 only modestly attenuated affinity. At pH values below 5.0, the receptor binding domains of Fcepsilon unfolded, and interaction of Fcepsilon with the Fcgamma-FcepsilonRIalpha fusion protein was abrogated. The unusual pH sensitivity of Fcepsilon may play a role in antigen-dependent regulation of receptor-bound, non-circulating IgE.

Novel antibody hinge regions for efficient production of CH2 domain-deleted antibodies.

HuCC49 deltaCH2 is a heavy chain constant domain 2 domain-deleted antibody under development as a radioimmunotherapeutic for treating carcinomas overexpressing the TAG-72 tumor antigen. Mammalian cell culture biosynthesis of HuCC49 deltaCH2 produces two isoforms (form A and form B) in an approximate 1:1 ratio, and consequently separation and purification of the desired form A isoform adversely impact process and yield. A protein engineering strategy was used to develop a panel of hinge-engineered HuCC49 deltaCH2 antibodies to identify hinge sequences to optimize production of the form A isoform. We found that adding a single proline residue at Kabat position 243, immediately adjacent to the carboxyl end of the core middle hinge CPPC domain, resulted in an increase from 39 to 51% form A isoform relative to the parent HuCC49 deltaCH2 antibody. Insertion of the amino acids proline-alanine-proline (PAP) at positions 243-245 enhanced production of the form A isoform to 72%. Insertion of a cysteine-rich 15-amino acid IgG3 hinge motif (CPEPKSCDTPPPCPR) in both of these mutant antibodies resulted in secretion of predominantly form A isoform with little or no detectable form B. Yields exceeding 98% of the form A isoform have been realized. Preliminary peptide mapping and mass spectrometry analysis suggest that at least two, and as many as five, inter-heavy chain disulfide linkages may be present.

Laboratory markers in the diagnosis of venous thromboembolism.

Selected blood tests may be useful in the diagnosis of venous thromboembolism (VTE), or in the identification of a congenital or acquired defect associated with the development of VTE. Several studies have shown the D-dimer assay to have a high negative predictive value but poor specificity when used in the detection of VTE. Yet in the emergency room setting, the D-dimer test may be useful if a detailed risk factor analysis for each patient is included in the diagnosis. The presence of such genetic thrombophilia markers as factor V Leiden, prothrombin 20210A mutation, and antiphospholipid antibodies significantly increases a patient's risk of a thrombotic event. The relative risk of thrombosis in factor V heterozygotes is at least 3 times higher than in the general population, whereas the increased risk of thrombosis in homozygotes is estimated to be 50- to 80-fold greater than those without the defect. Thromboembolic events are reported in approximately one third of antiphospholipid-positive patients. Other markers such as hyperhomocysteinemia and deficiencies of antithrombin, protein C, or protein S, when combined with the previous mutations, significantly increase a patient's risk of a thrombotic event. We feel that it is important to identify these ultra-high-risk patients to provide adequate counseling about the risk of thrombosis before elective surgical procedures. Often, lifelong anticoagulation may be needed as these patients and family members may need testing before taking birth control pills or hormonal replacement.

Thrombosis prophylaxis in orthopedic surgery: current clinical considerations.

Thrombosis prophylaxis in orthopedic surgery is an important consideration in order to avoid the morbidity and mortality of venous thromboembolism (VTE). Patients who do not receive prophylaxis, or receive inadequate prophylaxis, may be at risk for clinical or fatal pulmonary emboli, and a fatality, although rare, may be the first sign of a VTE. Although the surgeon may have corrected the patient's orthopedic problem, a symptomatic or asymptomatic venous thrombosis may become a new threat to the patient's quality of life. This problem places such patients at risk for recurrent VTE, as well as post-thrombotic syndrome, a progressive, lifelong disability. Methods of prophylaxis that prevent the most clots result in the fewest venous thromboembolic events, but no one method of prophylaxis is suitable for all patients. In order to select the appropriate modality, a careful risk assessment of each patient is necessary. Those at low or moderate risk levels do not require the same modalities that may be used in a patient with a previous history of thrombosis or with many risk factors. The purpose of this brief review is to examine the complications associated with venous thromboembolism and to discuss, in detail, the risk of thrombosis in orthopedic patients. In addition, thrombosis prophylaxis modalities are discussed and suggestions made based on current Chest Consensus Guidelines and FDA-approved products.