Servicemembers injured in combat often experience moderate to severe acute pain. Early and effective pain control in the prehospital setting has been shown to reduce the sequelae of untreated pain. ...Current data suggest that lack of point-of-injury (POI) analgesia has significant, downstream effects on healthcare quality and associated costs.
This was a process improvement project to determine the current rate of adherence to existing prehospital pain management guidelines. The records of patients who had sustained a major injury and met current Tactical Combat Casualty Care (TCCC) criteria for POI analgesia from July 2013 through March 2014 were reviewed to determine if pain medication was given in accordance with existing guidelines, including medication administration and routes. On 31 October 2013, the new TCCC guidelines were released. The "before" period was from July 2013 through October 2013. The "after" period was from November 2013 through March 2014.
During the project period, there were 185 records available for review, with 135 meeting TCCC criteria for POI analgesia (68 pre-, 66 postintervention). Prior to 31 October 2013, 17% of study patients received analgesia within guidelines at the POI compared with 35% in the after period. The most common medication administered pre-and post-release was oral transmucosal fentanyl citrate. Special Operations Forces had higher adherence rates to TCCC analgesia guidelines than conventional forces, but these still were low.
Less than half of all eligible combat casualties receive any analgesia at the POI. Further research is needed to determine the etiology of such poor adherence to current TCCC guidelines.
Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal antibodies (mAbs). Current ...challenges for engineering bsAbs include retention of the binding affinity of the parent mAb or antibody fragment, the ability to bind both targets simultaneously, and matching valency with biology. Other factors to consider include structural stability and expression of the recombinant molecule, both of which may have significant impact on its development as a therapeutic. Here, we incorporate selection of stable, potent single-chain variable fragments (scFvs) early in the engineering process to assemble bsAbs for therapeutic applications targeting the cytokines IL-17A/A and IL-23. Stable scFvs directed against human cytokines IL-23p19 and IL-17A/A were isolated from a human Fab phage display library via batch conversion of panning output from Fabs to scFvs. This strategy integrated a step for shuffling V regions during the conversion and permitted the rescue of scFv molecules in both the VHVL and the VLVH orientations. Stable scFvs were identified and assembled into several bispecific formats as fusions to the Fc domain of human IgG1. The engineered bsAbs are potent neutralizers of the biological activity of both cytokines (IC50 < 1 nM), demonstrate the ability to bind both target ligands simultaneously and display stability and productivity advantageous for successful manufacture of a therapeutic molecule. Pharmacokinetic analysis of the bsAbs in mice revealed serum half-lives similar to human mAbs. Assembly of bispecific molecules using stable antibody fragments offers an alternative to reformatting mAbs and minimizes subsequent structure-related and manufacturing concerns.
Passive immunization has been successfully employed for protection against bacterial and viral infections for over 100 years. Immunoglobulin Fc regions play a critical role in the clearance of ...bacterial pathogens by mediating antibody-dependent and complement-dependent cytotoxicity. Here we show that antibody fragments engineered to recognize the protective antigen component of the B. anthracis exotoxin with high affinity and conjugated to polyethylene glycol (PEG) for prolonged circulation half-life confer significant protection against inhalation anthrax despite their lack of Fc regions. The speed and lower manufacturing cost of bacterially expressed PEGylated antibody fragments could provide decisive advantages for anthrax prophylaxis. Importantly, our results suggest that PEGylated antibody fragments may represent a unique approach for mounting a rapid therapeutic response to emerging pathogen infections.
Targeting angiogenesis is a promising approach to the treatment of solid tumors and age-related macular degeneration (AMD). Inhibition of vascularization has been validated by the successful ...marketing of monoclonal antibodies (mAbs) that target specific growth factors or their receptors, but there is considerable room for improvement in existing therapies. Combination of mAbs targeting both the VEGF and PDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase inhibitors and the inability to combine efficiently with traditional chemotherapeutics. However, development costs and regulatory issues have limited the use of combinatorial approaches for the generation of more efficacious treatments. The concept of mediating disease pathology by targeting two antigens with one therapeutic was proposed over two decades ago. While mAbs are particularly suitable candidates for a dual-targeting approach, engineering bispecificity into one molecule can be difficult due to issues with expression and stability, which play a significant role in manufacturability. Here, we address these issues upstream in the process of developing a bispecific antibody (bsAb). Single-chain antibody fragments (scFvs) targeting PDGFRβ and VEGF-A were selected for superior stability. The scFvs were fused to both termini of human Fc to generate a bispecific, tetravalent molecule. The resulting molecule displays potent activity, binds both targets simultaneously, and is stable in serum. The assembly of a bsAb using stable monomeric units allowed development of an anti-PDGFRB/VEGF-A antibody capable of attenuating angiogenesis through two distinct pathways and represents an efficient method for rapid engineering of dual-targeting molecules.
Airway compromise is the third most common cause of potentially preventable combat death. Surgical cricothyrotomy is an infrequently performed but lifesaving airway intervention. There are limited ...published data on prehospital cricothyrotomy in civilian or military settings. Our aim was to prospectively describe the survival rate and complications associated with cricothyrotomy performed in the military prehospital and en route setting.
The Life-Saving Intervention (LSI) study is a prospective, institutional review board-approved, multicenter trial examining LSIs performed in the prehospital combat setting. We prospectively recorded LSIs performed on patients in theater who were transported to six combat hospitals. Trained site investigators evaluated patients on arrival and recorded demographics, vital signs, and LSIs performed. LSIs were predefined and include cricothyrotomies, chest tubes, intubations, tourniquets, and other procedures. From the large dataset, we analyzed patients who had a cricothyrotomy performed. Hospital outcomes were cross-referenced from the Department of Defense Trauma Registry. Descriptive statistics or Wilcoxon test (nonparametric) were used for data comparisons; statistical significance was set at p<.05. The primary outcome was success of prehospital and en route cricothyrotomy.
Of the 1,927 patients enrolled, 34 patients had a cricothyrotomy performed (1.8%). Median age was 24 years (interquartile range IQR: 22.5-25 years), 97% were men. Mechanisms of injury were blast (79%), penetrating (18%), and blunt force (3%), and 83% had major head, face, or neck injuries. Median Glasgow Coma Scale score (GCS) was 3 (IQR: 3-7.5) and four patients had GCS higher than 8. Cricothyrotomy was successful in 82% of cases. Reasons for failure included left main stem intubation (n=1), subcutaneous passage (n=1), and unsuccessful attempt (n=4). Five patients had a prehospital basic airway intervention. Unsuccessful endotracheal intubation preceded 15% of cricothyrotomies. Of the 24 patients who had the provider type recorded, six had a cricothyrotomy by a combat medic (pre-evacuation), and 18 by an evacuation helicopter medic. Combat-hospital outcome data were available for 26 patients, 13 (50%) of whom survived to discharge. The cricothyrotomy patients had more LSIs than noncricothyrotomy patients (four versus two LSIs per patient; p<.0011).
In our prospective, multicenter study evaluating cricothyrotomy in combat, procedural success was higher than previously reported. In addition, the majority of cricothyrotomies were performed by the evacuation helicopter medic rather than the prehospital combat medic. Prehospital military medics should receive training in decision making and be provided with adjuncts to facilitate this lifesaving procedure.
As US military combat operations draw down in Afghanistan, the military health system will shift focus to garrison- and hospital-based care. Maintaining combat medical skills while performing routine ...healthcare in military hospitals and clinics is a critical challenge for Combat medics. Current regulations allow for a wide latitude of Combat medic functions. The Surgeon General considers combat casualty care a top priority. Combat medics are expected to provide sophisticated care under the extreme circumstances of a hostile battlefield. Yet, in the relatively safe and highly supervised setting of contiguous US-based military hospitals, medics are rarely allowed to perform the procedures or administer medications they are expected to use in combat. This study sought to determine patients? opinions on the use of combat medics in their healthcare.
Patients in hospital emergency department (EDs) were offered anonymous surveys. Examples of Combat medic skills were provided. Participants expressed agreement using the Likert scale (LS), with scores ranging from "strongly agree" (LS score, 1) to "strongly disagree" (LS score, 5). The study took place in the ED at Bayne-Jones Army Community Hospital, Fort Polk, Louisiana. Surveys were offered to adult patients when they checked into the ED or to adults with other patients.
A total of 280 surveys were completed and available for analysis. Subjects agreed that Combat medic skills are important for deployment (LS score, 1.4). Subjects agreed that Combat medics should be allowed to perform procedures (LS score, 1.6) and administer medications (LS score, 1.6). Subjects would allow Combat medics to perform procedures (LS score, 1.7) and administer medications (LS score, 1.7) to them or their families. Subjects agreed that Combat medic activities should be a core mission for military treatment facilities (MTFs) (LS score, 1.6).
Patients support the use of Combat medics during clinical care. Patients agree that Combat medic use should be a core mission for MTFs. Further research is needed to optimize Combat medic integration into patient healthcare.
background: Optimal airway management protocols for the prehospital battlefield setting have not been defined. Airway management strategies in this environment must take into account the injury ...patterns, the environment and training requirements of military prehospital providers.
This is a post-hoc, sub-group analysis of the Registry of Emergency Airways Arriving at Combat Hospitals or REACH database. This study examines only those patients who had advanced airways placed for trauma by an enlisted military medic at the point of injury. results: Twenty (100%) of the patients had a traumatic injury, 19 (95%) were male, and 13 (65%) had a gun shot wounds (GSWs) as the mechanism of injury. The majority, 12 (60%) patients had an esophageal-tracheal airway device placed. Of the remaining patients, four (20%) underwent endotracheal intubation, three (15%) had a surgical cricothyroidotomy performed, and one (5%) had a Laryngeal Mask Airway (LMA) placed. Seventeen (85%) of the twenty patients were dead on arrival or died shortly after arrival at the Combat Support Hospital (CSH). All of the patients that died had a Glasgow Coma Scale (GCS) of three upon arrival. The Glasgow Coma Scale provides a score in the range 3-15; patients with scores of 3-8 are usually said to be in a coma. Three patients in this group survived to transfer from the CSH. Two of the transfers were lost to follow up, one with a GSW to the head and GCS of three, the other with a GCS of five from injuries sustained in an explosion. The third patient had a surgical cricothyroidotomy (SC) performed in the field for an expanding neck hematoma and recovered fully following surgery. conclusions: Casualties that tolerate invasive airway management without sedation in the context of trauma prognosticates a very high mortality. Airway management algorithms for military providers should reflect the casualties encountered on the battlefield not patients in cardiac arrest which predominate in the civilian EMS airway management practice. Further data are needed to understand the injuries encountered on the battlefield and to develop airway management solutions that optimize outcomes of patients with battlefield trauma.
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